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Vasodilates. Michael Evans April 17, 2008. Overview. History Purposes of vasodilates Mechanisms of different vasodilates Commonly used vasodilators, for therapeutic effects. History.

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Michael Evans

April 17, 2008

  • History
  • Purposes of vasodilates
  • Mechanisms of different vasodilates
  • Commonly used vasodilators, for therapeutic effects
  • Nobel Prize in Medicine awarded in 1998 to 3 physicians "for their discoveries concerning nitric oxide as a signalling molecule in the cardiovascular system"
history continued
History, continued
  • Synthesized in 1846, nitroglycerin was first used to treat anginal attacks in 1879. It was granted FDA approval in 1938.
  • Explosion of vasodilator therapy research in the 1970’s
    • When ACE inhibitor therapy first appeared
  • More research in the 80’s and 90’s to determine long-term effects, as usage to garner acute effects has already been proven to work
    • One can build up a tolerance to vasodilators, so dosages must be increased or there must be a nitrate-free interval
  • Since all methods work via different mechanisms and pathways, there’s no such thing as simple “vasodilator research”
    • Nitroprusside
    • Nitrates
    • ACE inhibitors
    • Angiotensin II antagonists
    • Calcium Channel Blockers
  • Nitroprusside, nitrates, hydralazine are direct vasodilators
  • AII antagonists and ACE inhibitors also have indirect components
history continued5
History, continued
  • VHeFTI trial (1986) – first to prove increased survival rates with vasodilator treatment [for patients with Class II and Class III heart failure]
    • Known as a mortality study
  • Vasodilation affects the relationship between mean arterial pressure, cardiac output, and total peripheral resistance
  • Your heart pumps against a constant pressure, and you can damage your heart if TPR is too high [hypertension/high blood pressure]
  • Although blood viscosity [hematocrit-determined] and length of blood vessels contribute to TPR, the most important variable is vessel diameter, which relates directly to surrounding smooth muscle
homeostatic mechanisms
Homeostatic Mechanisms
  • Baroreceptors
    • Constant monitor
    • Neck/chest most important
  • When there is a change in blood pressure, physiologic mechanisms triggered
extreme dilation of blood vessels
Extreme Dilation of Blood Vessels
  • Alcohol
  • Some allergic reactions
  • Some antidepressants
    • amitriptyline
  • Antihypertensive drugs that dilate blood vessels (such as calcium channel blockers, angiotensin-converting enzyme inhibitors, and angiotensin II receptor blockers)
  • Nitrates
  • Bacterial infections
  • Heat
  • Nerve damage (such as that due to diabetes, amyloidosis, or spinal cord injuries)
    • In this case, the homeostatic controls lose their function
endogenous rising from within vasodilators
Endogenous [rising from within] Vasodilators
  • Depolarization, which yields decreased intracellular Ca2+
  • Nitric Oxide Pathway, stimulating cGMP  MLCK pathway, which ends up decreasing intracellular Ca2+
  • Beta-2 Andrenergic Receptor antagonists, histamine, prostaglandins, and prostacyclin
  • VIP
  • Adenosine
  • ATP and ADP
  • L-Arginine
  • Bradykinin
  • Muscle use
endogenous vasodilators hyperpolarization
Endogenous Vasodilators: Hyperpolarization
  • Endothelium-derived hyperpolarizing factor [EDHF]
  • Depolarization, which opens Voltage-gated K+ channels
  • Increase in Interstitial K+
  • All of the above hyperpolarize the membrane, closing voltage-dependent calcium channels, decreasing intracellular Ca2+
  • Effectively the same as Ca2+ channel blockers
hyperpolarization intracellular ca 2
Hyperpolarization: Intracellular Ca2+
  • As you know, muscle contraction occurs when VDCC’s open, allowing Ca2+ to flow into the cell
  • A vasodilator needs to inhibit smooth muscle contraction [around blood vessels]
  • Thus, membrane hyperpolarization to prevent these voltage gated channels from opening works to achieve this goal
endogenous vasodilators nitric oxide
Endogenous Vasodilators: Nitric Oxide
  • Nitric Oxide acts on the lyase enzyme Guanylate Cyclase [GC]
  • This enzyme catalyzes the conversion of GTP to 3’,5’-cyclic guanosine monophosphate [better known as cGMP] and pyrophosphate
  • Because there are multiple GC’s, one membrane-bound and one soluble, it is important to clarify that the NO-receptor is the soluble GC receptor
  • cGMP then regulates cellular proteins, yielding vasodilation



cgmp mechanisms of action
cGMP Mechanisms of Action
  • Second messenger
  • Activates intracellular protein kinases [pk’s]
  • cGMP relaxes smooth muscles
renin angiotensin aldosterone system as it pertains to vasodilation
Renin-Angiotensin-Aldosterone Systemas it pertains to vasodilation
  • RAA system is blocked with ACEI
  • Angiotensin II is turned off
  • This allows indirect acute vasodilatation through withdrawal of angiotensin II and the accumulation of bradykinin (as ACEI are kininases) which also contributes to the vasodilator effect
  • 9-AA Peptide Chain
  • Released from Venules
  • Endothelium-dependent vasodilator
  • Broken down by Angiotensin-converting enzyme (ACE)
exogenous from outside the body vasodilators
Exogenous [from outside the body] Vasodilators
  • Quiet, dark
  • Adenosine antagonists
  • Alpha-blockers
  • Amyl nitrite - popper
  • Alcohol [ethanol]
  • Histamine-inducers
  • Nitric Oxide Inducers
  • THC
environmental factors
Environmental Factors
  • Noise
    • Excessive noise, annoying noise
    • Raise blood pressure, cause hypertension
    • Increased stress shown by study
      • 5-10 point rise in blood pressure, vasoconstriction
  • Light
    • Clinically measurable stress found from overexposure
    • People that work in extremely bright environments are more prone to hypertension
calcium channel blockers
Calcium Channel Blockers
  • Calcium channel blockers reduce heart rate
  • Dilate the blood vessels of the heart
    • Decrease oxygen demand
    • Increase oxygen supply
  • Net drop in BP
alpha blockers
  • Alpha-adrenergic blocking agents
  • In both arteries and smooth muscles
  • The blocked adrenergic receptors are G protein-coupled receptors
    • Catecholamines – adrenaline/noradrenaline[epi/norepi]
    • If catecholamines bind, increased HR, vasoconstriction
  • However, if B-adrenergic receptors are bound by epi or norepi, vasodilation occurs
nitric oxide no inducers
Nitric Oxide [NO] Inducers
  • Glyceryl trinitrate (Nitroglycerin)
  • Prodrug, must be denitrated to produce active NO
  • Once active, these nitrates are called “nitrovasodilators”
mechanisms for denitration
Mechanisms for Denitration
  • Nitroglycerin can be denitrated in many ways
  • There are many hypotheses as to the mechanism of bioactivation
    • Nitrates react with sulfhydryl groups
    • Enzymatic breakdown
      • Glutathione S-transferase, Cytochrome P450, Xanthine oxidoreductase
    • Catalyzed denitration by mitochondrial aldehyde dehydrogenase
  • Ultimately, GTN is broken down into 1,2-glyceryl dinitrate + Free NO
other nitric oxide no inducers
Other Nitric Oxide [NO] Inducers
  • Isosorbide mononitrate & Isosorbide dinitrate
    • Preventatives of angina, reduced heart workload
  • Pentaerythritol Tetranitrate (PETN)
    • Lentonitrat – drug commonly used, pure PETN
    • So reactive…one of the strongest high explosives known
  • Sodium nitroprusside
    • Salt that is a source of NO, often administered via IV
    • For patients with extreme hypertension
  • PDE5 inhibitors: these agents indirectly increase the effects of nitric oxide
    • Sildenafil (Viagra)
    • Tadalafil
    • Vardenafil
now what free no
Now what? Free NO
  • NO is a potent activator of guanylyl cyclase (GC) by heme-dependent mechanisms
  • Activation results in cGMP formation from guanosine triphosphate (GTP)
  • Thus, NO increases the level of cGMP within the cell.
  • GENERIC NAME: nitroglycerin
  • BRAND NAME: Nitro-Bid; Nitro-Dur; Nitrostat; Transderm-Nitro; Minitran; Deponit; Nitrol
  • USES: frequently used to lower blood pressure when treating angina pectoris, and also used during anginal attacks [both as a prevention method, and as an acute treatment]
  • Extended release tablets, translingual spray, and transdermal patches
  • Literature recommends not to stack with other high blood pressure medications, because of additive effects
ace inhibitors
ACE inhibitors
  • Class of Drugs: ACE (angiotensin converting enzyme) inhibitors
  • Generic (Brand Name)
    • captopril (Capoten)
    • benazepril (Lotensin)
    • enalapril (Vasotec)
    • lisinopril (Prinivil, Zestril)
    • fosinopril (Monopril)
    • ramipril (Altace)
    • perindopril (Aceon)
    • quinapril (Accupril)
    • moexipril (Univasc)
    • trandolapril (Mavik)
  • USES:
    • Hypertension treatment
    • Heart failure
viagra sildenafil citrate
Viagra (sildenafil citrate)
  • More than 65% of men with high blood pressure also have ED.
  • PDE5 Inhibitor
  • Side Effects
    • Priaprism
    • Sudden blindness
otc vasodilates
OTC Vasodilates
  • Preworkout supplements
  • Taken 30 minutes before exercise
  • Stimulate L-Arginine pathway, along with NOS
  • ^ S. Rosen and P. Olin, Hearing Loss and Coronary Heart Disease, Archives of Otolaryngology, 82:236 (1965)