Hindawi Publishing CorporationBioMed Research InternationalVolume 2013 Article ID 193048 5 pageshttpdxdoiorg1011552013193048

Review ArticleRole of Dopaminergic Receptors in GlaucomatousDisease Modulation

Nicola Pescosolido1 Francesco Parisi2 Paola Russo2

Giuseppe Buomprisco2 and Marcella Nebbioso2

1 Department of Cardiovascular Respiratory Nephrologic Anesthesiologic and Geriatric Sciences Sapienza University of RomePiazzale Aldo Moro 5 00161 Rome Italy

2 Department of Sense Organs Centre of Ocular Electrophysiology Sapienza University of Rome Piazzale Aldo Moro 500161 Rome Italy

Correspondence should be addressed to Marcella Nebbioso marcellanebbiosouniroma1it

Received 14 April 2013 Revised 6 June 2013 Accepted 12 June 2013

Academic Editor Paolo Fogagnolo

Copyright copy 2013 Nicola Pescosolido et al This is an open access article distributed under the Creative Commons AttributionLicense which permits unrestricted use distribution and reproduction in any medium provided the original work is properlycited

Both studies on animals and humans suggest the presence of dopamine (DA) receptors in the anterior segment of the eye Theirrole in the dynamics of intraocular pressure (IOP) is not yet clear DA

2and DA

3receptors are mainly located on postganglionic

sympathetic nerve endings Their stimulation reduces the release of norepinephrine and suppresses the production of aqueoushumorDA

1receptors seem to bemore expressed by the ciliary body and the outflowpathway of aqueous humorThe administration

of DA1-selective agonists stimulates the production of aqueous humor increasing IOP whereas DA

2- and DA

3-selective agonists

could reduce IOP and therefore the risk to develop a glaucoma (GL) GL is a broad spectrum of eye diseases which have incommon the damage to the optic nerve and the progressive loss of the visual field Further studies are desirable to clarify the roleof the dopaminergic system and the usefulness of DA

2and DA

3agonists in reducing IOP

1 Introduction

Biological basis of glaucoma (GL) are not yet fully under-stood and the factors involved in its progression are notyet fully identified The most important risk factor is highintraocular pressure (IOP) due to the reduction in theoutflow of aqueous humor through the iridocorneal angle[1 2] Other risk factors are aging (in elderly the prevalence ofthe disease is higher) family history African-Caribbean racehigh myopia (gt4D) thinner cornea lens pseudoexfoliationlow blood pressure (diastolic one in particular) and localand systemic vascular risk factors (optic disc hemorrhage oratrophy vasospasm etc) [1ndash4]

Physiologically IOP is regulated by a proper balancebetween secretion and drainage of aqueous humor This isproduced by ciliary bodyrsquos epithelium into the posteriorchamber from which passively diffuses into the anterior onethrough pupil [3ndash5] Once in the anterior chamber about80 of aqueous humor outflows through the trabecularmeshwork and then in a small vessel called Schlemmrsquos canal

Finally through aqueous veins it comes out from ocularbulb by episcleral veins and reaches the bloodstream Theremaining 20 of aqueous humor flows independently fromIOP through the uveoscleral outflow or along nerves andsmall ocular vessels [4ndash7]

High IOP is one of the most important risk factorsinvolved in GL and is the only one against whom actualtherapies are really effective Epidemiological studies showedthat the risk of GL increases by 12 for each 1mmHg increaseof IOP [1 2 8] To date GL is the second leading cause ofblindness in the world [8] GL can be congenital or acquiredThe further classification in primary open-angle glaucoma(POAG) and primary angle-closure glaucoma (PACG) con-cerns the mechanisms that hinders aqueous humor outflowIn primary GL the increase of IOP is not associated withother ocular disorders while in secondary GL a recognizablefactor ocular or nonocular one alters the outflow of aqueoushumor In western countries POAG is more common thanPACG [1 2 8]

2 BioMed Research International

Postsynaptic membrane

InhibitoryG-protein

AdenylatecyclaseDopamine

DopamineD2 receptor

Figure 1 Structures of dopamine receptors (DA2DA3) and G-

protein coupled to receptors

Molecular events responsible for GL are still for themost part unknown Several molecules are able to regulateIOP adrenergic cholinergic serotonergic and dopaminergicsystems are all involved

Dopamine (DA) is a simple organic chemical in thecatecholamine family released from postganglionic nervefibers of the superior cervical dopaminergic ganglion in theaqueous humor [9ndash12] and exerts its action by binding to 5different types of DA receptors (DA

1minus5) which belong to the

superclass of G-proteins coupled receptorsDA receptors are grouped in two distinct families DA

1-

like receptors (which include DA1and DA

5receptors) and

DA2-like receptors like DA

2 DA3 and DA

4[11ndash14] The

main difference between those families of receptors concernsthe action of G-proteins DA

1-like receptor has a Gs-protein

whose activation results in an increase of cyclic AMP (cAMP)mediated by adenylate cyclase [9 10 12] DA

2-like receptors

are coupled to a Gi-protein which determines insteadthe inhibition of adenylate cyclase and consequentially adecrease of cAMP (Figure 1)

The aim of this review is to investigate specifically thedopaminergic influence on IOP to evaluate the role of newhypotensive drugs

2 Studies on Animals

Early studies of the role of DA in GL on animal modelsled to contrasting results Shannon et al [15] showed thatDA administered topically increases IOP in rabbit eyesand haloperidol (DA inverse agonist) can contrast thataction Green and Elijah [16] noticed by contrast thatIOP decreased during parenteral administration of DAindicating that a different route of administration of DAproduces different effects on IOP In 1984 Potter et al[17] studied the sequel of topical administration of DA

and its methylated analogs N-methyl-dopamine (NMDA)NN-dimethyl dopamine (DMDA) and NN-Di-n-propyldopamine (DPDA) in eyes of healthy rabbits and of sym-pathectomized ones Thus in normal rabbits DA DMDAand NMDA induced an increase of IOP unilaterally whileDPDA induced a bilateral hypotension after unilateral topicaladministration

Furthermore in sympathectomized rabbits they notedthe following results

(1) the administration of NMDA and DMDA producedan exaggerated ocular hypertension followed byhypotension

(2) the hypotensive effects of DPDA registered in normalrabbits eyes were absent in sympathectomized ones

In summary they assessed that DA and its analoguesproduce two different effects

(A) a direct and postjunctional effect mediated by DAagonists that bind to DA

1 120572 and 120573 receptors

(B) an indirect and prejunctional (or ldquoneuronalrdquo) effectmediated by DA agonists that bind 120572

2and DA

2

receptors

Green et al [9 16] studying rabbitrsquos ciliary epitheliumin vitro observed that DA increases passive permeabilityand active secretion of aqueous humor Both effects couldbe inhibited by 120572 and 120573 antagonists phentolamine andsotalol respectively but not by a relatively selective DAantagonist (butaclamol) [18] The secretory function of DAwas subsequently confirmed by studies that identified onnonpigmented epithelium of the ciliary body of animalsand humans the phosphoprotein 31015840ndash51015840 monophosphate(DARPP-32) which regulates adenosine andDA systems [19]

Potter et al however showed that topical administrationof some ergoline (lergotrile pergolide) and an ergopeptide(bromocriptine) both in rabbits and monkeys decreasedIOP by acting on DA

2receptors [17 20 21] The action of

DA2receptors was further confirmed by a subsequent study

by Potter [12] He noted a decrease hypotensive effect ofergoline in eyes of rabbits pretreated with domperidone (aDA2antagonist) and surgical sympathectomy

In summary

(1) the decrease of IOP mediated by ergot derivatives ispartly dependent to sympathetic neuronal activity

(2) probably DA2receptors are expressed in the sym-

pathetic ganglion andor sympathetic postganglionicnerveendings

(3) ocular hypotension is just partially due to the inhi-bition of formation of aqueous humor To furtherconfirm that indirect effects are responsible for lower-ing IOP Savolainen et al [22] reported that selectiveDA21205722agonist like CHF1035 and its metabolite

CHF1024 if instilled in rabbitrsquos eyes have similareffects to brimonidine in lowering IOP but CHF1035has a long lasting action too

BioMed Research International 3

These data suggest the presence of DA receptors inthe anterior segment but in order to better understandand investigate their role it was important to preciselyidentify where the structures were present Many biochem-ical immunohistochemical and functional studies have beenperformed on animal tissue samples to find DA

1receptors

localization but not DA2ones DA

1receptors are present

on ciliary body epithelium of bovine [11 19] and on ciliaryprocesses epithelium of rabbit [9 15 18] confirming that theirstimulation causes from one side an increased production ofaqueous humor and on the other hand an altered outflowof it affecting the tone of ciliary muscle DA

2receptors main

localization seems to be the postganglionic presynaptic nerveending [22]

In addition to the previously mentioned receptors Chuet al showed the involvement of a specific DA receptor theDA3 responsible for IOP hypotonization in an animal model

of rabbit [23] Recently some authors studied the hypotensiveeffect of 7-hydroxy-2-dipropilaminotetralina (7OH-DPAT)themain agonist of DA

3receptor on rabbit eyes [23] showing

that

(1) IOP lowering effect of 7-OH-DPATwas due in part tothe reduction of the production of aqueous humor

(2) the nervous site of action of 7-OH-DPAT has beenidentified immunohistochemically as the DA

3recep-

tor of ciliary body and has been associated with thedecrease of hypotensive effects in rabbits deprived ofsympathetic nerve endings

(3) the inhibition of the hypotensive effect of 7-OH-DPAT by DA

3receptor antagonists (U99194A and

UH232) and the deprivation of postganglionic sym-pathetic endings together with the immunohisto-chemical data showed that the primary site of actionof 7-OH-DPAT is located in the presynaptic postgan-glionic nerve endings of the ciliary body of rabbiteyes

A similar study conducted on mice was performed byBucolo et al [14] The authors observed that topical appli-cation of 7-OH-DPAT 120572 DA

3preferring receptor against

significantly decreased in wild-type (WT) mice both inan ocular normotensive group and an ocular hypertensivesteroid-induced group Instead there were no changes of IOPin DA

3receptor knockout mice Moreover genetic analysis

conducted on ocular tissues of WT mice with PCR showedseveral genes encoding for all DA receptors but the absenceof the receptor gene in DA

3KOmice [14]

3 Studies on Humans

The expression of DA2receptors in the anterior segment of

the eye in humans has been confirmed by functional data butthere are no studies which revealed their localization

Unlike DA2receptors DA

1have also been identified

in human eyes [19] with biochemical and autoradiographictechniques using [3H]-SCH-23390 a selective antagonist ofDA1receptor DA

1receptors were present on uveoscleral

tissue trabecular meshwork and ciliary processes [7] Eleven

eyes enucleated because of trauma but with no involvementof the iridocorneal angle were analyzed Seven eyes weretreated for GL while four of them had a normal IOPAlthough the sample size was very small a higher responsedue to DA

1receptors was noticed in eyes with normal IOP

[7]Mekki et al demonstrated in a double-blind study that

in 8 healthy volunteers without IOP alteration treated withoral bromocriptine (125mg) IOP decreased (compared toplacebo) at 3 and 4 hours after the administration with noeffects on systemic arterial pressure and on pupilrsquos diameter[24 25] These results were later confirmed by a studyinvolving patients suffering from Parkinsonrsquos disease andPOAG In fact a decrease in IOP occurred when levodopawas replaced by bromocriptine per os (25mg) [26] Thisdrug has effects on the production of prolactin and Mekki etal showed that the eye drops containing bromocriptine canreduce IOP compared to placebo [24 25]

In a double-blind randomized and prospective studyIOP was measured in 24 healthy subjects at baseline and 24 and 6 hours after the instillation of topical timolol (025)and bromocriptine (005) Both bromocriptine and timololdecreased IOP significantly from baseline with no differencebetween them at 2 and 4 h but at 6 h bromocriptine wasmore effective than timolol [27]

Al-Sereiti et al showed that the hypotensive effect ofpergolide (25 micrograms orally) was antagonized by apretreatment with oral domperidone (15mg) a DA

2receptor

low-selective peripheral antagonist [28]DA1receptor agonists were topically administered (DA

ibopamine fenoldopam and 3B90) in a study performedon 20 patients with POAG [29] The authors demonstratedthat the increase of IOP after the administration of thosemolecules was not inhibited neither by the administration ofhaloperidol nor by already known hypotensive drugs Just theadministration of a selective DA

1agonist (SCH-23390) was

capable to reduce IOP confirming that those receptors areinvolved in determining IOP

Karnezis et al showed that intravenous administrationof angiotensin II norepinephrine and fenoldopam increasedIOP in human subjects by the stimulation of DA

1receptors

[30] Subsequently it was confirmed that the stimulation byfenoldopam could alter the outflow of the aqueous humorincreasing IOP [31]

Among DA1receptor agonists we can also include the

34-di-isobutyrrylester of N-methyldopamine better knownas ibopamine [32 33] This widely studied molecule has thefollowing pharmacological properties

(1) it increases the production of aqueous humor stim-ulating DA

1receptors both in healthy eyes and in

glaucomatous ones(2) it is a valid provocative test to study the efficiency

of aqueous humor outflow pathways in fact in closerelatives of patients with POAG the instillation ofibopamine 2 causes an increase in IOPwhich wouldnot occur in subjects without familiarity for POAG

Those data explain that high IOP due to the administra-tion of ibopamine is not caused by the increased production

4 BioMed Research International

Autonomic ganglion

Varicosity

Effectororgan

Postganglionicneurotransmitter

Centralnervoussystem

Preganglionicfiber

Postganglionicfiber

Preganglionicneurotransmitter

1205722

receptorsreceptors

DA2 DA

3 and

DA1 120572 and 120573

Figure 2 Prejunctional indirect effects and postjunctional directeffects of dopamine (DA) and its analogues

IOP

Aqueous Aqueoushumor flowhumor flow

receptorreceptors

Bromocriptine DPDA CHF1035 7-OH-DPAT

Dopamine fenoldopam ibopamine NMDA DMDA

DA1DA

2-DA

3

Figure 3 Effects of dopamine (DA) receptors on aqueous humorflow DMDA NN-dimethyldopamine DPDA NN-di-n-propyld-opamine NMDA N-methyldopamine 7-OH-DPAT 7-hydroxy-2-dipropylaminotetralin

of aqueous humor but by an alteration of the outflow path-ways [13 32ndash34] Ibopamine induces a cycloplegic mydriasisnot acting on 120572 receptors Moreover it can be used inhypotensive syndromes like anterior uveitis or damage of theciliary body or after GL filtration surgery [33 34]

Recently Virno et al [35] assessed the effect of ibopaminea D1-dopamine agonist on IOP in offsprings of parents withPOAG as a consequence of outflow structures impairmentD1-dopaminergic stimulation due to ibopamine increasesIOP as a result of increased production of the aqueoushumor in participants with an impaired outflow The studyshowed that after 2 ibopamine administration there wasa significant increase in aqueous humor production both inglaucomatous and normal eyesThe intraocular hypertensiveresponse due to ibopamine in normotensive eyes is a sign ofinitial outflow impairment and therefore a predisposition tointraocular hypertension and possible GL

After this overview we can conclude that the effects ofDA and its analogs on IOP are complex they can have bothdirect effects (postjunctional) and indirect (prejunctional)ones The postjunctional effects of DA agonists can stimulate120572 120573 and DA

1receptors Similarly indirect effects neuronal

may be mediated by 1205722 DA2and DA

3receptors (Figure 2)

In particular DA1agonists seems to increase the production

of aqueous humor with a consequent increase of IOP whileDA2agonists are responsible of a decrease of IOP (Figure 3)

4 Conclusions

Although several classes of drugs are known to reduce IOPjust 5 of them are used in clinical practice It is still necessaryto look for the most powerful (and safer) therapeutic agentin order to reduce the serious consequences of GL Fromthe studies carried out on animals and humans discussedpreviously we can conclude that DA

2 and DA

3agonists

have an important influence on the modulation of IOPwith significant implications for the management of patientsaffected by GL

Further studies are needed to clarify the role of thedopaminergic system and the usefulness of DA

2and DA

3

agonists in lowering IOP

Conflict of Interests

There are no potential conflict of interests or any financial orpersonal relationshipswith other people or organizations thatcould inappropriately influence conduct and findings of thisstudy

References

[1] H A Quigley and A T Broman ldquoThe number of peoplewith glaucoma worldwide in 2010 and 2020rdquo British Journal ofOphthalmology vol 90 no 3 pp 262ndash267 2006

[2] H A Quigley ldquoGlaucomardquo The Lancet vol 377 no 9774 pp1367ndash1377 2011

[3] Y Zhong J Wang and X Luo ldquoIntegrins in trabecularmeshwork and optic nerve head possible association withthe pathogenesis of glaucomardquo Journal of Biomedicine andBiotechnology vol 2013 Article ID 202905 8 pages 2013

[4] N Pescosolido C Cavallotti D Rusciano and M NebbiosoldquoTrabecular meshwork in normal and pathological eyesrdquoUltra-structural Pathology vol 36 no 2 pp 102ndash107 2012

[5] G Scarsella M Nebbioso S Stefanini A Librando and NPescosolido ldquoDegenerative effects in rat eyes after experimentalocular hypertensionrdquo European Journal of Histochemistry vol56 no 4 article e42 pp 265ndash271 2012

[6] R F Brubaker ldquoMeasurement of uveoscleral outflow inhumansrdquo Journal of Glaucoma vol 10 no 5 pp S45ndashS48 2001

[7] C Cavallotti N Pescosolido V Pescosolido and G IannettildquoDetermination of dopamine D1 receptors in the human uveoscleral tissue by light microscope autoradiographyrdquo Interna-tional Ophthalmology vol 23 no 3 pp 171ndash179 2001

[8] S Kingman ldquoGlaucoma is second leading cause of blindnessgloballyrdquo Bulletin of the World Health Organization vol 82 no11 pp 887ndash888 2004

[9] K Green A Hensley and G Lollis ldquoDopamine stimulation ofpassive permeability and secretion in the isolated rabbit ciliaryepitheliumrdquo Experimental Eye Research vol 29 no 4 pp 423ndash427 1979

[10] B Libet ldquoWhich postsynaptic action of dopamine is mediatedby cyclic AMPrdquo Life Sciences vol 24 no 12 pp 1043ndash1057 1979

BioMed Research International 5

[11] M D Lograno E Daniele and S Govoni ldquoBiochemical andfunctional evidence for the presence of dopamine D1 receptorsin the bovine ciliary bodyrdquo Experimental Eye Research vol 51no 5 pp 495ndash501 1990

[12] D E Potter ldquoDo dopamine and dopamine receptors have rolesin modulating function in the anterior segmentThe evidencerdquoProgress in Retinal and Eye Research vol 15 no 1 pp 103ndash1111996

[13] C Prunte I Nuttli R Markstein and C Kohler ldquoEffects ofdopamine D-1 and D-2 receptors on intraocular pressure inconscious rabbitsrdquo Journal of Neural Transmission vol 104 no2-3 pp 111ndash123 1997

[14] C Bucolo G M Leggio A Maltese A Castorina V DrsquoAgataand F Drago ldquoDopamine-3 receptor modulates intraocularpressure implications for glaucomardquo Biochemical Pharmacol-ogy vol 83 no 5 pp 680ndash686 2012

[15] R P Shannon A Mead and M L Sears ldquoThe effect ofdopamine on the intraocular pressure and pupil of the rabbiteyerdquo Investigative Ophthalmology vol 15 no 5 pp 371ndash3801976

[16] K Green and D Elijah ldquoDrug effects on aqueous humor for-mation and pseudofacility in normal rabbit eyesrdquo ExperimentalEye Research vol 33 no 3 pp 239ndash245 1981

[17] D E Potter J A Burke and F W Chang ldquoAlteration in ocularfunction induced by phenylethylamine analogs of dopaminerdquoCurrent Eye Research vol 3 no 6 pp 851ndash859 1984

[18] R Mancino L Cerulli A Ricci and F Amenta ldquoDirectdemonstration of dopamine D1-like receptor sites in the ciliarybody of the rabbit eye by light microscope autoradiographyrdquoNaunyn-Schmiedebergrsquos Archives of Pharmacology vol 346 no6 pp 644ndash648 1992

[19] R A Stone A M Laties H C Hemmings Jr C C Ouimetand P Greengard ldquoDARPP-32 in the ciliary epithelium ofthe eye a neurotransmitter-regulated phosphoprotein of brainlocalizes to secretory cellsrdquo The Journal of Histochemistry andCytochemistry vol 34 no 11 pp 1465ndash1468 1986

[20] D E Potter and J A Burke ldquoEffects of ergoline derivatives onintraocular pressure and iris function in rabbits and monkeysrdquoCurrent Eye Research vol 2 no 5 pp 281ndash288 1983

[21] D E Potter and J A Burke ldquoAn in vivo model for dissociatingalpha 2-and DA2-adrenoceptor activity in an ocular adnexautility of the cat nictitatingmembrane preparationrdquoCurrent EyeResearch vol 3 no 11 pp 1289ndash1298 1984

[22] J Savolainen J Rautio R Razzetti and T Jarvinen ldquoA novelD2-dopaminergic and alpha2-adrenoceptor receptor agonistinduces substantial and prolonged IOP decrease in normoten-sive rabbitsrdquo The Journal of Pharmacy and Pharmacology vol55 no 6 pp 789ndash794 2003

[23] E Chu T-C Chu and D E Potter ldquoMechanisms and sitesof ocular action of 7-hydroxy-2- dipropylaminotetralin adopamine3 receptor agonistrdquo Journal of Pharmacology andExperimental Therapeutics vol 293 no 3 pp 710ndash716 2000

[24] Q A Mekki S M Hassan and P Turner ldquoBromocriptinelowers intraocular pressure without affecting blood pressurerdquoThe Lancet vol 1 no 8336 pp 1250ndash1251 1983

[25] Q A Mekki S J Warrington and P Turner ldquoBromocriptineeyedrops lower intraocular pressure without affecting prolactinlevelsrdquoThe Lancet vol 1 no 8371 pp 287ndash288 1984

[26] A Lustig ldquoDoes bromocriptine enhance the effect of drugs thatreduce intraocular pressurerdquo Deutsche Medizinische Wochen-schrift vol 108 no 43 pp 1656ndash1657 1983

[27] O Elibol C Guler K Arici A Topalkara and S DemircanldquoThe determination of additive effect and intraocular pressurelowering effects of 005 bromocriptine and 025 timololrdquoInternational Ophthalmology vol 20 no 1ndash3 pp 53ndash55 1997

[28] M R Al-Sereiti R F P Quik A Hedges and P TurnerldquoAntagonism by domperidone of the ocular hypotensive effectof pergoliderdquo European Journal of Clinical Pharmacology vol38 no 5 pp 461ndash463 1990

[29] M Virno A Gazzaniga L Taverniti J Pecori Giraldi andF de Gregorio ldquoDopamine dopaminergic drugs and ocularhypertensionrdquo International Ophthalmology vol 16 no 4-5 pp349ndash353 1992

[30] T A Karnezis M B Murphy R R Weber K S Nelson B JTripathi and R C Tripathi ldquoEffects of selective dopamine-1receptor activation on intraocular pressure inmanrdquo Experimen-tal Eye Research vol 47 no 5 pp 689ndash697 1988

[31] J R Piltz R A Stone S Boike et al ldquoFenoldopam a selectivedopamine-1 receptor agonist raises intraocular pressure inmales with normal intraocular pressurerdquo Journal of OcularPharmacology andTherapeutics vol 14 no 3 pp 203ndash216 1998

[32] C Prunte and J Flammer ldquoThe novel dopamine D-1 antagonistand D-2 agonist SDZ GLC-756 lowers intraocular pressurein healthy human volunteers and in patients with glaucomardquoOphthalmology vol 102 no 9 pp 1291ndash1297 1995

[33] L Magacho F E Lima M L Costa F A Fayad N LGuimaraes and M P Avila ldquoIbopamine provocative test andglaucoma consideration of factors that may influence theexaminationrdquo Current Eye Research vol 28 no 3 pp 189ndash1932004

[34] I F Hepsen H Yilmaz and U C Keskin ldquoThe comparisonof topical ibopamine 2 with tonography to identify the out-flow resistance in eyes with ocular hypertensionrdquo OphthalmicResearch vol 37 no 1 pp 17ndash22 2005

[35] MVirno R Sampaolesi J Pecori Giraldi et al ldquoIbopamine D1-dopaminergic agonist in the diagnosis of glaucomardquo Journal ofGlaucoma 2011

BioMed Research International 3

These data suggest the presence of DA receptors inthe anterior segment but in order to better understandand investigate their role it was important to preciselyidentify where the structures were present Many biochem-ical immunohistochemical and functional studies have beenperformed on animal tissue samples to find DA

1receptors

localization but not DA2ones DA

1receptors are present

on ciliary body epithelium of bovine [11 19] and on ciliaryprocesses epithelium of rabbit [9 15 18] confirming that theirstimulation causes from one side an increased production ofaqueous humor and on the other hand an altered outflowof it affecting the tone of ciliary muscle DA

2receptors main

localization seems to be the postganglionic presynaptic nerveending [22]

In addition to the previously mentioned receptors Chuet al showed the involvement of a specific DA receptor theDA3 responsible for IOP hypotonization in an animal model

of rabbit [23] Recently some authors studied the hypotensiveeffect of 7-hydroxy-2-dipropilaminotetralina (7OH-DPAT)themain agonist of DA

3receptor on rabbit eyes [23] showing

that

(1) IOP lowering effect of 7-OH-DPATwas due in part tothe reduction of the production of aqueous humor

(2) the nervous site of action of 7-OH-DPAT has beenidentified immunohistochemically as the DA

3recep-

tor of ciliary body and has been associated with thedecrease of hypotensive effects in rabbits deprived ofsympathetic nerve endings

(3) the inhibition of the hypotensive effect of 7-OH-DPAT by DA

3receptor antagonists (U99194A and

UH232) and the deprivation of postganglionic sym-pathetic endings together with the immunohisto-chemical data showed that the primary site of actionof 7-OH-DPAT is located in the presynaptic postgan-glionic nerve endings of the ciliary body of rabbiteyes

A similar study conducted on mice was performed byBucolo et al [14] The authors observed that topical appli-cation of 7-OH-DPAT 120572 DA

3preferring receptor against

significantly decreased in wild-type (WT) mice both inan ocular normotensive group and an ocular hypertensivesteroid-induced group Instead there were no changes of IOPin DA

3receptor knockout mice Moreover genetic analysis

conducted on ocular tissues of WT mice with PCR showedseveral genes encoding for all DA receptors but the absenceof the receptor gene in DA

3KOmice [14]

3 Studies on Humans

The expression of DA2receptors in the anterior segment of

the eye in humans has been confirmed by functional data butthere are no studies which revealed their localization

Unlike DA2receptors DA

1have also been identified

in human eyes [19] with biochemical and autoradiographictechniques using [3H]-SCH-23390 a selective antagonist ofDA1receptor DA

1receptors were present on uveoscleral

tissue trabecular meshwork and ciliary processes [7] Eleven

eyes enucleated because of trauma but with no involvementof the iridocorneal angle were analyzed Seven eyes weretreated for GL while four of them had a normal IOPAlthough the sample size was very small a higher responsedue to DA

1receptors was noticed in eyes with normal IOP

[7]Mekki et al demonstrated in a double-blind study that

in 8 healthy volunteers without IOP alteration treated withoral bromocriptine (125mg) IOP decreased (compared toplacebo) at 3 and 4 hours after the administration with noeffects on systemic arterial pressure and on pupilrsquos diameter[24 25] These results were later confirmed by a studyinvolving patients suffering from Parkinsonrsquos disease andPOAG In fact a decrease in IOP occurred when levodopawas replaced by bromocriptine per os (25mg) [26] Thisdrug has effects on the production of prolactin and Mekki etal showed that the eye drops containing bromocriptine canreduce IOP compared to placebo [24 25]

In a double-blind randomized and prospective studyIOP was measured in 24 healthy subjects at baseline and 24 and 6 hours after the instillation of topical timolol (025)and bromocriptine (005) Both bromocriptine and timololdecreased IOP significantly from baseline with no differencebetween them at 2 and 4 h but at 6 h bromocriptine wasmore effective than timolol [27]

Al-Sereiti et al showed that the hypotensive effect ofpergolide (25 micrograms orally) was antagonized by apretreatment with oral domperidone (15mg) a DA

2receptor

low-selective peripheral antagonist [28]DA1receptor agonists were topically administered (DA

ibopamine fenoldopam and 3B90) in a study performedon 20 patients with POAG [29] The authors demonstratedthat the increase of IOP after the administration of thosemolecules was not inhibited neither by the administration ofhaloperidol nor by already known hypotensive drugs Just theadministration of a selective DA

1agonist (SCH-23390) was

capable to reduce IOP confirming that those receptors areinvolved in determining IOP

Karnezis et al showed that intravenous administrationof angiotensin II norepinephrine and fenoldopam increasedIOP in human subjects by the stimulation of DA

1receptors

[30] Subsequently it was confirmed that the stimulation byfenoldopam could alter the outflow of the aqueous humorincreasing IOP [31]

Among DA1receptor agonists we can also include the

34-di-isobutyrrylester of N-methyldopamine better knownas ibopamine [32 33] This widely studied molecule has thefollowing pharmacological properties

(1) it increases the production of aqueous humor stim-ulating DA

1receptors both in healthy eyes and in

glaucomatous ones(2) it is a valid provocative test to study the efficiency

of aqueous humor outflow pathways in fact in closerelatives of patients with POAG the instillation ofibopamine 2 causes an increase in IOPwhich wouldnot occur in subjects without familiarity for POAG

Those data explain that high IOP due to the administra-tion of ibopamine is not caused by the increased production

4 BioMed Research International

Autonomic ganglion

Varicosity

Effectororgan

Postganglionicneurotransmitter

Centralnervoussystem

Preganglionicfiber

Postganglionicfiber

Preganglionicneurotransmitter

1205722

receptorsreceptors

DA2 DA

3 and

DA1 120572 and 120573

Figure 2 Prejunctional indirect effects and postjunctional directeffects of dopamine (DA) and its analogues

IOP

Aqueous Aqueoushumor flowhumor flow

receptorreceptors

Bromocriptine DPDA CHF1035 7-OH-DPAT

Dopamine fenoldopam ibopamine NMDA DMDA

DA1DA

2-DA

3

Figure 3 Effects of dopamine (DA) receptors on aqueous humorflow DMDA NN-dimethyldopamine DPDA NN-di-n-propyld-opamine NMDA N-methyldopamine 7-OH-DPAT 7-hydroxy-2-dipropylaminotetralin

of aqueous humor but by an alteration of the outflow path-ways [13 32ndash34] Ibopamine induces a cycloplegic mydriasisnot acting on 120572 receptors Moreover it can be used inhypotensive syndromes like anterior uveitis or damage of theciliary body or after GL filtration surgery [33 34]

Recently Virno et al [35] assessed the effect of ibopaminea D1-dopamine agonist on IOP in offsprings of parents withPOAG as a consequence of outflow structures impairmentD1-dopaminergic stimulation due to ibopamine increasesIOP as a result of increased production of the aqueoushumor in participants with an impaired outflow The studyshowed that after 2 ibopamine administration there wasa significant increase in aqueous humor production both inglaucomatous and normal eyesThe intraocular hypertensiveresponse due to ibopamine in normotensive eyes is a sign ofinitial outflow impairment and therefore a predisposition tointraocular hypertension and possible GL

After this overview we can conclude that the effects ofDA and its analogs on IOP are complex they can have bothdirect effects (postjunctional) and indirect (prejunctional)ones The postjunctional effects of DA agonists can stimulate120572 120573 and DA

1receptors Similarly indirect effects neuronal

may be mediated by 1205722 DA2and DA

3receptors (Figure 2)

In particular DA1agonists seems to increase the production

of aqueous humor with a consequent increase of IOP whileDA2agonists are responsible of a decrease of IOP (Figure 3)

4 Conclusions

Although several classes of drugs are known to reduce IOPjust 5 of them are used in clinical practice It is still necessaryto look for the most powerful (and safer) therapeutic agentin order to reduce the serious consequences of GL Fromthe studies carried out on animals and humans discussedpreviously we can conclude that DA

2 and DA

3agonists

have an important influence on the modulation of IOPwith significant implications for the management of patientsaffected by GL

Further studies are needed to clarify the role of thedopaminergic system and the usefulness of DA

2and DA

3

agonists in lowering IOP

Conflict of Interests

There are no potential conflict of interests or any financial orpersonal relationshipswith other people or organizations thatcould inappropriately influence conduct and findings of thisstudy

References

[1] H A Quigley and A T Broman ldquoThe number of peoplewith glaucoma worldwide in 2010 and 2020rdquo British Journal ofOphthalmology vol 90 no 3 pp 262ndash267 2006

[2] H A Quigley ldquoGlaucomardquo The Lancet vol 377 no 9774 pp1367ndash1377 2011

[3] Y Zhong J Wang and X Luo ldquoIntegrins in trabecularmeshwork and optic nerve head possible association withthe pathogenesis of glaucomardquo Journal of Biomedicine andBiotechnology vol 2013 Article ID 202905 8 pages 2013

[4] N Pescosolido C Cavallotti D Rusciano and M NebbiosoldquoTrabecular meshwork in normal and pathological eyesrdquoUltra-structural Pathology vol 36 no 2 pp 102ndash107 2012

[5] G Scarsella M Nebbioso S Stefanini A Librando and NPescosolido ldquoDegenerative effects in rat eyes after experimentalocular hypertensionrdquo European Journal of Histochemistry vol56 no 4 article e42 pp 265ndash271 2012

[6] R F Brubaker ldquoMeasurement of uveoscleral outflow inhumansrdquo Journal of Glaucoma vol 10 no 5 pp S45ndashS48 2001

[7] C Cavallotti N Pescosolido V Pescosolido and G IannettildquoDetermination of dopamine D1 receptors in the human uveoscleral tissue by light microscope autoradiographyrdquo Interna-tional Ophthalmology vol 23 no 3 pp 171ndash179 2001

[8] S Kingman ldquoGlaucoma is second leading cause of blindnessgloballyrdquo Bulletin of the World Health Organization vol 82 no11 pp 887ndash888 2004

[9] K Green A Hensley and G Lollis ldquoDopamine stimulation ofpassive permeability and secretion in the isolated rabbit ciliaryepitheliumrdquo Experimental Eye Research vol 29 no 4 pp 423ndash427 1979

[10] B Libet ldquoWhich postsynaptic action of dopamine is mediatedby cyclic AMPrdquo Life Sciences vol 24 no 12 pp 1043ndash1057 1979

BioMed Research International 5

[11] M D Lograno E Daniele and S Govoni ldquoBiochemical andfunctional evidence for the presence of dopamine D1 receptorsin the bovine ciliary bodyrdquo Experimental Eye Research vol 51no 5 pp 495ndash501 1990

[12] D E Potter ldquoDo dopamine and dopamine receptors have rolesin modulating function in the anterior segmentThe evidencerdquoProgress in Retinal and Eye Research vol 15 no 1 pp 103ndash1111996

[13] C Prunte I Nuttli R Markstein and C Kohler ldquoEffects ofdopamine D-1 and D-2 receptors on intraocular pressure inconscious rabbitsrdquo Journal of Neural Transmission vol 104 no2-3 pp 111ndash123 1997

[14] C Bucolo G M Leggio A Maltese A Castorina V DrsquoAgataand F Drago ldquoDopamine-3 receptor modulates intraocularpressure implications for glaucomardquo Biochemical Pharmacol-ogy vol 83 no 5 pp 680ndash686 2012

[15] R P Shannon A Mead and M L Sears ldquoThe effect ofdopamine on the intraocular pressure and pupil of the rabbiteyerdquo Investigative Ophthalmology vol 15 no 5 pp 371ndash3801976

[16] K Green and D Elijah ldquoDrug effects on aqueous humor for-mation and pseudofacility in normal rabbit eyesrdquo ExperimentalEye Research vol 33 no 3 pp 239ndash245 1981

[17] D E Potter J A Burke and F W Chang ldquoAlteration in ocularfunction induced by phenylethylamine analogs of dopaminerdquoCurrent Eye Research vol 3 no 6 pp 851ndash859 1984

[18] R Mancino L Cerulli A Ricci and F Amenta ldquoDirectdemonstration of dopamine D1-like receptor sites in the ciliarybody of the rabbit eye by light microscope autoradiographyrdquoNaunyn-Schmiedebergrsquos Archives of Pharmacology vol 346 no6 pp 644ndash648 1992

[19] R A Stone A M Laties H C Hemmings Jr C C Ouimetand P Greengard ldquoDARPP-32 in the ciliary epithelium ofthe eye a neurotransmitter-regulated phosphoprotein of brainlocalizes to secretory cellsrdquo The Journal of Histochemistry andCytochemistry vol 34 no 11 pp 1465ndash1468 1986

[20] D E Potter and J A Burke ldquoEffects of ergoline derivatives onintraocular pressure and iris function in rabbits and monkeysrdquoCurrent Eye Research vol 2 no 5 pp 281ndash288 1983

[21] D E Potter and J A Burke ldquoAn in vivo model for dissociatingalpha 2-and DA2-adrenoceptor activity in an ocular adnexautility of the cat nictitatingmembrane preparationrdquoCurrent EyeResearch vol 3 no 11 pp 1289ndash1298 1984

[22] J Savolainen J Rautio R Razzetti and T Jarvinen ldquoA novelD2-dopaminergic and alpha2-adrenoceptor receptor agonistinduces substantial and prolonged IOP decrease in normoten-sive rabbitsrdquo The Journal of Pharmacy and Pharmacology vol55 no 6 pp 789ndash794 2003

[23] E Chu T-C Chu and D E Potter ldquoMechanisms and sitesof ocular action of 7-hydroxy-2- dipropylaminotetralin adopamine3 receptor agonistrdquo Journal of Pharmacology andExperimental Therapeutics vol 293 no 3 pp 710ndash716 2000

[24] Q A Mekki S M Hassan and P Turner ldquoBromocriptinelowers intraocular pressure without affecting blood pressurerdquoThe Lancet vol 1 no 8336 pp 1250ndash1251 1983

[25] Q A Mekki S J Warrington and P Turner ldquoBromocriptineeyedrops lower intraocular pressure without affecting prolactinlevelsrdquoThe Lancet vol 1 no 8371 pp 287ndash288 1984

[26] A Lustig ldquoDoes bromocriptine enhance the effect of drugs thatreduce intraocular pressurerdquo Deutsche Medizinische Wochen-schrift vol 108 no 43 pp 1656ndash1657 1983

[27] O Elibol C Guler K Arici A Topalkara and S DemircanldquoThe determination of additive effect and intraocular pressurelowering effects of 005 bromocriptine and 025 timololrdquoInternational Ophthalmology vol 20 no 1ndash3 pp 53ndash55 1997

[28] M R Al-Sereiti R F P Quik A Hedges and P TurnerldquoAntagonism by domperidone of the ocular hypotensive effectof pergoliderdquo European Journal of Clinical Pharmacology vol38 no 5 pp 461ndash463 1990

[29] M Virno A Gazzaniga L Taverniti J Pecori Giraldi andF de Gregorio ldquoDopamine dopaminergic drugs and ocularhypertensionrdquo International Ophthalmology vol 16 no 4-5 pp349ndash353 1992

[30] T A Karnezis M B Murphy R R Weber K S Nelson B JTripathi and R C Tripathi ldquoEffects of selective dopamine-1receptor activation on intraocular pressure inmanrdquo Experimen-tal Eye Research vol 47 no 5 pp 689ndash697 1988

[31] J R Piltz R A Stone S Boike et al ldquoFenoldopam a selectivedopamine-1 receptor agonist raises intraocular pressure inmales with normal intraocular pressurerdquo Journal of OcularPharmacology andTherapeutics vol 14 no 3 pp 203ndash216 1998

[32] C Prunte and J Flammer ldquoThe novel dopamine D-1 antagonistand D-2 agonist SDZ GLC-756 lowers intraocular pressurein healthy human volunteers and in patients with glaucomardquoOphthalmology vol 102 no 9 pp 1291ndash1297 1995

[33] L Magacho F E Lima M L Costa F A Fayad N LGuimaraes and M P Avila ldquoIbopamine provocative test andglaucoma consideration of factors that may influence theexaminationrdquo Current Eye Research vol 28 no 3 pp 189ndash1932004

[34] I F Hepsen H Yilmaz and U C Keskin ldquoThe comparisonof topical ibopamine 2 with tonography to identify the out-flow resistance in eyes with ocular hypertensionrdquo OphthalmicResearch vol 37 no 1 pp 17ndash22 2005

[35] MVirno R Sampaolesi J Pecori Giraldi et al ldquoIbopamine D1-dopaminergic agonist in the diagnosis of glaucomardquo Journal ofGlaucoma 2011

4 BioMed Research International

Autonomic ganglion

Varicosity

Effectororgan

Postganglionicneurotransmitter

Centralnervoussystem

Preganglionicfiber

Postganglionicfiber

Preganglionicneurotransmitter

1205722

receptorsreceptors

DA2 DA

3 and

DA1 120572 and 120573

Figure 2 Prejunctional indirect effects and postjunctional directeffects of dopamine (DA) and its analogues

IOP

Aqueous Aqueoushumor flowhumor flow

receptorreceptors

Bromocriptine DPDA CHF1035 7-OH-DPAT

Dopamine fenoldopam ibopamine NMDA DMDA

DA1DA

2-DA

3

Figure 3 Effects of dopamine (DA) receptors on aqueous humorflow DMDA NN-dimethyldopamine DPDA NN-di-n-propyld-opamine NMDA N-methyldopamine 7-OH-DPAT 7-hydroxy-2-dipropylaminotetralin

of aqueous humor but by an alteration of the outflow path-ways [13 32ndash34] Ibopamine induces a cycloplegic mydriasisnot acting on 120572 receptors Moreover it can be used inhypotensive syndromes like anterior uveitis or damage of theciliary body or after GL filtration surgery [33 34]

Recently Virno et al [35] assessed the effect of ibopaminea D1-dopamine agonist on IOP in offsprings of parents withPOAG as a consequence of outflow structures impairmentD1-dopaminergic stimulation due to ibopamine increasesIOP as a result of increased production of the aqueoushumor in participants with an impaired outflow The studyshowed that after 2 ibopamine administration there wasa significant increase in aqueous humor production both inglaucomatous and normal eyesThe intraocular hypertensiveresponse due to ibopamine in normotensive eyes is a sign ofinitial outflow impairment and therefore a predisposition tointraocular hypertension and possible GL

After this overview we can conclude that the effects ofDA and its analogs on IOP are complex they can have bothdirect effects (postjunctional) and indirect (prejunctional)ones The postjunctional effects of DA agonists can stimulate120572 120573 and DA

1receptors Similarly indirect effects neuronal

may be mediated by 1205722 DA2and DA

3receptors (Figure 2)

In particular DA1agonists seems to increase the production

of aqueous humor with a consequent increase of IOP whileDA2agonists are responsible of a decrease of IOP (Figure 3)

4 Conclusions

Although several classes of drugs are known to reduce IOPjust 5 of them are used in clinical practice It is still necessaryto look for the most powerful (and safer) therapeutic agentin order to reduce the serious consequences of GL Fromthe studies carried out on animals and humans discussedpreviously we can conclude that DA

2 and DA

3agonists

have an important influence on the modulation of IOPwith significant implications for the management of patientsaffected by GL

Further studies are needed to clarify the role of thedopaminergic system and the usefulness of DA

2and DA

3

agonists in lowering IOP

Conflict of Interests

There are no potential conflict of interests or any financial orpersonal relationshipswith other people or organizations thatcould inappropriately influence conduct and findings of thisstudy

References

[1] H A Quigley and A T Broman ldquoThe number of peoplewith glaucoma worldwide in 2010 and 2020rdquo British Journal ofOphthalmology vol 90 no 3 pp 262ndash267 2006

[2] H A Quigley ldquoGlaucomardquo The Lancet vol 377 no 9774 pp1367ndash1377 2011

[3] Y Zhong J Wang and X Luo ldquoIntegrins in trabecularmeshwork and optic nerve head possible association withthe pathogenesis of glaucomardquo Journal of Biomedicine andBiotechnology vol 2013 Article ID 202905 8 pages 2013

[4] N Pescosolido C Cavallotti D Rusciano and M NebbiosoldquoTrabecular meshwork in normal and pathological eyesrdquoUltra-structural Pathology vol 36 no 2 pp 102ndash107 2012

[5] G Scarsella M Nebbioso S Stefanini A Librando and NPescosolido ldquoDegenerative effects in rat eyes after experimentalocular hypertensionrdquo European Journal of Histochemistry vol56 no 4 article e42 pp 265ndash271 2012

[6] R F Brubaker ldquoMeasurement of uveoscleral outflow inhumansrdquo Journal of Glaucoma vol 10 no 5 pp S45ndashS48 2001

[7] C Cavallotti N Pescosolido V Pescosolido and G IannettildquoDetermination of dopamine D1 receptors in the human uveoscleral tissue by light microscope autoradiographyrdquo Interna-tional Ophthalmology vol 23 no 3 pp 171ndash179 2001

[8] S Kingman ldquoGlaucoma is second leading cause of blindnessgloballyrdquo Bulletin of the World Health Organization vol 82 no11 pp 887ndash888 2004

[9] K Green A Hensley and G Lollis ldquoDopamine stimulation ofpassive permeability and secretion in the isolated rabbit ciliaryepitheliumrdquo Experimental Eye Research vol 29 no 4 pp 423ndash427 1979

[10] B Libet ldquoWhich postsynaptic action of dopamine is mediatedby cyclic AMPrdquo Life Sciences vol 24 no 12 pp 1043ndash1057 1979

BioMed Research International 5

[11] M D Lograno E Daniele and S Govoni ldquoBiochemical andfunctional evidence for the presence of dopamine D1 receptorsin the bovine ciliary bodyrdquo Experimental Eye Research vol 51no 5 pp 495ndash501 1990

[12] D E Potter ldquoDo dopamine and dopamine receptors have rolesin modulating function in the anterior segmentThe evidencerdquoProgress in Retinal and Eye Research vol 15 no 1 pp 103ndash1111996

[13] C Prunte I Nuttli R Markstein and C Kohler ldquoEffects ofdopamine D-1 and D-2 receptors on intraocular pressure inconscious rabbitsrdquo Journal of Neural Transmission vol 104 no2-3 pp 111ndash123 1997

[14] C Bucolo G M Leggio A Maltese A Castorina V DrsquoAgataand F Drago ldquoDopamine-3 receptor modulates intraocularpressure implications for glaucomardquo Biochemical Pharmacol-ogy vol 83 no 5 pp 680ndash686 2012

[15] R P Shannon A Mead and M L Sears ldquoThe effect ofdopamine on the intraocular pressure and pupil of the rabbiteyerdquo Investigative Ophthalmology vol 15 no 5 pp 371ndash3801976

[16] K Green and D Elijah ldquoDrug effects on aqueous humor for-mation and pseudofacility in normal rabbit eyesrdquo ExperimentalEye Research vol 33 no 3 pp 239ndash245 1981

[17] D E Potter J A Burke and F W Chang ldquoAlteration in ocularfunction induced by phenylethylamine analogs of dopaminerdquoCurrent Eye Research vol 3 no 6 pp 851ndash859 1984

[18] R Mancino L Cerulli A Ricci and F Amenta ldquoDirectdemonstration of dopamine D1-like receptor sites in the ciliarybody of the rabbit eye by light microscope autoradiographyrdquoNaunyn-Schmiedebergrsquos Archives of Pharmacology vol 346 no6 pp 644ndash648 1992

[19] R A Stone A M Laties H C Hemmings Jr C C Ouimetand P Greengard ldquoDARPP-32 in the ciliary epithelium ofthe eye a neurotransmitter-regulated phosphoprotein of brainlocalizes to secretory cellsrdquo The Journal of Histochemistry andCytochemistry vol 34 no 11 pp 1465ndash1468 1986

[20] D E Potter and J A Burke ldquoEffects of ergoline derivatives onintraocular pressure and iris function in rabbits and monkeysrdquoCurrent Eye Research vol 2 no 5 pp 281ndash288 1983

[21] D E Potter and J A Burke ldquoAn in vivo model for dissociatingalpha 2-and DA2-adrenoceptor activity in an ocular adnexautility of the cat nictitatingmembrane preparationrdquoCurrent EyeResearch vol 3 no 11 pp 1289ndash1298 1984

[22] J Savolainen J Rautio R Razzetti and T Jarvinen ldquoA novelD2-dopaminergic and alpha2-adrenoceptor receptor agonistinduces substantial and prolonged IOP decrease in normoten-sive rabbitsrdquo The Journal of Pharmacy and Pharmacology vol55 no 6 pp 789ndash794 2003

[23] E Chu T-C Chu and D E Potter ldquoMechanisms and sitesof ocular action of 7-hydroxy-2- dipropylaminotetralin adopamine3 receptor agonistrdquo Journal of Pharmacology andExperimental Therapeutics vol 293 no 3 pp 710ndash716 2000

[24] Q A Mekki S M Hassan and P Turner ldquoBromocriptinelowers intraocular pressure without affecting blood pressurerdquoThe Lancet vol 1 no 8336 pp 1250ndash1251 1983

[25] Q A Mekki S J Warrington and P Turner ldquoBromocriptineeyedrops lower intraocular pressure without affecting prolactinlevelsrdquoThe Lancet vol 1 no 8371 pp 287ndash288 1984

[26] A Lustig ldquoDoes bromocriptine enhance the effect of drugs thatreduce intraocular pressurerdquo Deutsche Medizinische Wochen-schrift vol 108 no 43 pp 1656ndash1657 1983

[27] O Elibol C Guler K Arici A Topalkara and S DemircanldquoThe determination of additive effect and intraocular pressurelowering effects of 005 bromocriptine and 025 timololrdquoInternational Ophthalmology vol 20 no 1ndash3 pp 53ndash55 1997

[28] M R Al-Sereiti R F P Quik A Hedges and P TurnerldquoAntagonism by domperidone of the ocular hypotensive effectof pergoliderdquo European Journal of Clinical Pharmacology vol38 no 5 pp 461ndash463 1990

[29] M Virno A Gazzaniga L Taverniti J Pecori Giraldi andF de Gregorio ldquoDopamine dopaminergic drugs and ocularhypertensionrdquo International Ophthalmology vol 16 no 4-5 pp349ndash353 1992

[30] T A Karnezis M B Murphy R R Weber K S Nelson B JTripathi and R C Tripathi ldquoEffects of selective dopamine-1receptor activation on intraocular pressure inmanrdquo Experimen-tal Eye Research vol 47 no 5 pp 689ndash697 1988

[31] J R Piltz R A Stone S Boike et al ldquoFenoldopam a selectivedopamine-1 receptor agonist raises intraocular pressure inmales with normal intraocular pressurerdquo Journal of OcularPharmacology andTherapeutics vol 14 no 3 pp 203ndash216 1998

[32] C Prunte and J Flammer ldquoThe novel dopamine D-1 antagonistand D-2 agonist SDZ GLC-756 lowers intraocular pressurein healthy human volunteers and in patients with glaucomardquoOphthalmology vol 102 no 9 pp 1291ndash1297 1995

[33] L Magacho F E Lima M L Costa F A Fayad N LGuimaraes and M P Avila ldquoIbopamine provocative test andglaucoma consideration of factors that may influence theexaminationrdquo Current Eye Research vol 28 no 3 pp 189ndash1932004

[34] I F Hepsen H Yilmaz and U C Keskin ldquoThe comparisonof topical ibopamine 2 with tonography to identify the out-flow resistance in eyes with ocular hypertensionrdquo OphthalmicResearch vol 37 no 1 pp 17ndash22 2005

[35] MVirno R Sampaolesi J Pecori Giraldi et al ldquoIbopamine D1-dopaminergic agonist in the diagnosis of glaucomardquo Journal ofGlaucoma 2011

BioMed Research International 5

[11] M D Lograno E Daniele and S Govoni ldquoBiochemical andfunctional evidence for the presence of dopamine D1 receptorsin the bovine ciliary bodyrdquo Experimental Eye Research vol 51no 5 pp 495ndash501 1990

[12] D E Potter ldquoDo dopamine and dopamine receptors have rolesin modulating function in the anterior segmentThe evidencerdquoProgress in Retinal and Eye Research vol 15 no 1 pp 103ndash1111996

[13] C Prunte I Nuttli R Markstein and C Kohler ldquoEffects ofdopamine D-1 and D-2 receptors on intraocular pressure inconscious rabbitsrdquo Journal of Neural Transmission vol 104 no2-3 pp 111ndash123 1997

[14] C Bucolo G M Leggio A Maltese A Castorina V DrsquoAgataand F Drago ldquoDopamine-3 receptor modulates intraocularpressure implications for glaucomardquo Biochemical Pharmacol-ogy vol 83 no 5 pp 680ndash686 2012

[15] R P Shannon A Mead and M L Sears ldquoThe effect ofdopamine on the intraocular pressure and pupil of the rabbiteyerdquo Investigative Ophthalmology vol 15 no 5 pp 371ndash3801976

[16] K Green and D Elijah ldquoDrug effects on aqueous humor for-mation and pseudofacility in normal rabbit eyesrdquo ExperimentalEye Research vol 33 no 3 pp 239ndash245 1981

[17] D E Potter J A Burke and F W Chang ldquoAlteration in ocularfunction induced by phenylethylamine analogs of dopaminerdquoCurrent Eye Research vol 3 no 6 pp 851ndash859 1984

[18] R Mancino L Cerulli A Ricci and F Amenta ldquoDirectdemonstration of dopamine D1-like receptor sites in the ciliarybody of the rabbit eye by light microscope autoradiographyrdquoNaunyn-Schmiedebergrsquos Archives of Pharmacology vol 346 no6 pp 644ndash648 1992

[19] R A Stone A M Laties H C Hemmings Jr C C Ouimetand P Greengard ldquoDARPP-32 in the ciliary epithelium ofthe eye a neurotransmitter-regulated phosphoprotein of brainlocalizes to secretory cellsrdquo The Journal of Histochemistry andCytochemistry vol 34 no 11 pp 1465ndash1468 1986

[20] D E Potter and J A Burke ldquoEffects of ergoline derivatives onintraocular pressure and iris function in rabbits and monkeysrdquoCurrent Eye Research vol 2 no 5 pp 281ndash288 1983

[21] D E Potter and J A Burke ldquoAn in vivo model for dissociatingalpha 2-and DA2-adrenoceptor activity in an ocular adnexautility of the cat nictitatingmembrane preparationrdquoCurrent EyeResearch vol 3 no 11 pp 1289ndash1298 1984

[22] J Savolainen J Rautio R Razzetti and T Jarvinen ldquoA novelD2-dopaminergic and alpha2-adrenoceptor receptor agonistinduces substantial and prolonged IOP decrease in normoten-sive rabbitsrdquo The Journal of Pharmacy and Pharmacology vol55 no 6 pp 789ndash794 2003

[23] E Chu T-C Chu and D E Potter ldquoMechanisms and sitesof ocular action of 7-hydroxy-2- dipropylaminotetralin adopamine3 receptor agonistrdquo Journal of Pharmacology andExperimental Therapeutics vol 293 no 3 pp 710ndash716 2000

[24] Q A Mekki S M Hassan and P Turner ldquoBromocriptinelowers intraocular pressure without affecting blood pressurerdquoThe Lancet vol 1 no 8336 pp 1250ndash1251 1983

[25] Q A Mekki S J Warrington and P Turner ldquoBromocriptineeyedrops lower intraocular pressure without affecting prolactinlevelsrdquoThe Lancet vol 1 no 8371 pp 287ndash288 1984

[26] A Lustig ldquoDoes bromocriptine enhance the effect of drugs thatreduce intraocular pressurerdquo Deutsche Medizinische Wochen-schrift vol 108 no 43 pp 1656ndash1657 1983

[27] O Elibol C Guler K Arici A Topalkara and S DemircanldquoThe determination of additive effect and intraocular pressurelowering effects of 005 bromocriptine and 025 timololrdquoInternational Ophthalmology vol 20 no 1ndash3 pp 53ndash55 1997

[28] M R Al-Sereiti R F P Quik A Hedges and P TurnerldquoAntagonism by domperidone of the ocular hypotensive effectof pergoliderdquo European Journal of Clinical Pharmacology vol38 no 5 pp 461ndash463 1990

[29] M Virno A Gazzaniga L Taverniti J Pecori Giraldi andF de Gregorio ldquoDopamine dopaminergic drugs and ocularhypertensionrdquo International Ophthalmology vol 16 no 4-5 pp349ndash353 1992

[30] T A Karnezis M B Murphy R R Weber K S Nelson B JTripathi and R C Tripathi ldquoEffects of selective dopamine-1receptor activation on intraocular pressure inmanrdquo Experimen-tal Eye Research vol 47 no 5 pp 689ndash697 1988

[31] J R Piltz R A Stone S Boike et al ldquoFenoldopam a selectivedopamine-1 receptor agonist raises intraocular pressure inmales with normal intraocular pressurerdquo Journal of OcularPharmacology andTherapeutics vol 14 no 3 pp 203ndash216 1998

[32] C Prunte and J Flammer ldquoThe novel dopamine D-1 antagonistand D-2 agonist SDZ GLC-756 lowers intraocular pressurein healthy human volunteers and in patients with glaucomardquoOphthalmology vol 102 no 9 pp 1291ndash1297 1995

[33] L Magacho F E Lima M L Costa F A Fayad N LGuimaraes and M P Avila ldquoIbopamine provocative test andglaucoma consideration of factors that may influence theexaminationrdquo Current Eye Research vol 28 no 3 pp 189ndash1932004

[34] I F Hepsen H Yilmaz and U C Keskin ldquoThe comparisonof topical ibopamine 2 with tonography to identify the out-flow resistance in eyes with ocular hypertensionrdquo OphthalmicResearch vol 37 no 1 pp 17ndash22 2005

[35] MVirno R Sampaolesi J Pecori Giraldi et al ldquoIbopamine D1-dopaminergic agonist in the diagnosis of glaucomardquo Journal ofGlaucoma 2011