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Pathophysiology of HypertensionPathophysiology of Hypertension
and Endothelial Dysfunction inand Endothelial Dysfunction in
Patients With Diabetes MellitusPatients With Diabetes Mellitus
January 24January 24thth 20032003
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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
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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
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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
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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
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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
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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
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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
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Endothelial dysfunction in DMEndothelial dysfunction in DM
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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
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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
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Endothelium-dependent vasodilator and vasoconstrictor mechanisms
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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.
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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
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M h i f i i dM h i f i i d d th lid th li
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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 --))
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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.
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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)
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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
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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
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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
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F 2+ C bi l i lFe 2+ Cu can cause biological
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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
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Source of OHSource of OH.. Might be theMight be the
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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
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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
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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
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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
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A i id
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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
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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
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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
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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
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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
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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
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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
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Endothelin in DMEndothelin in DM
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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
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The contribution of diminished arterialThe contribution of diminished arterial
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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
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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)
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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
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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
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Endothelial dysfunction in hypertensionEndothelial dysfunction in hypertension
d di b ff f
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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
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Effects of treatmentEffects of treatment
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
Effects of treatmentEffects of treatment
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Effects of treatmentEffects of treatment
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)
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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)
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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