pathophysiology of hypertension and endothelial dysfunction in patients joice

7/28/2019 Pathophysiology of Hypertension and Endothelial Dysfunction in Patients Joice

1/65

Pathophysiology of HypertensionPathophysiology of Hypertension

and Endothelial Dysfunction inand Endothelial Dysfunction in

Patients With Diabetes MellitusPatients With Diabetes Mellitus

January 24January 24thth 20032003


2/65

Epidemiology in DMEpidemiology in DM >10 million Americans with diabetes>10 million Americans with diabetes

90-95% of whom have type 2 diabetes90-95% of whom have type 2 diabetes 798,000 new cases of diabetes diagnosed each year798,000 new cases of diabetes diagnosed each year

5 million more cases are undiagnosed, untreated5 million more cases are undiagnosed, untreated

13 million have impaired glucose tolerance13 million have impaired glucose tolerance

All patients are at risk for associated metabolic disorders anAll patients are at risk for associated metabolic disorders anmicro- and macrovascular complicationsmicro- and macrovascular complications

Annually, CV disease >77,000 deaths in diabetes-related deaAnnually, CV disease >77,000 deaths in diabetes-related dea

The primary risk for a heart attack in type 2 diabetes is asThe primary risk for a heart attack in type 2 diabetes is as

high as in pts with ischemic heart diseasehigh as in pts with ischemic heart disease Diabetesrisk equivalent for CV diseaseDiabetesrisk equivalent for CV disease

Associated risk factors (lipids) should be treated asAssociated risk factors (lipids) should be treated as

a ressivel in diabetes as in heart diseasea ressivel in diabetes as in heart disease


3/65

Epidemiology of hypertension in DMEpidemiology of hypertension in DM

Morbidity & mortality associated with DMMorbidity & mortality associated with DM

macrovascular & microvascular complicationsmacrovascular & microvascular complications

The prevalence is greater in diabetics withThe prevalence is greater in diabetics with

hypertensionhypertension The prevalence of hypertension in DM pts isThe prevalence of hypertension in DM pts is

higher, especially in younger personshigher, especially in younger persons

40% at age 45 years, and increases to 60% by40% at age 45 years, and increases to 60% by

age 75 yearsage 75 years


4/65

CV events and DMCV events and DM

Risk of CV fatal or nonfatal event or renalRisk of CV fatal or nonfatal event or renal

insufficiency ---is also greater in diabeticsinsufficiency ---is also greater in diabetics

Diabetics are at increased risk for all CV eventsDiabetics are at increased risk for all CV events

including stroke, recurrent hospitalization for MI orincluding stroke, recurrent hospitalization for MI or

unstable angina, heart failure, and recurrent MIunstable angina, heart failure, and recurrent MI

Dr Haffner: the cardiovascular risk of patients withDr Haffner: the cardiovascular risk of patients with

diabetes who have not had an MI is comparable withdiabetes who have not had an MI is comparable with

that of nondiabetic patients who have sustained anthat of nondiabetic patients who have sustained an

MIMI


5/65

Pathophysiology of hypertension inPathophysiology of hypertension in

DMDM

The derangements in glucose, lipid, and proteinThe derangements in glucose, lipid, and protein

metabolism lead tometabolism lead to

functional abnormalities in autonomic nervesfunctional abnormalities in autonomic nerves

overproduction of vasoconstrictor factors thatoverproduction of vasoconstrictor factors thatincrease vascular toneincrease vascular tone

concomitant reductions in the biologic actionsconcomitant reductions in the biologic actions

of vasodilatorsof vasodilators

resulting in an increase in BPresulting in an increase in BP


6/65

Vasoactive substancesVasoactive substances

Cause structural changes in the CV system andCause structural changes in the CV system and

in the kidney through effects onin the kidney through effects on

Vascular smooth muscle cell hypertrophyVascular smooth muscle cell hypertrophy

Hyperplasia, angiogenesis, cellular apoptosis,Hyperplasia, angiogenesis, cellular apoptosis,macrophage/fibroblast activation withmacrophage/fibroblast activation with

augmented formation of extracellular matrixaugmented formation of extracellular matrix

Adhesive interactions of circulating leukocytesAdhesive interactions of circulating leukocytes

and platelets with the vessel walland platelets with the vessel wall


7/65

Processes important in the development orProcesses important in the development or

perpetuation of hypertension in diabeticsperpetuation of hypertension in diabetics

Alterations in the balanced production of vasodilatorAlterations in the balanced production of vasodilator

& vasoconstrictor substances from the endothelium& vasoconstrictor substances from the endothelium

Altered vascular smooth muscle responses to theseAltered vascular smooth muscle responses to these

substancessubstances Resistance of peripheral tissues & selected lipidResistance of peripheral tissues & selected lipid

metabolic processes to the actions of insulinmetabolic processes to the actions of insulin

Alterations in the cellular & extracellular elementsAlterations in the cellular & extracellular elements

that comprise the vessel wallthat comprise the vessel wall


8/65

Reactive oxygen species (ROS)Reactive oxygen species (ROS)

DiabeticsDiabeticsincreasedincreased metabolic processes thatmetabolic processes that

produceproduce reactive oxygen species (ROS)reactive oxygen species (ROS)

ROS serve as signaling mechanisms mediateROS serve as signaling mechanisms mediate

many of the functional & structural vascularmany of the functional & structural vascularabnormalities observed in diabeticsabnormalities observed in diabetics

Thus, hypertension in diabetics probablyThus, hypertension in diabetics probably

results from a series of interrelated, complexresults from a series of interrelated, complex

functional and structural abnormalitiesfunctional and structural abnormalities


9/65

Endothelial dysfunction in DMEndothelial dysfunction in DM


10/65


11/65

Endothelial production of vasoactivEndothelial production of vasoactive

factorsfactors

Normal endothelium is pivotal in theNormal endothelium is pivotal in the

maintenance of normal vascular homeostasismaintenance of normal vascular homeostasis

through a balanced production of vasodilatorthrough a balanced production of vasodilator

and vasoconstrictor substancesand vasoconstrictor substances

Endothelium-derived vasodilatorsEndothelium-derived vasodilators

Endothelium-derived vasoconstrictorsEndothelium-derived vasoconstrictors


12/65


13/65

VasoconstrictorsVasoconstrictors

From the sympathetic nerves, circulation,From the sympathetic nerves, circulation,

endotheliumendothelium

Norepinephrine (NE)Norepinephrine (NE)

Angiotensin IIAngiotensin II Thromoxane A2Thromoxane A2

5-hydroxyeicosatetaraenoic acid (5-HETE)5-hydroxyeicosatetaraenoic acid (5-HETE)

Endothelin (ET)-1Endothelin (ET)-1


14/65

Endothelium-dependent vasodilator and vasoconstrictor mechanisms


15/65

Endothelium-derived NO & vascular toneEndothelium-derived NO & vascular tone

NO-a potent mediator of vascular relaxation throughNO-a potent mediator of vascular relaxation through

action on soluble cGMP in VSMC to inhibit ca-dependentaction on soluble cGMP in VSMC to inhibit ca-dependentcontractioncontraction

NO synthesis & release occurs continuously under basalNO synthesis & release occurs continuously under basal

conditions & can be increased through activation ofconditions & can be increased through activation ofmuscarinic, thrombin, purinergic, and ETmuscarinic, thrombin, purinergic, and ET

BBreceptorsreceptors in thein the

endothelial-cell plasma membrane that mediate the actionsendothelial-cell plasma membrane that mediate the actions

ofofacetylcholine, thrombin, ADP, and ET-1acetylcholine, thrombin, ADP, and ET-1 respectivelyrespectively

Changes in vascular wall shear forces associated withChanges in vascular wall shear forces associated with

increased flow also increase NO releaseincreased flow also increase NO release

Sustained increase in BP-by continuous administration ofSustained increase in BP-by continuous administration of

stereoselective inhibitors of NO synthase further indicates-stereoselective inhibitors of NO synthase further indicates-

NO is important in maintenance a vasodilated state.NO is important in maintenance a vasodilated state.


16/65


17/65


18/65


19/65


20/65


21/65

NO and endothelial dysfunction in diabetesNO and endothelial dysfunction in diabetes

Type 1 diabetes-Type 1 diabetes--impaired endothelium-dependent-impaired endothelium-dependent

vasodilationvasodilation in response toin response to acetylcholineacetylcholine and similarand similaragonists that stimulate the release of NOagonists that stimulate the release of NO

Type 1 and 2 diabetesendothelium-dependentType 1 and 2 diabetesendothelium-dependent

vasodilatory responses to brachial artery infusions ofvasodilatory responses to brachial artery infusions ofacetylcholine, methacholine, and similar agonistsacetylcholine, methacholine, and similar agonists areareimpaired in the forearmimpaired in the forearm

In normotensive type 2 diabetesdemonstration of bluntedIn normotensive type 2 diabetesdemonstration of blunted

endothelium-dependent vasodilation suggests that theendothelium-dependent vasodilation suggests that the

endothelial abnormalities cannot be ascribed solely to theendothelial abnormalities cannot be ascribed solely to the

impaired endothelium-dependent vasodilationimpaired endothelium-dependent vasodilation Contribution of prostaglandins to abnormalities inContribution of prostaglandins to abnormalities in

endothelial function is minimalendothelial function is minimal


22/65

M h i f i i dM h i f i i d d th lid th li


23/65

Mechanisms of impairedMechanisms of impaired endotheliumendothelium--

derived vasodilation in diabetesderived vasodilation in diabetes

Biologic actionsBiologic actions ofofNO are diminishedNO are diminished inindiabetes, but production of NO is actuallydiabetes, but production of NO is actually

increasedincreased

Increase in the production of ROSIncrease in the production of ROS by severalby several

vascular components in diabeticsvascular components in diabetics Interactions of NO & superoxide anionInteractions of NO & superoxide anion withinwithin

the microenvironment of the vessel wall--the microenvironment of the vessel wall--

inactivation of NO & formation of the potentinactivation of NO & formation of the potent

oxidant radical,oxidant radical, peroxynitrite (OONOperoxynitrite (OONO --))


24/65

Hyperglycemia in DMHyperglycemia in DM

Associated with diminished biologic actions of NOAssociated with diminished biologic actions of NO

Tesfamariam: impaired vasodilatory responses toTesfamariam: impaired vasodilatory responses to highhigh

glucose levels-glucose levels--caused by-caused by increased oxygen-derived freeincreased oxygen-derived free

radicalsradicals through a protein kinase C-mediatedthrough a protein kinase C-mediated

mechanism that stimulates the formation ofmechanism that stimulates the formation of

vasoconstrictor prostanoidsvasoconstrictor prostanoids The vasoconstrictor effect can be abolished by aldoseThe vasoconstrictor effect can be abolished by aldose

reductase inhibitorsreductase inhibitors

High glucose increase both NO synthase expression &High glucose increase both NO synthase expression &

superoxide anion generation by aortic endothelial cells.superoxide anion generation by aortic endothelial cells.


25/65

Dyslipidemia in DM (1)Dyslipidemia in DM (1) Elevated TG, low HDL-c, and elevated IDLinsulinElevated TG, low HDL-c, and elevated IDLinsulin

resistance syndromeresistance syndrome Hypercholesterolemia is associated with impairedHypercholesterolemia is associated with impaired

endothelium-dependent vasodilation in humanendothelium-dependent vasodilation in human

forearm & pig coronary arteries & rabbit aortaforearm & pig coronary arteries & rabbit aorta

These functional vascular changes associated withThese functional vascular changes associated withIncrease generation of ROSIncrease generation of ROS

Persistence of endothelial NO releasePersistence of endothelial NO release

Increased generation of OONO-Increased generation of OONO-

Oxidative modification of LDLOxidative modification of LDL

D li id i i DM (2)D li id i i DM (2)


26/65

Dyslipidemia in DM (2)Dyslipidemia in DM (2)

The extent ofThe extent ofROS formationROS formation-also be a determinant of-also be a determinant of

endothelial NO release-it may affect the proportion ofendothelial NO release-it may affect the proportion ofcirculating and tissue cholesterol that has been oxidizedcirculating and tissue cholesterol that has been oxidized

Oxidatively modified LDLOxidatively modified LDL--impair endothelium-dependent--impair endothelium-dependent

vasodialtion more than native LDL in vascular ringvasodialtion more than native LDL in vascular ring

HypertriglyceridemiaHypertriglyceridemia-independent risk factor for CAD-independent risk factor for CAD Postprandial hypertriglyceridemia--cause a transientPostprandial hypertriglyceridemia--cause a transient

impairment of endothelium-dependent vasodilation in normimpairment of endothelium-dependent vasodilation in norm

volunteersvolunteers

Postprandial hypertriglyceridemia is more exaggerated inPostprandial hypertriglyceridemia is more exaggerated in

type 2 diabetics & associated with higher forearm venous frtype 2 diabetics & associated with higher forearm venous frradical & greater impairment of flow-dependent vasodilatioradical & greater impairment of flow-dependent vasodilatio


27/65

Increased oxidative stress in diabetesIncreased oxidative stress in diabetes

Oxidative stressimbalance between the production ofOxidative stressimbalance between the production ofROS and the numerous antioxidant defense mechanismsROS and the numerous antioxidant defense mechanisms

present in biologic systemspresent in biologic systems

Reactive oxygen species (ROS) includeReactive oxygen species (ROS) include superoxide anionsuperoxide anion

that is converted to hydrogen peroxide boththat is converted to hydrogen peroxide both

enzymatically and by several isoforms of the enzymeenzymatically and by several isoforms of the enzyme

superoxide dismutasesuperoxide dismutase

In diabetes,In diabetes, overproduction of ROSoverproduction of ROS overwhelms normaloverwhelms normal

antioxidant defenses with consequent alterations in bothantioxidant defenses with consequent alterations in both

the function and the structure of the CV systemthe function and the structure of the CV system


28/65

The reduction of oxygenThe reduction of oxygen

O2+ eO2+ e--

------------------------------

O2O2.-.-

(superoxide radical)(superoxide radical) O2O2 .-.- + 2 H+ 2 H++ +e+e- --------- -------- H202 (hydrogen peroxide)H202 (hydrogen peroxide) H2O2 + eH2O2 + e -- ---------------------- OHOH-- ++ OHOH.. (hydroxyl radical)(hydroxyl radical)

OHOH..

+ e+ e--

----------------------------

OHOH--

(hydroxyl ion)(hydroxyl ion) 2 OH2 OH-- + 2 H+ 2 H++-------------- 2H2O2H2O Overall O2 +4 HOverall O2 +4 H++ + 4 e+ 4 e-- ---------------- 2H2O2H2O


29/65

F 2+ C bi l i lFe 2+ Cu can cause biological


30/65

Fe 2+, Cu can cause biologicalFe 2+, Cu can cause biological

damagedamage

O2 + FeO2 + Fe 2+2+ FeFe 3+3+ + O2+ O2 .-.- 2O22O2 .-.- +2 H+2 H++ H2O2+ O2H2O2+ O2 H2O2 + FeH2O2 + Fe 2+2+ OHOH .. + OH+ OH-- + Fe+ Fe 3+3+ (Fenton(Fenton

reaction)reaction) This makes highly damaging hydroxyl radicalThis makes highly damaging hydroxyl radical

O2O2 .-.- + H2O2+ H2O2 Cu, FeCu, Fe OHOH .. + OH+ OH-- + O2+ O2


31/65


32/65


33/65

Source of OHSource of OH.. Might be theMight be the


34/65

Source of OHSource of OH.. Might be theMight be the

reaction of O2reaction of O2.-.- with NOwith NO

O2O2 .-.- + NO+ NO.. ONOOONOO -- (peroxynitrite)(peroxynitrite) ONOOONOO-- + H+ H++ ONOOHONOOH

ONOOHONOOH OH-like species OH-like species


35/65


36/65


37/65


38/65

Sources of reactive oxygen species in DMSources of reactive oxygen species in DM

Enzyme or processesEnzyme or processes Tissue sourceTissue sourceNADP(H) oxidaseNADP(H) oxidase VSMCs, leukocytesVSMCs, leukocytes

Hemeoxygenase-1Hemeoxygenase-1 Endothelium, VSMCsEndothelium, VSMCs

Mitochondrial oxidationMitochondrial oxidation All cellsAll cells

Cyclooxygenase, lipoxygenaseCyclooxygenase, lipoxygenase Endothelium, VSMCsEndothelium, VSMCs

Cytochrome P450 monooxygenasesCytochrome P450 monooxygenases All cellsAll cells

Xanthine oxidaseXanthine oxidase Endothelium, VSMCsEndothelium, VSMCs


39/65

Production of ROS by circulating leukocyteProduction of ROS by circulating leukocyte

ROS generatedROS generated by isolated lymphocytes withoutby isolated lymphocytes withoutstimulation or after exposure to thestimulation or after exposure to the formylformyl

tripeptide, fMLPtripeptide, fMLP, was significantly higher in type 2, was significantly higher in type 2

DMDM

Most of the increased ROS was blocked by theMost of the increased ROS was blocked by the

addition ofaddition ofsodium azidesodium azide, a scavenger of singlet, a scavenger of singlet

oxygen and of hydrogen peroxide, but not byoxygen and of hydrogen peroxide, but not by

superoxide dismutasesuperoxide dismutase


40/65

AntioxidantsAntioxidants

Antioxidants reported to reverse the pathologicAntioxidants reported to reverse the pathologicalterations for which ROS are thought to be resposiblealterations for which ROS are thought to be resposible

Acute exposure of isolated tissues or intact animals withAcute exposure of isolated tissues or intact animals with

experimental diabetes toexperimental diabetes to superoxide dismutasesuperoxide dismutase eithereither

alone or in combination with catalase reported toalone or in combination with catalase reported to

improve or normalize impaired endothelium-dependentimprove or normalize impaired endothelium-dependentvasodilationvasodilation

Simultaneous infusion ofSimultaneous infusion ofascorbate and methacholineascorbate and methacholineinto the brachial artery of type 1 or type 2 diabetes wasinto the brachial artery of type 1 or type 2 diabetes was

reported to augment forearm blood flow compared withreported to augment forearm blood flow compared withthe response to methacholine alonethe response to methacholine alone


41/65

A i id


42/65

AntioxidantsAntioxidants

The investigators reported that no effect ofThe investigators reported that no effect ofvitamin Cvitamin Con endothelium-independent vasodilation producedon endothelium-independent vasodilation produced

by either sodium nitroprusside or verapamil andby either sodium nitroprusside or verapamil and

didnot improve endothelium-dependent vasodilationdidnot improve endothelium-dependent vasodilation

in nondiabetic subjectsin nondiabetic subjects

Recently reported that ascobate restores the trnsientRecently reported that ascobate restores the trnsientblunting of endothelium-mediated vasodilation inblunting of endothelium-mediated vasodilation in

nondiabetic individuals with acute hyperglycemianondiabetic individuals with acute hyperglycemia

The results of chronic supplementation withThe results of chronic supplementation with vitaminvitamin

C, vitamin E, andC, vitamin E, and -carotene-carotene have shown nohave shown nosignificant retardation of CV disease progressionsignificant retardation of CV disease progression

Nutrients and antioxidant defenceNutrients and antioxidant defenceNutrient Examples of useful roles in the human bodyNutrient Examples of useful roles in the human body


43/65

Nutrient Examples of useful roles in the human bodyNutrient Examples of useful roles in the human body

IronIron Catalase, correct functioning of mitochondri, HbCatalase, correct functioning of mitochondri, Hb

MangansesManganses Mn-SOD in mitochondriaMn-SOD in mitochondria

CopperCopper Cu,Zn-SOD, caeruloplasminCu,Zn-SOD, caeruloplasmin

ZincZinc Cu,Zn-SOD: more generalized antioxidant properties? Stabilizer ofCu,Zn-SOD: more generalized antioxidant properties? Stabilizer of

membrane structuremembrane structureProteinsProteins Sulphur-containing amino acids are needed to make GSH. SODs, catalase,Sulphur-containing amino acids are needed to make GSH. SODs, catalase,glutathione reductase and peroxidases, metal transport, and storage proteins.glutathione reductase and peroxidases, metal transport, and storage proteins.

Albumin may be a sacrificial antioxidant carrier of copper in plasmaAlbumin may be a sacrificial antioxidant carrier of copper in plasma

RiboflavinRiboflavin Glutathione reductase, correct functioning of mitochondria, needed to makeGlutathione reductase, correct functioning of mitochondria, needed to make

FMN and FADFMN and FAD

SeleniumSelenium Glutathione peroxidases; thyroid funciton; may aid detoxification of carcinogensGlutathione peroxidases; thyroid funciton; may aid detoxification of carcinogens

Vitamin EVitamin E Protection against lipid peroxidation; may also help to stabilize membrane structurProtection against lipid peroxidation; may also help to stabilize membrane structur

Vitamin CVitamin C Hydroxylase enzymes, water-soluble antioxidant, recycles vitamin E, reducesHydroxylase enzymes, water-soluble antioxidant, recycles vitamin E, reducesnitrosamine carcinogensnitrosamine carcinogens

B-caroteneB-carotene Precursor of vitamin A. May have some antioxidant properties-powerful scaverger Precursor of vitamin A. May have some antioxidant properties-powerful scaverger

singlet O2, may react with peroxyl radicals. Some reports that it inhibits lipidsinglet O2, may react with peroxyl radicals. Some reports that it inhibits lipid

peroxidation in membranes, but only at low O2 concentrationsperoxidation in membranes, but only at low O2 concentrations

LycopeneLycopene Orange-red pigment in tomatoes. Powerful scavenger of singlet )2. Suggested to be aOrange-red pigment in tomatoes. Powerful scavenger of singlet )2. Suggested to be a

antioxidant in vivo, but this has not yet been establishedantioxidant in vivo, but this has not yet been established

Retinol (Vit A)Retinol (Vit A) Some antioxidant properties demonstrated in vitro, but no good evidence that it actSome antioxidant properties demonstrated in vitro, but no good evidence that it actas an antioxidant in vivoas an antioxidant in vivo

NicotinamideNicotinamide Needed to make NAD+, NADH, NADP+, NADPHneeded for glutathione reductasNeeded to make NAD+, NADH, NADP+, NADPHneeded for glutathione reductas

Important in cell metabolism and energy productionImportant in cell metabolism and energy production

Insulin resistance syndrome andInsulin resistance syndrome and


44/65

Insulin resistance syndrome andsu es s ce sy d o e d

endothelial dysfunctionendothelial dysfunction

Syndrome of insulin resistance may precede the onsetSyndrome of insulin resistance may precede the onsetof overt type 2 diabetesof overt type 2 diabetes

The clinical features include hyperinsulinemia,The clinical features include hyperinsulinemia,

truncal obesity, hypertension, and dyslipidemiatruncal obesity, hypertension, and dyslipidemia

characterized by elevated serum TG, low HDL-C, andcharacterized by elevated serum TG, low HDL-C, andincreased IDLincreased IDL

These hallmarks are thought to result from relativeThese hallmarks are thought to result from relative

insensitivity of selected tissues, particularly skeletalinsensitivity of selected tissues, particularly skeletal

muscle, to the action of insulinmuscle, to the action of insulin

I li i t dI li i t d


45/65

Insulin resistance syndromeInsulin resistance syndrome

It is hypothesized that compensatoryIt is hypothesized that compensatory hyperinsulinemiahyperinsulinemiamaintains the serum glucose within the normal rangemaintains the serum glucose within the normal range

until pancreatic isletuntil pancreatic islet -cells can no longer produce-cells can no longer producesufficient insulin, and overt type 2 diabetes occursufficient insulin, and overt type 2 diabetes occur

Insulin resistance is associated with a clustering of CVInsulin resistance is associated with a clustering of CV

risk factors that predispose patients with this metabolicrisk factors that predispose patients with this metabolicsyndrome to later CV eventssyndrome to later CV events

There is evidence ofThere is evidence ofsympathetic nervous systemsympathetic nervous system

activationactivation that may contribute to the hypertension thatthat may contribute to the hypertension that

develops.develops.

I li i t dI li i t d


46/65

Insulin resistance syndromeInsulin resistance syndrome

Insulin itself promotes vasodilationInsulin itself promotes vasodilation, in part, in partthroughthrough stimulation of endothelial NO releasestimulation of endothelial NO release

This vasodilatory action may beThis vasodilatory action may be

counterbalanced in the insulin resistancecounterbalanced in the insulin resistance

syndrome by the development of hypertension,syndrome by the development of hypertension,

which independently impairs endothelium-which independently impairs endothelium-

dependent vasodilationdependent vasodilation

Endothelin and endothelialEndothelin and endothelial


47/65

dysfunction in diabetesdysfunction in diabetes

Endothelin-1Endothelin-1, a 21-amino-acid peptide, is the, a 21-amino-acid peptide, is thepredominant isoform of the endothelin peptidepredominant isoform of the endothelin peptide

family that includes ET-2, ET-3, and ET-4family that includes ET-2, ET-3, and ET-4

Endothelin-1Endothelin-1 is produced primarily byis produced primarily by

endothelial cells but can also be synthesized byendothelial cells but can also be synthesized byvascular smooth muscle cells (VSMCs) and byvascular smooth muscle cells (VSMCs) and by

macrophagesmacrophages

The action of ET-1 are mediated by 2 receptorThe action of ET-1 are mediated by 2 receptor

subtypes,subtypes, ETETAA and ETand ETBB receptorsreceptors

E d th liEndothelin


48/65

EndothelinEndothelin ETETAA receptorreceptor mediate themediate the vasoconstrictor effectsvasoconstrictor effects of the peptidof the peptide

ETETB receptorsreceptors on the endothelium stimulateson the endothelium stimulates synthesis of NOsynthesis of NO Increased ET-1Increased ET-1 associated with decreased endothelium-associated with decreased endothelium-

dependent vasodilation, a reduction in the biologic actions of Ndependent vasodilation, a reduction in the biologic actions of N

and an increased production of oxygen-derived free radicalsand an increased production of oxygen-derived free radicals

These effects are thought to contribute toThese effects are thought to contribute toheightened vasoconstriction and increased blood pressureheightened vasoconstriction and increased blood pressure

increased monocyte adhesion to the vascular wallincreased monocyte adhesion to the vascular wall

increased thrombosisincreased thrombosis

a vascular inflammatory responsea vascular inflammatory responseaugmented proliferation of VSMCsaugmented proliferation of VSMCs


49/65


50/65


51/65


52/65


53/65

Endothelin in DMEndothelin in DM


54/65

PlasmaPlasma ET-1 are increasedET-1 are increased in type 2 diabetesin type 2 diabetes

Most of the ET-1 cause vasoconstriction of VSMCsMost of the ET-1 cause vasoconstriction of VSMCsthrough a paracrine effect mediated bythrough a paracrine effect mediated by ETETAA receptorsreceptors

Infusion of ET-1 cause sustained increases in BPInfusion of ET-1 cause sustained increases in BP

Nonselective ETNonselective ETAA/ET/ETBB antagonist,antagonist, bosentanbosentan, lowers BP in, lowers BP in

patients with essential hypertensionpatients with essential hypertension PlasmaPlasma ET-1ET-1-may be a-may be a marker for atheroscleroticmarker for atherosclerotic

disease in type 2 diabetic patientsdisease in type 2 diabetic patients

ET-1 participate in the fibrotic process--an essentialET-1 participate in the fibrotic process--an essential

component of the glomerulosclerosis, cardiac andcomponent of the glomerulosclerosis, cardiac and

vascular remodling, and atherosclerosis that occur at anvascular remodling, and atherosclerosis that occur at anaccelerated rate in hypertensive type 2 diabeticsaccelerated rate in hypertensive type 2 diabetics


55/65

The contribution of diminished arterialThe contribution of diminished arterial


56/65

compliance to hypertension in diabetescompliance to hypertension in diabetes

The large conduit arteries, such as aorta, and majorThe large conduit arteries, such as aorta, and majormuscular arteries, such as carotid, brachial, radial,muscular arteries, such as carotid, brachial, radial,

renal, and femoral arteries, tend to becomerenal, and femoral arteries, tend to become lessless

distensible with advancing age and in diabeticdistensible with advancing age and in diabetic ptspts

independent of ageindependent of age

TheThe loss of arterial complianceloss of arterial compliance is associated with anis associated with anincrease in systolic BP, a fall in diastolic BP, and aincrease in systolic BP, a fall in diastolic BP, and a

widening of the pulse pressurewidening of the pulse pressure

Widened pulse pressureWidened pulse pressure is an independent predictoris an independent predictor

of CV risk, more potent than either systolic orof CV risk, more potent than either systolic ordiastolic BPdiastolic BP

Diminished arterial compliance toDiminished arterial compliance to


57/65

hypertension in diabeteshypertension in diabetes

Distensibility is reduced by arterial wall structuralDistensibility is reduced by arterial wall structuralalterations produced by atheroscelrotic plaquesalterations produced by atheroscelrotic plaques

Accompanied by aAccompanied by a change in the protein compositionchange in the protein composition of theof the

extracellular matrix of the arterial wall--as the replacementextracellular matrix of the arterial wall--as the replacement

of elastic collagen withof elastic collagen with less distensible collagenless distensible collagen Expansion of theExpansion of the acellular extracellular matrixacellular extracellular matrix

accompanied by a reduction in vascular wall cellularityaccompanied by a reduction in vascular wall cellularity

Vasoactive substances such asVasoactive substances such as endothelin, angiotensin, andendothelin, angiotensin, and

diminished NOdiminished NO may contribute to these changes in arterialmay contribute to these changes in arterialwall structurewall structure

Advanced glycation end products (AGEs)Advanced glycation end products (AGEs)


58/65

Advanced glycation end products (AGEs)Advanced glycation end products (AGEs)

AGEsAGEs formed by the nonenzymatic binding of glucose toformed by the nonenzymatic binding of glucose to

lipids or to free amino groups on proteinslipids or to free amino groups on proteins The formation of AGEs isThe formation of AGEs is inhibited by NOinhibited by NO, whose biologic, whose biologic

actions are blunted in diabeticsactions are blunted in diabetics

The increased stiffness of the arterial wall contributes toThe increased stiffness of the arterial wall contributes to

isolated hypertensionisolated hypertension The increased systolic pressure in turn produces anThe increased systolic pressure in turn produces an

increased workload on the left ventricle, resulting inincreased workload on the left ventricle, resulting in

increased left ventricular massincreased left ventricular mass

Reduction arterial wall compliance linked to increased CVReduction arterial wall compliance linked to increased CVrisk in type 1 & 2 diabetics and occur early in the course ofrisk in type 1 & 2 diabetics and occur early in the course ofDM before vascular disease is clinically apparentDM before vascular disease is clinically apparent

Adverse consequences associated withAdverse consequences associated with

i f i i i i


59/65

endothelial dysfunction in diabetes mellitusendothelial dysfunction in diabetes mellitus

Decreased NO formation, release, and actionDecreased NO formation, release, and action Increased formation of reactive oxygen speciesIncreased formation of reactive oxygen species

Decreased prostacyclin formation and releaseDecreased prostacyclin formation and release

Increased formation of vasoconstrictor prostanoidIncreased formation of vasoconstrictor prostanoid

Increased formation and release of ET-1Increased formation and release of ET-1 Increased lipid oxidationIncreased lipid oxidation

Increased cytokine and growth factor productionIncreased cytokine and growth factor production

Increased adhesion molecule expressionIncreased adhesion molecule expression

HypertensionHypertension Changes in heart and vessel wall structureChanges in heart and vessel wall structure

Acceleration of the atherosclerotic processAcceleration of the atherosclerotic process


60/65

Endothelial dysfunction in hypertensionEndothelial dysfunction in hypertension

d di b ff f


61/65

and diabetes: effects of treatmentand diabetes: effects of treatment Treatment of HTN with any agent that lowers BP couldTreatment of HTN with any agent that lowers BP could

improve impaired endothelium-dependent vasodilationimprove impaired endothelium-dependent vasodilation BP reduction with nonselective agents may have a differentBP reduction with nonselective agents may have a different

effect in diabetics than in nondiabetics with HTN, becauseeffect in diabetics than in nondiabetics with HTN, becauseshear stress abnormalities seem to contribute to endotheliashear stress abnormalities seem to contribute to endothelial

dysfunction in hypertensives but not in type 2 diabeticsdysfunction in hypertensives but not in type 2 diabetics ACEIACEI seem to be particularly beneficial in improving orseem to be particularly beneficial in improving or

normalizing blunted endothelium-dependent vasodilationnormalizing blunted endothelium-dependent vasodilation

in some patients with type 1 and type 2 diabetesin some patients with type 1 and type 2 diabetes

Recently, restoration of impaired endothelium-dependentRecently, restoration of impaired endothelium-dependent

vasodilation in type 2 diabetics occurred after Tx withvasodilation in type 2 diabetics occurred after Tx withangiotensin II AT1 receptor antagonist, losartanangiotensin II AT1 receptor antagonist, losartan

Effects of treatmentEffects of treatment


62/65


Reduction in the formation of or a blockade of theReduction in the formation of or a blockade of the

action ofaction ofangiotensin IIangiotensin II, a potent, a potent vasoconstrictorvasoconstrictor thatthat

is responsible foris responsible for increasing ROS formation byincreasing ROS formation by

VSMCsVSMCs

Angiotensin II is also either directly or indirectlyAngiotensin II is also either directly or indirectly

responsible for additional vascular effects, includingresponsible for additional vascular effects, includingincreased proinflammatory adhesion moleculeincreased proinflammatory adhesion molecule

expression, increased cytokine and growth factorexpression, increased cytokine and growth factor

expression, increased ET-1 formation, and anexpression, increased ET-1 formation, and anincrease in endothelial scavenger receptors forincrease in endothelial scavenger receptors for

oxidized LDL cholesteroloxidized LDL cholesterol



63/65


Thus, ACEI inhibit all these deleterious downstreamThus, ACEI inhibit all these deleterious downstreameffects and potentiate the action of bradykinin byeffects and potentiate the action of bradykinin by

inhibiting its breakdowninhibiting its breakdown

These selective angiotensin II-mediated adverseThese selective angiotensin II-mediated adverse

effects on the vasculature, on the heart, and on theeffects on the vasculature, on the heart, and on thekidney may account for thekidney may account for the substantial benefit onsubstantial benefit on

morbidity and mortalitymorbidity and mortality observed in diabetic patientsobserved in diabetic patients

at risk for CV and renal disease treated with an ACEat risk for CV and renal disease treated with an ACE

inhibitor compared with placeboinhibitor compared with placebo

Summary (1)Summary (1)


64/65

Summary (1)y ( ) There is compelling evidence for endothelial dysfunctionThere is compelling evidence for endothelial dysfunction

in both type 1 and type 2 diabeticsin both type 1 and type 2 diabetics This dysfunction is manifest as blunting of the biologicThis dysfunction is manifest as blunting of the biologic

effect of a potent endothelium-derived vasodialtor, NO,effect of a potent endothelium-derived vasodialtor, NO,

and increased production of vasoconstrictors such asand increased production of vasoconstrictors such as

angiotensin II, ET-1, and cyclooxygenase andangiotensin II, ET-1, and cyclooxygenase and

lipoxygenase products of arachidonic acid metabolismlipoxygenase products of arachidonic acid metabolism These agents and other cytokines and growth factorsThese agents and other cytokines and growth factors

whose production they stimulate cause acute increases inwhose production they stimulate cause acute increases in

vascular tone, resulting in increases in BP, and vascularvascular tone, resulting in increases in BP, and vascular

and cardiac remodling that contributes to theand cardiac remodling that contributes to themicrovascular, macrovascular, and renal complicationsmicrovascular, macrovascular, and renal complications

in diabetesin diabetes

Summary (2)Summary (2)


65/65

S y ( )y ( )

Reactive oxygen speciesReactive oxygen species, overproduced in, overproduced indiabetics, serve as signaling molecules thatdiabetics, serve as signaling molecules that

mediate many of the cellular biochemicalmediate many of the cellular biochemical

reactions that result in these deleterious effectsreactions that result in these deleterious effects

Treatment withTreatment with antioxidantsantioxidants and withand withinhibitors of the renin-angiotensin systeminhibitors of the renin-angiotensin system maymay

reverse some of the pathologic vascularreverse some of the pathologic vascular

changes associated with endothelialchanges associated with endothelial

dysfunctiondysfunction

pathophysiology of hypertension and endothelial dysfunction in patients joice

Documents