brain peptides and blood pressure control

TIPS - Noven#ber 1081 :,.,~t~

relevant in this regard. Although the latter areas might be very. relcwmt in st,me aspects of psychic dependence, e.g. in affcctive or emotional ones. there is indirect evidence that the striatum plays a considerable role in programming and guiding self-administration behaviour.

Rolls and his co-workers = fimnd that certain neurones in the striatum responded to very specific environmental cues connected with a situation of reinfiwcement. e.g. ft~d presented in a special situation. An increase in DA transmission in the striatum might affect the response to these kind of cues: Broekkamp and his co- workers ~ suggest that "in the neostriatum. instructed by dopaminergic reinforcement. the relevant cues are .~lected to produce motivational or motor activity at the v e o moment at which the.~ cues are pre.~nt in the environment'. Recent findings of several laboratories suggest that an increase in striatal DA turnover can be induced not only by opioids, but also by environmental stimuli, connected with the administration of them ~. Furthermore. active self-

administration ol :in opioid induee~ a more pronounced increa.~ in stnatal DA turnover than passive administration of the same do.~s ~ith the .~me time-schedule'°. These observations seem to be interesting in relation to the mell-knomn fact that certain environmental stimuli easily induce a relapse into drug-taking behavit,ur in patients being dctoxified from the drug. and that active sclf-adminislration of a drug might he more rewarding than being treated with it by a schedule not designed by the recipient.

Reading fist I l la~ ,emann. U.. VVinkler. M . r id Kus~hmsk~. K

( I t~/4llJ Xaunyn-.Schmwdeherg~ A r th Pharnlukol

3171. I ] 9 - 1 4 4

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Arch. PharmaA,d. 28 I. i 6 7 - ! 73 S c h ~ a r t L 1 - ( ' . . Pollard. I / . t _h ,nns . ( . Mal ln ,x . B.. ( i r ,~, . ( " . Pradcllc~. P ,rod l)rlo.. F ( i q'r'Y,) m .4dvante~ it! Bto(-hemt(al P~.;:, h¢,pharnlut ,,l,~g x ({.osta. I-.. and Trahucchi . M.. ed~,). Voi I s . pp. 2 4 5 - 2 6 4 . Raven Press. N c ~ ~t ork

-~ Per l . A. . D e W a l d . L A. and ( ia l lagcr . D. ~ .

(1979) in Catecholamme~: Bas:c at~d ( T m u a l

Fronuers ( U ~ i n . E.. Kopin . i. J . . r o d Barcha~. J..

thc~-kkamp. ( 1 i . ~.an I~t,nlzcn. P ..X X! and ~,arl bh~,,,um. J X! I 1'477t m P l i , it.t,t, ,I,,t,l ,,¢th,

~trtatunl i ( t~q;l'...I~ R . ! , ,hm.m ~. I t XI and ~.an d~.'n Flcrekcn. I | ! ! . ¢d-ll pp ¢~!-"2.

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b Ko ln t . l ~kx . ( and l - ~ p ~ : l , ~ R t 1197 ell led l ' t :x. ~ 'd .4nl %n i ff~ it:,,/ ;~. 247~- 2 4 " ,

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i'~ t t hi, I),'lo,.ttden~ ,. 1( , , I d l y re I and i i, , t imer-- Ice. I- . ed,.I. [I[1 hN.-~l. %prmt:c[-~ erl , , , . II¢lhl~.

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Brain peptides and blood pressure control Thomas Unger, Detlev Ganten, Rudolf E. Lang and Wolfgang Rascher Depar tmem o f Pharmacology Universi~' o f Heidelberg. and ( ;erman In.sti, ae 6,r High Bh,~d l'r,.~.~ure Rcse,~n-h.

i m Neuenheimer Feld 366, D-6(tO0 Heidelberg. F. R. G.

'Dump a peptide or fragment of it into the brain and look for anything: you stand a good chance of finding something. So why not look into brain peptide effects on central blood pressure control.'

Apart from this euphemistic approach, there is, indeed, reason to believe that some brain peptides arc involved in central mechanisms of blood pressure reg- ulation ~, t,. In. ( I ) They occur in cardiovascular control centers ~.'. (2) Specific receptors of high affinity have been discovered in the brain". (3) When injected into the brain, they have effects on blood pressure, which can be prevented by competitive antagonists n.ta. (4) Peptide levels and metabolism are altered in hypertensive statesL (5) There is a supersensitivity to brain peptides in experimental models of hypertensionn.tL (6) Neuropeptides interact with other blood pressure controlling neurotransmitters*, and (7) central inhibition of brain peptide synthesis or

receptor interaction has marked cardiovascular effects', n.

In this article, we shall briefly discuss angiotensin, antidiuretic hormone (ADH). opioid peptides, kinins, and substance P as examples relevant to a possible role of brain peptides in blood pressure conrad.

Angiotensin

For many years, the rcnin-angiotensin system (RAS) has beea known to be a peptide system contributing to blood prexsure control and volume homeostasis through the action of the octapeptide angiotensin I! (ANG I!) which circulates in the bhs~d and promotes vasoconstriction and aldosteronc release from the adrenal gland.

20 years ago, it was demonstrated that circulating ANG 11 can raise blood pressure also by a direct action on the brain z Is. Ten years later, evidence was presented that renin exists in the brain". This and the subsequent discovew of other components

of the RAS in the brain s~ t6 ~ave r i~ to the hypothesis that a complete endogenou~ RAS existed in the CNS. The RAS ha,, thu~ experienced what has recenth been found for mare other peptide~: the exclusive tra- ditional h~.-alization had to be abandoned and ne** functi,m,. **ere disco, ercd at ne,~ sites of action.

Studies to elucidate a t~ssible function of the RAS in the br:u, ~ c r c undertaken using ~'x eral approachc~.

The pharmacological ext~'riment-~ can be summarized to indicate that circulating plasma angiotcn~in certainh, ha,, cardio- ~a.~ular effects on the brain at ~ites ~here the bh~,d-brain barrier is deficient (-rea l.x~strema, h.x i.x~thalamus). Angioten- sin does not treeh cro~,s the blood-brain barrier, ho~evcr, and centralh applied ANG il raise.s blood pre,,sure at ,,ire,, and b~ mechanism.,, different from pla,ma ANG 11 =" H'ta

Effect.,, of stimulation of the blo~x nt hc,,i.~ o f e n d o g e n o u s brain a r l g l o t e n , i i n v r e r c

imcstigated in doge, and rat.~ '~ 'L Purified renm (EC 3.4.tlq. ! t~) from brain or kidnc~ ~as iniected into the brain ~cntriclcs. l hc cerebrospinal fluid (CSF) and brain con- tain high concentrations of the high molecular ~eight peptide precursor angiotensinogen from which the inactive decapeptide angiotensin 1 (ANG 1) is cleaved. Converting e n ~ m e (EC 3.4.15.1). which is present in CSF. the brush border of choroid plexus and in braiu tissue then converts ANG ! to the effector

t ' Flsc,.~r~%~rth-lto|l.;lnd Flts'.nlt-dp;ztl Plrt.~ 1'4'ql

290 TIPS - November i 981

octapeptide of the RAS, ANG lI. Interac- tion of brain ANG I1 with its receptors produced the same biological responses as seen after application of synthetic ANG I!: increases of blood pressure, drinking, and release of vasopressin (ADH) Lm and adrenocorticotrophic hormone (ACTH) s into the circulation; an elevation of sympathetic tone, and a rise in plasma nor- adrenaline and adrenaline (Fig. 1).

The cardiovascular and endocrine responses could be completely prevented by intraventricular administration of renin inhibitor or converting-enzyme inhibitors and by central angiotec~in receptor blockade with saralasin'. This dc..monstrated

that the bi,)iogical responses to intraven- t r icular renin were indeed elicited by endogeaous ANG 11 generation in the brain. The possibility of stimulating and inhibiting ANG !1 synthesis at each step of the enzymatic cascade gives the brain RAS a unique place among brai,.i peptide sys- tems,

Pharmacological interference with the brain RAS in order to study the pathophysiological role of endogenous ANG I1 was performed in different types of experimental hypertension, particularly in spontaneously hypertensive rats (SHR). Several investigators have shown that injection or chronic infusion of the

J

I

]Catecholamines J I AcT. I NE, E I ADH ,, I I Car t icosteronll

sympathetic tone H20 vascular reabsorptmn reaclivity

k~dney function brain ANG'gen vasoconstriction electrolytes

I BLOOD PRE SSURE

sensitivity '~ (SHR) ANG. ENK SUB P

m brain RAS - - CSF ANG I' ---brain ANG II receptors 1' receptor blockade. BP ~,

increased in $HR plasma renin

tig. i. General outline o f possible mechanisms involved in the blood prcsswe effects following central peptidergic s ~im alation. Black arrows ind~cate hormones which are released. In the ca~e o f ~giotensin, release of antidiureric h~rmone (,4 DH), adrenocorticot~ophic ho,,mone ( A CTH) and catecholamines ~ well documented. Also indicated aye possible neuronal pathtmy$ ~ The lower part summarizes some mechanbms by which the syml~hetic nee. vous system, ADH, ACTH. and conicosterone contribute to the elevation o fblood pressure. On the right, data )fwouring the concept o f a cemral peptidergic stimulation in spontaneously hypertensive rats (SHR) are listed: supersensitivity to central peln~tes (angiotensin !i, enkephalins, substance P), incremed levels o~coml~onents o flhe renin.angimensin system (RAS) it: r~e brain and cerebrospinal ]luid (CSFL up.regulated receptors for angiotensin in the brain, and reduction o/blood pressure in response to central blockade oy peptide receptors (angiotensin, enkephalins). In the blood, these rats exhibit a humoral pattern similar to the one seen alter central pepflde adminiuration, while the peripheral RAS is suppressed. Mechanbms for other peptides are discussed in the text.

angiotensin receptor antagonist saralasin into the brain ventricles of SHR produced a fall in blood pressure, while the antagonist had no effect when applied intra- venously~, It.

Inhibition of brain converting enzyme by captopril similarly produced a reduction in blood pressure in SHR. This depressor effect of the converting-enzyme inhibitor occurred at doses which were not effective or were much less effective by the intravenous route, and the blood pressure tall coincided with the degree and time course of converting-enzyme inhibition in the brain. Chronic oral treatment with converting-enzyme inhibitors lowered blood pressure in SHR and produced characteristic signs of RAS inhibition not only in the plasma but also in blood pressure controlling brain areas. It was con- cluded from these experiments that brain ANG 11 contributed to high blood pressure in SHR.

Antidluretk hormone Antiduretic hormone (ADH) is a cir-

culating vasopressor peptide which, it is also claimed, exerts a sensitizing action on the bamreceptor reflex TM, a mechanism by which hypertension might be prevented. Recent observations of reduced ADH levels in young SHR in brain areas closely connected with the baroreceptor reflex arch, namely the brain stem and the hypothalamus (unpublished), could thus be indicative of a genetic defect contributing to the known attenuation of the baroreflex and, thereby, to hypertension in these rats.

OOog peptges Although the opioid peptides were dis-

covered only a few years ago, their cardiovascular effects have already become a rather complex story. Depending on the site of action, the type of substance, the species, and its state of ~.onsciousness, quite different and frequently contradictory results have been tteported ~-'.t'. In addi- tion, it has not always been clear whether the effects on blood pressure were direct or whether they were secondary to unrelated biological actions of the peptides.

The short-chain pentapeptides leu- cine-enkephalin (Leu-ENK), methionine-enkephalin and its stable analogue D-Ala'-methionine enkephalin (DAME) appear to be pressor when administered to the brain ventricular system of conscious animals it. Long-chain opioid peptides such as beta-endorphin were revealed to have mainly depressor effects*, but biphasic depressor and pressor re-

T I P S - N o v e m b e r 1 9 8 1 2',..

sponses have also been described for other endorphins and for methionine--enkephalin', in alpha.ddoralose anaesthetized rats. for example, DAME was depressor, while it clearly increased blood pressure at the same dose in conscious animals. Cen- tral administration of the opioid receptor antagonist naloxone blocked the pressor response, and central administration of the opioid receptor antagonist diprenorphine completely inhibited the pressor as well as the depressor response to DAME, indicat- ing that these effects were produced by stimulation of morphinomimetic receptors in the brain. Experiments with receptor antagonists suggest that different subpopu- lations of opioid receptors in the brain mediate the responses to different morphinomimetic peptides '~.

Rats with genetic hypertension exhibit a supersensitivity to intracerebroventricular Leu-ENK it, and blood pressure can be lowered in these animals by central opiate receptor blockade with diprenorphine (Fig. 2). These results indicate that endogenous opioid peptides may be involved in the maintenance of high blood pressure in SHR.

Interestingly, the pressor responses to intraventricular Leu-ENK and DAME are always accompanied by increases in heart rate. Stimulation of sympathetic activity or attenuation of the baroreceptor reflex could be responsible for this phenomenon. Indeed, a marked attenuation of the vagal component of the baroreceptor reflex in enkephalin-treated animals has been observed ~=. This is in harmony with the finding that opioid peptides have been found in the nucleus tractus solitarii of the brain stem, which represents the first synapse of the baroreceptor reflex, and with the finding of an impaired baroreceptor reflex in SHR.

Substance P

Substance P is an undecapeptide with a wide distribution within the central and peripheral nervous system and a broad spectrum of biological activities. Tradi- tionally, this peptide has been associated with the perception of pain. Its peripheral blood pressure reducing action was described almost 50 years ago but, when applied to the brain, substance P has marked pressor activity in conscious and anaesthetized animals '=. The GABA derivative baclofen [/](4-chloro- phenyi)GABA], reported to inhibit several actions of substance P was shown to block the pressor responses to substance P almost completely 's. This suggested the possibility

the mediation of the peptide's central cardiovascular e fleets.

As with angiotensin and enkephalins. the pressor responses to intraventricularly injected substance P are drastically increased in SHR when compared to normotensive Wistar Kyoto control rats. However, in contrast to the enkephalins which invariably elicit tachycardia together with blood pressure increases, a distinct difference in the blood pressure increase- associated heart rate responses was observed berveen SHR and Wistar Kyoto rats, namely tachycardza in the hypertensive animal~ ~nd brady~ardia in the Wistar Kyoto ratsUt This. together with results obtained after barorectptor deafferentia- tion, led to the conclusion that the central pressor action of substance P, like thai of the enkeph~lins, is buffered by the baroreceptor reflex in the normotensive Wistar Kyoto rats, but is not buffered in the SHR. Altered baroreceptor reflex function might be responsible for the observed supersensitivity to centrally acting peptides in SHR and this, in turn, could be a pathogenetic mechanism contributing to their hypertensive disease.

Kiains Bradykinhl. an endogenous nonapeptide

present in the blood, is a potent vasodilator and blood pressure lowering agent in the periphery, and in the brain, like substance P. It was observed, however, that it elicited pressor and net depressor responses when

AMAP mmHg

30

20

10

0 -

- I 0

- 2 0

-30

administered centrally. These findings have been confirmed and expanded by several authors t~. There is evidence that cholinergic mechanisms are involved in the ,~entral pressor action of bradykinin, but alpha-adrenoceptors and even histamine receptors appear to be involved as well.

The pressor action of intraventricular bradykinin can be potentiated and pro- longed by intraventricular pretreatment ~,ith low doses of converting-en~'me fnhibitorstt This strongly suggests that the -ame enzyme, namely convening enzyme (kininase II) which degrades kinins in the periphery, is also responsible for the bradykinin breakdown in the brain, lnjec- lion of high doses (5(10 /=g) of the converting-enzyme inhibitor capt,~pril in SHR causes a biphasic blood pressure response: an initial maAed increase followed by a long-lasting blood pressure fall. it haLs been speculated that the initial increase is caused by a potentiatk0n of the pressor action of endogenous kinins in the brain n. while the depressor effect is due to ANG Ii inhibition.

Mede of ae t t~ e f l m m pqNMes

The mechanism by which the central cardiovascular effects of pept,~des arc relayed to the periphe~, does not seem to be identical for all peptides.

The peripheral portion of the symp3th- etic nervous system and circulating vasopressin each contribute about one half of the acute pressor response to intraventricu-

\

t

\

J.

• t t

10

l IME AFIER INJECTION

Z SEM n 9

x p<~.05 ] SHRsD vS WKY xx p<0C1 J

WKY

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Fig. 2. Biood press~w responses to mlections o f the opioid receptor antagontw diprenorphme ¢ i O0 tag) into the lat- eral brain ventricle o f conscious spontaneouMy hypertensive rat~ (SHRw) and normown.ttve Wistar Kvou~ rats ¢ W K Y). Note the pronounced blood pressure full in SH K~p ,'hen compared u) W K Y. ~W A P. mean arterial blown1

of GABAergic neurons being involved in pressure. (T. Yukimura.e/aL unpublished.)

292 TIPS -,Vovember 1981

larly injected angiotensin",". On the other hand. the central pressor action of enkephalins and substance P does not appear to be dependent on vasopressin release, since, in contrast to angiotensin, circulating vasopressin is not elevated alter central administration of peptides of either type. and blockade of peripheral vasopressin receptors does not inhibit the centrally evoked pressor effecls of substance P.

The sympathetic nervous system appears to be important for the mediation of tht: central effects of these peptides to me periphery, it has been shown, for in- stance, that: intraventricular injection of enkephalins in dogs enhances myocardial contractility. Following intraventricular injections of substance P, increases ~n circulating mwadrenaline and adrenaline were observed, and the centrally evoked pres~r effects could be completely prevented by peripheral alpha-adrenoceptor blockade with prazosin".

Most information concerning the mechanism~ and structures in the brain involved in the central peptide effects on cardiovascular function have been gathered in the case of angiotensin: brain areas sensitive to ANG 11 such as the o~anum vasculosum laminae terminalis (OVLT), the subfornical organ or certain areas within the dorsal medulla oblongata, have been identified, and specific ANG I1 receptors have been demonstrated in some of these regions ~,''. Interactions between angiotensin and catecholamines in the brain have been observed". Stimulation of the synthesis of brain ANG 11 produced changes in catecholamine turnover in the hypothahtmus and in the medulla oblongata. suggestin[~ an influence of the peptide cm catecholaminergic neurotransmission in the brain. Receatly. we ha~,e observed that the blood pressure and drinking responses 1o intraventricular administration of angiotensin wer.: blunted by stimulation of GABA receptors or inhibition of GABA degradation and could be restored by a GABA antagonist, lnleracttons of opioid peptides with brain catecholamines have also been described, and a possible rela- tionship of substance P to the GABA system is discussed above. It is clear, however, that much remains to be learned about the peptidergic pathways in the brain which control blood pressure and interact with known, cardiovascular centres.

Condusion

A number of mainly pharmacological experimental data indicate a possible role of brain peptides in cardiovascular control. The pathophysiological importance of

the~ observations is suggested by experiments involving stimulation or inhibition of the endogenous peptides. Inhibitors of converting enzyme, which interfere with peptide synthesis and degradation, are pres- ently used as antihypertensive agents. Evidence has been presented that inhibition of the brain RAS may contribute to the antihypertensive mechanisms of converting-enzyme inhibitors in some types of hypertension, it has been found that converting enzyme not only converts ANG I to ANG 11, but is identical with the kinin-degrading enzyme kininase I1, and has properties in common with the enkephalin and substance P-degrading enzymes.

The introduction of substances which interact with neuropeptide synthesis and degradation has improved our understand- ing of the role of central peptidergic pathways for blood pressure comrol, and may help to deveiop antihypertensive drugs which interfere with the cardiovascular actions of brain peptides.

Reading l ist 1 Bolme. P., Fuxe, K., Agnati, L. F., Bradley, R.

and Smithies. J. (1978) Eur. J. Pharnuu'ol. 48, 319-324

2 Buckley. J. P. and Fem~rio, C. M. (eds) (1977) Central Actions o f Angiotensin and Related Hor. mones, Pergamon Press, New York

Correa. F. M. A., Innis. R. B., Uh~. (L R. and Sn.vder, S. It. (It)79) Proc. Nail Acad. Sci. U.S.A. 76, 1489-14t)3

4 Fuse. K., Andetsson, K.. (]al|ten, 1)., tlfkfelt. T. and Eneroth. P. (Ig80) in En:ymath" Re/ease of Vasoactive Peptides (Gross, F. :md Vogel. It, G., ed:0, pp, I¢~1-170, Raven Press, New York

5 Ganten. D, and Speck. G. (1~78) Biochem. PharmacoL 27, 2379-2389

O Hirose, S., Yokosawa, H. and inagami, 1'. ( I q78) Nature (Lomlon), 274, 392-3tJ3

7 lt{ikfelt. T.. EIdv, R.. Johansson, ()., Ljungdahl. A., Sehultzberg, M.. Fuse, K., Goldstein, M., Nilsson, t3., Pcrnow, P.. Terenius, L., Ganten, D., Jeft'coate, S. L., Rehfeld, J. and Said, S. (1978) in P~ychopharmacology: A Generation o f Progres,~

" (Lipton, M. A., DiMascio, A. and Killam, K. F.. eds), pp. 39-4~t~, Raven Press, New York

8 Laubie, M., Schmitl, H., Vincent, M. and Remond, G. (1977) Ear. J. PharmacoL I t~. 67-7 I

9 Marx, J. L. (1979) Science, 205.880--889 I () Monlani. J. P., Liard, J. F. and M6hring, J. (1980)

Circ. Rex. 47, 346--355 I I Phillips, M. !., Weyhenmcyer, J., Felix, D.,

Ganten, D. and Hoffman, W.E. (!~79) /q,d. Proc. Fed. Am. Soc. Exp, Biol, 38, 22~,(~226~

12 Schaz, K., Stock, G,, Simon, W., Schl(ir, K H.. Unger, Th., Rockhold. R. and Gantcn, D. ( I qS0) itypertension, 2. 395-407

13 Severs, W. B, and Daniels-Severs, A. E. (1973) Pharmacol. Rev. 25, 415--449

14 Snyder, S. H. (! 981,))Science, 209, 97¢~--983 15 Unger, Th,, Rockhold, R.W., Yukimura, T.,

Rettig, R,, Rascher, W. and Ganten, D, ( 1981 ) in Central Nervrnt~ System Mechanisms in Hyperten- sion (Buckle v, J. P. and Ferrario, C. M., eds), pp. I 15-I 27, Raven Press. New York

I(~ Wallis, C. J. and Primz, M. P. (1980) Endocrinol- ogy, 106, 337-342

Thomm" Unger (left) was born in Uberlit~gen ILake of Constance. F. R. G., in ! 950, He studied medicine in Munich, Leeds (England) and Heidelberg, After abtairing his M.D. degree in ! 976. he spent 2 years as a research fellow at the Clinical Research Institute o f Montreal Since 1978. he has been research assistant at the Departmenl of Pharmucology. UniversiB" o~ tleidelberp.

DetleL" Gamen esecond fiom left) wct~ bonz in Liineburg, northern Germany. in 1941, After 2 years in agriculture, he sn~died medicine in Wiirzburg and Ti~bingen. Germany, and in Montpellie'r, France. and obtained hi~. M.D degree in ! ~68. From 196V to 1973. he was a senior research fellow at the Clinical Research Institute o f Montreal and gained a Ph.D. at McGill Universit),. Since 1974, he has been Profi, ssor oJ" Experimental Medicine at the Departmem of Pharmacology, Unirers~ty of Heidelberg, and, since 1979. St'ientiftc Director of the German hlsti. tute for High Blood Pressure Research.

Rudolf l:. Lang (third flora left) wm born in Augsburg. Bavaria! in 19111. He sit,died medicine in Erlangen, bmsbru¢ k (Austria) and Munich. From ! 909 to ! 971. he worked at the Mat- Planck- institute for Protein Research in Munk h for his M.D. degree, and between 1071 and 1980 at the Department of Endocrinology. University Hos. pital of[rim. He is currendy a research assistant at the Department o f Pharmacology. Universi~. o~ Heideiberg.

Wol fgang Rascher (right) wax born in Bad Neuenahr. Rhineland, West Gernmny, in I q S O. lie studied medicine at Cologne and Heidelberg and obtained his M.D. degree bz ! 076. Since 1977, he has been research assisumt at the Deparmrenl o f Pharmacology, Uni~eersity o f Heidelberg.

brain peptides and blood pressure control

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