VasodilatesVasodilatesMichael EvansMichael Evans

April 17, 2008April 17, 2008

OverviewOverview

HistoryHistory Purposes of Purposes of

vasodilatesvasodilates Mechanisms of Mechanisms of

different different vasodilatesvasodilates

Commonly used Commonly used vasodilators, for vasodilators, for therapeutic effectstherapeutic effects

HistoryHistory

Nobel Prize in Medicine awarded in Nobel Prize in Medicine awarded in 1998 to 3 physicians "for their 1998 to 3 physicians "for their discoveries concerning nitric oxide discoveries concerning nitric oxide as a signalling molecule in the as a signalling molecule in the cardiovascular system" cardiovascular system"

History, continuedHistory, continued Synthesized in 1846, nitroglycerin was first used to treat anginal Synthesized in 1846, nitroglycerin was first used to treat anginal

attacks in 1879. It was granted FDA approval in 1938. attacks in 1879. It was granted FDA approval in 1938. Explosion of vasodilator therapy research in the 1970’sExplosion of vasodilator therapy research in the 1970’s

When ACE inhibitor therapy first appearedWhen ACE inhibitor therapy first appeared More research in the 80’s and 90’s to determine long-term More research in the 80’s and 90’s to determine long-term

effects, as usage to garner acute effects has already been proven effects, as usage to garner acute effects has already been proven to workto work

One can build up a tolerance to vasodilators, so dosages must be One can build up a tolerance to vasodilators, so dosages must be increased or there must be a nitrate-free intervalincreased or there must be a nitrate-free interval

Since all methods work via different mechanisms and pathways, Since all methods work via different mechanisms and pathways, there’s no such thing as simple “vasodilator research”there’s no such thing as simple “vasodilator research”

NitroprussideNitroprusside NitratesNitrates ACE inhibitorsACE inhibitors Angiotensin II antagonistsAngiotensin II antagonists Calcium Channel BlockersCalcium Channel Blockers

Nitroprusside, nitrates, hydralazine are direct vasodilatorsNitroprusside, nitrates, hydralazine are direct vasodilators AII antagonists and ACE inhibitors also have indirect componentsAII antagonists and ACE inhibitors also have indirect components

History, continuedHistory, continued VHeFTI trial (1986) – first to prove increased VHeFTI trial (1986) – first to prove increased

survival rates with vasodilator treatment [for survival rates with vasodilator treatment [for patients with Class II and Class III heart failure]patients with Class II and Class III heart failure] Known as a mortality studyKnown as a mortality study

Vasodilation affects the relationship between Vasodilation affects the relationship between mean arterial pressure, cardiac output, and total mean arterial pressure, cardiac output, and total peripheral resistanceperipheral resistance

Your heart pumps against a constant pressure, Your heart pumps against a constant pressure, and you can damage your heart if TPR is too high and you can damage your heart if TPR is too high [hypertension/high blood pressure][hypertension/high blood pressure]

Although blood viscosity [hematocrit-determined] Although blood viscosity [hematocrit-determined] and length of blood vessels contribute to TPR, the and length of blood vessels contribute to TPR, the most important variable is vessel diameter, which most important variable is vessel diameter, which relates directly to surrounding smooth muscle relates directly to surrounding smooth muscle

Blood VesselsBlood Vessels

Homeostatic Homeostatic MechanismsMechanisms

BaroreceptorsBaroreceptors Constant monitorConstant monitor Neck/chest most Neck/chest most

importantimportant When there is a When there is a

change in blood change in blood pressure, pressure, physiologic physiologic mechanisms mechanisms triggeredtriggered

Extreme Dilation of Blood Extreme Dilation of Blood Vessels Vessels

Alcohol Alcohol Some allergic reactions Some allergic reactions Some antidepressantsSome antidepressants

amitriptyline amitriptyline Antihypertensive drugs that Antihypertensive drugs that

dilate blood vessels (such as dilate blood vessels (such as calcium channel blockers, calcium channel blockers, angiotensin-converting enzyme angiotensin-converting enzyme inhibitors, and angiotensin II inhibitors, and angiotensin II receptor blockers) receptor blockers)

Nitrates Nitrates Bacterial infections Bacterial infections Heat Heat Nerve damage (such as that Nerve damage (such as that

due to diabetes, amyloidosis, due to diabetes, amyloidosis, or spinal cord injuries) or spinal cord injuries)

In this case, the homeostatic In this case, the homeostatic controls lose their functioncontrols lose their function

Endogenous [rising from Endogenous [rising from within] Vasodilatorswithin] Vasodilators

Depolarization, which Depolarization, which yields decreased yields decreased intracellular Caintracellular Ca2+2+

Nitric Oxide Nitric Oxide Pathway, stimulating Pathway, stimulating cGMP cGMP MLCK MLCK pathway, which ends pathway, which ends up decreasing up decreasing intracellular Caintracellular Ca2+2+

Beta-2 Andrenergic Beta-2 Andrenergic Receptor antagonists, Receptor antagonists, histamine, histamine, prostaglandins, and prostaglandins, and prostacyclinprostacyclin

VIPVIP AdenosineAdenosine ATP and ADPATP and ADP L-ArginineL-Arginine BradykininBradykinin Muscle useMuscle use

Endogenous Vasodilators: Endogenous Vasodilators: HyperpolarizationHyperpolarization

Endothelium-derived hyperpolarizing Endothelium-derived hyperpolarizing factor [EDHF]factor [EDHF]

Depolarization, which opens Voltage-gated Depolarization, which opens Voltage-gated K+ channelsK+ channels

Increase in Interstitial K+Increase in Interstitial K+ All of the above hyperpolarize the All of the above hyperpolarize the

membrane, closing voltage-dependent membrane, closing voltage-dependent calcium channels, decreasing calcium channels, decreasing intracellular intracellular CaCa2+2+

Effectively the same as CaEffectively the same as Ca2+2+ channel channel blockersblockers

Hyperpolarization: Hyperpolarization: Intracellular CaIntracellular Ca2+2+

As you know, muscle contraction As you know, muscle contraction occurs when VDCC’s open, allowing occurs when VDCC’s open, allowing CaCa2+2+ to flow into the cell to flow into the cell

A vasodilator needs to inhibit smooth A vasodilator needs to inhibit smooth muscle contraction [around blood muscle contraction [around blood vessels]vessels]

Thus, membrane hyperpolarization to Thus, membrane hyperpolarization to prevent these voltage gated channels prevent these voltage gated channels from opening works to achieve this goalfrom opening works to achieve this goal

Endogenous Vasodilators: Endogenous Vasodilators: Nitric OxideNitric Oxide

Nitric Oxide acts on the Nitric Oxide acts on the lyase enzyme Guanylate lyase enzyme Guanylate Cyclase [GC]Cyclase [GC]

This enzyme catalyzes the This enzyme catalyzes the conversion of GTP to 3’,5’-conversion of GTP to 3’,5’-cyclic guanosine cyclic guanosine monophosphate [better monophosphate [better known as cGMP] and known as cGMP] and pyrophosphatepyrophosphate

Because there are Because there are multiple GC’s, one multiple GC’s, one membrane-bound and one membrane-bound and one soluble, it is important to soluble, it is important to clarify that the NO-clarify that the NO-receptor is the soluble GC receptor is the soluble GC receptorreceptor

cGMP then regulates cGMP then regulates cellular proteins, yielding cellular proteins, yielding vasodilationvasodilation

GTP

cGMP

cGMP Mechanisms of cGMP Mechanisms of ActionAction

Second Second messengermessenger

Activates Activates intracellular intracellular protein kinases protein kinases [pk’s][pk’s]

cGMP relaxes cGMP relaxes smooth musclessmooth muscles

Renin-Angiotensin-Renin-Angiotensin-Aldosterone SystemAldosterone System

as it pertains to vasodilationas it pertains to vasodilation RAA system is blocked with ACEIRAA system is blocked with ACEI Angiotensin II is turned offAngiotensin II is turned off This allows indirect acute This allows indirect acute

vasodilatation through withdrawal of vasodilatation through withdrawal of angiotensin II and the accumulation angiotensin II and the accumulation of bradykinin (as ACEI are kininases) of bradykinin (as ACEI are kininases) which also contributes to the which also contributes to the vasodilator effect vasodilator effect

BradykininBradykinin 9-AA Peptide Chain9-AA Peptide Chain Released from VenulesReleased from Venules Endothelium-dependent vasodilatorEndothelium-dependent vasodilator Broken down by Angiotensin-converting Broken down by Angiotensin-converting

enzyme (ACE)enzyme (ACE)

Exogenous [from outside Exogenous [from outside the body] Vasodilatorsthe body] Vasodilators

Quiet, darkQuiet, dark Adenosine antagonistsAdenosine antagonists Alpha-blockersAlpha-blockers Amyl nitrite - popperAmyl nitrite - popper Alcohol [ethanol]Alcohol [ethanol] Histamine-inducersHistamine-inducers Nitric Oxide InducersNitric Oxide Inducers THCTHC

Environmental FactorsEnvironmental Factors

NoiseNoise Excessive noise, annoying noiseExcessive noise, annoying noise Raise blood pressure, cause hypertensionRaise blood pressure, cause hypertension Increased stress shown by studyIncreased stress shown by study

5-10 point rise in blood pressure, vasoconstriction5-10 point rise in blood pressure, vasoconstriction

LightLight Clinically measurable stress found from Clinically measurable stress found from

overexposureoverexposure People that work in extremely bright People that work in extremely bright

environments are more prone to hypertensionenvironments are more prone to hypertension

Calcium Channel Calcium Channel BlockersBlockers

Calcium channel blockers reduce Calcium channel blockers reduce heart rateheart rate

Dilate the blood vessels of the heartDilate the blood vessels of the heart Decrease oxygen demand Decrease oxygen demand Increase oxygen supplyIncrease oxygen supply

Net drop in BPNet drop in BP

Alpha-BlockersAlpha-Blockers Alpha-adrenergic Alpha-adrenergic

blocking agentsblocking agents In both arteries and In both arteries and

smooth musclessmooth muscles The blocked The blocked

adrenergic receptors adrenergic receptors are G protein-coupled are G protein-coupled receptorsreceptors

Catecholamines – Catecholamines – adrenaline/noradrenaline[epi/norepi]adrenaline/noradrenaline[epi/norepi]

If catecholamines bind, increased HR, If catecholamines bind, increased HR, vasoconstrictionvasoconstriction

However, if B-However, if B-adrenergic receptors adrenergic receptors are bound by epi or are bound by epi or norepi, vasodilation norepi, vasodilation occursoccurs

More on Alpha Adrenergic More on Alpha Adrenergic ReceptorsReceptors

Nitric Oxide [NO] Nitric Oxide [NO] InducersInducers

Glyceryl trinitrate (Nitroglycerin) Glyceryl trinitrate (Nitroglycerin) Prodrug, must be denitrated to Prodrug, must be denitrated to

produce active NOproduce active NO Once active, these nitrates are Once active, these nitrates are

called “nitrovasodilators”called “nitrovasodilators”

Mechanisms for Mechanisms for DenitrationDenitration

Nitroglycerin can be denitrated in many Nitroglycerin can be denitrated in many waysways

There are many hypotheses as to the There are many hypotheses as to the mechanism of bioactivationmechanism of bioactivation Nitrates react with sulfhydryl groupsNitrates react with sulfhydryl groups Enzymatic breakdownEnzymatic breakdown

Glutathione S-transferase, Cytochrome P450, Glutathione S-transferase, Cytochrome P450, Xanthine oxidoreductase Xanthine oxidoreductase

Catalyzed denitration by mitochondrial Catalyzed denitration by mitochondrial aldehyde dehydrogenasealdehyde dehydrogenase

Ultimately, GTN is broken down into 1,2-Ultimately, GTN is broken down into 1,2-glyceryl dinitrate + Free NOglyceryl dinitrate + Free NO

Other Nitric Oxide [NO] Other Nitric Oxide [NO] InducersInducers

Isosorbide mononitrate & Isosorbide dinitrate Isosorbide mononitrate & Isosorbide dinitrate Preventatives of angina, reduced heart workloadPreventatives of angina, reduced heart workload

Pentaerythritol Tetranitrate (PETN) Pentaerythritol Tetranitrate (PETN) Lentonitrat – drug commonly used, pure PETNLentonitrat – drug commonly used, pure PETN So reactive…one of the strongest high explosives knownSo reactive…one of the strongest high explosives known

Sodium nitroprusside Sodium nitroprusside Salt that is a source of NO, often administered via IVSalt that is a source of NO, often administered via IV For patients with extreme hypertensionFor patients with extreme hypertension

PDE5 inhibitors: these agents indirectly increase PDE5 inhibitors: these agents indirectly increase the effects of nitric oxide the effects of nitric oxide Sildenafil (Viagra) Sildenafil (Viagra) Tadalafil Tadalafil Vardenafil Vardenafil

Now what? Free NONow what? Free NO

NO is a potent activator of guanylyl NO is a potent activator of guanylyl cyclase (GC) by heme-dependent cyclase (GC) by heme-dependent mechanisms mechanisms

Activation results in cGMP formation Activation results in cGMP formation from guanosine triphosphate (GTP)from guanosine triphosphate (GTP)

Thus, NO increases the level of Thus, NO increases the level of cGMP within the cell. cGMP within the cell.

NitroglycerinNitroglycerin GENERIC NAME: nitroglycerinGENERIC NAME: nitroglycerin BRAND NAME: Nitro-Bid; Nitro-Dur; Nitrostat; Transderm-BRAND NAME: Nitro-Bid; Nitro-Dur; Nitrostat; Transderm-

Nitro; Minitran; Deponit; NitrolNitro; Minitran; Deponit; Nitrol USES: frequently used to lower blood pressure when treating USES: frequently used to lower blood pressure when treating

angina pectoris, and also used during anginal attacks [both angina pectoris, and also used during anginal attacks [both as a prevention method, and as an acute treatment]as a prevention method, and as an acute treatment]

Extended release tablets, translingual spray, and Extended release tablets, translingual spray, and transdermal patchestransdermal patches

Literature recommends not to stack with other high blood Literature recommends not to stack with other high blood pressure medications, because of additive effectspressure medications, because of additive effects

ACE inhibitorsACE inhibitors Class of Drugs: ACE Class of Drugs: ACE

(angiotensin converting (angiotensin converting enzymeenzyme) ) inhibitorsinhibitors

Generic (Brand Name)Generic (Brand Name) captopril (Capoten)captopril (Capoten) benazepril (Lotensin)benazepril (Lotensin) enalapril (Vasotec) enalapril (Vasotec) lisinopril (Prinivil, Zestril)lisinopril (Prinivil, Zestril) fosinopril (Monopril)fosinopril (Monopril) ramipril (Altace)ramipril (Altace) perindopril (Aceon) perindopril (Aceon) quinapril (Accupril)quinapril (Accupril) moexipril (Univasc)moexipril (Univasc) trandolapril (Mavik)trandolapril (Mavik)

USES:USES: Hypertension treatmentHypertension treatment Heart failureHeart failure

Viagra (sildenafil citrate)Viagra (sildenafil citrate)

More than 65% of men with high More than 65% of men with high blood pressure also have ED. blood pressure also have ED.

PDE5 InhibitorPDE5 Inhibitor Side EffectsSide Effects

PriaprismPriaprism Sudden blindnessSudden blindness

OTC VasodilatesOTC Vasodilates

Preworkout Preworkout supplementssupplements

Taken 30 Taken 30 minutes before minutes before exerciseexercise

Stimulate L-Stimulate L-Arginine Arginine pathway, along pathway, along with NOSwith NOS

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