Vasodilates

1. Vasodilates Michael Evans April 17, 2008

2. Overview • History • Purposes of vasodilates • Mechanisms of different vasodilates • Commonly used vasodilators, for therapeutic effects

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

4. 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

5. 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

6. Blood Vessels

7. Homeostatic Mechanisms • Baroreceptors • Constant monitor • Neck/chest most important • When there is a change in blood pressure, physiologic mechanisms triggered

8. 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

9. 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

10. 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

11. 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

12. 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 GTP cGMP

13. cGMP Mechanisms of Action • Second messenger • Activates intracellular protein kinases [pk’s] • cGMP relaxes smooth muscles

14. 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

15. Bradykinin • 9-AA Peptide Chain • Released from Venules • Endothelium-dependent vasodilator • Broken down by Angiotensin-converting enzyme (ACE)

16. Exogenous [from outside the body] Vasodilators • Quiet, dark • Adenosine antagonists • Alpha-blockers • Amyl nitrite - popper • Alcohol [ethanol] • Histamine-inducers • Nitric Oxide Inducers • THC

17. 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

18. 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

19. 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

20. More on Alpha Adrenergic Receptors

21. Nitric Oxide [NO] Inducers • Glyceryl trinitrate (Nitroglycerin) • Prodrug, must be denitrated to produce active NO • Once active, these nitrates are called “nitrovasodilators”

22. 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

23. 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

24. 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.

25. Nitroglycerin • 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

26. 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

27. Viagra (sildenafil citrate) • More than 65% of men with high blood pressure also have ED. • PDE5 Inhibitor • Side Effects • Priaprism • Sudden blindness

28. OTC Vasodilates • Preworkout supplements • Taken 30 minutes before exercise • Stimulate L-Arginine pathway, along with NOS

29. Sources • http://nobelprize.org/nobel_prizes/medicine/laureates/1998/index.html • http://en.wikipedia.org/wiki/Nitric_oxide • http://www.medicinenet.com/nitroglycerin/article.htm • http://www.medicinenet.com/ace_inhibitors/article.htm • http://www.seloken.com/3430_9816.aspx?l1=&l2=&mid= • ^ S. Rosen and P. Olin, Hearing Loss and Coronary Heart Disease, Archives of Otolaryngology, 82:236 (1965) • http://en.wikipedia.org/wiki/Environmental_noise#cite_note-7 • http://en.wikipedia.org/wiki/Adrenergic_receptor#Alpha_.CE.B1_receptors • http://health.nytimes.com/health/guides/disease/coronary-heart-disease/other-medications.html • http://www.merck.com/mmhe/print/sec03/ch023/ch023a.html • http://en.wikipedia.org/wiki/Bradykinin • http://content.answers.com/main/content/wp/en-commons/thumb/4/47/220px-Nitroglycerin-2D-skeletal.png • http://en.wikipedia.org/wiki/Amitriptyline • http://wwwchem.csustan.edu/chem4400/SJBR/Image1.gif • http://fig.cox.miami.edu/~cmallery/150/memb/fig11x12.jpg • http://www.usm.maine.edu/~newton/Chy251_253/Lectures/BiopolymersIII/BradykininPrimary.gif • http://www.mc.uky.edu/pharmacology/images/ped_fin2.gif • http://en.wikipedia.org/wiki/PDE5_inhibitor