Beneficial Actions of Nitrates in
`Cardiovascular Disease
`
`Jonathan Abrams, MD
`
`Nitroglycerin and the long-acting nitrates have been
`with lower systolic and diastolic pressures. These
`changes are caused by a redistribution of the circu-
`used in cardiovascular medicine for >100 years.
`lating blood volume away from the heart to the ve-
`Nitrates are widely utilized for the various anginal
`syndromesandarealso used in congestive heart fail-
`nous capacitance system, with a fall in venous return
`ure and patients with left ventricular dysfunction. The
`to the heart. Theafterloadorarterial effects of nitrates
`are alsouseful in decreasing myocardial oxygen con-
`potential mechanisms for relief of myocardial isch-
`emia with nitrates are multiple. The nitrovasodilators
`sumption. Considerable evidence confirmsa variety of
`are a related group of drugs thatresult in the forma-
`mechanisms whereby nitrates
`increase coronary
`blood flow, including epicardial coronary artery di-
`tion ofnitric oxide (NO) within vascular smooth mus-
`lation, stenosis enlargement, enhancedcollateral size
`cle cells. NO stimulates the enzyme guanylate cyclase,
`and flow,
`improvement of endothelial dysfunction,
`which results in increases in cyclic guanosine mono-
`phosphate and vasodilation. In the presence of ath-
`and prevention or reversal of coronary artery vaso-
`erosclerosis, endothelial dysfunction is ubiquitous and
`constriction. These effects help increase nutrient cor-
`associated with decreased NO availability, probably
`onary blood flow to zones of myocardial ischemia.
`due to increased destruction of NO byfree radical
`Recent data with the nitroglycerin patch confirm that
`myocardialischemia is decreased after nitrate admin-
`anions. Nitrovasodilators, including the nitrates, sup-
`ply exogenous NOto the vascular wall and improve
`istration. Nitroprusside, another nitrovasodilator, is a
`the vasodilator state. Whennitrates are administered,
`commonly used intravenous agent for lowering arte-
`endothelial-dependentstimuli cause relaxation rather
`rial pressure andleft ventricularfilling pressure. This
`than constriction in the setting of endothelial dys-
`drug is highly effective for the treatment of acute or
`function. Nitrates also have antiplatelet effects, and
`severe hypertension and congestive heart failure.
`recent evidence confirms that these drugs decrease
`However,there are data suggesting thatnitroprusside
`platelet aggregation and thrombosis formation. This
`may be deleterious in the presence of acute myocar-
`may play an important role in the therapy of acute
`dial ischemia, perhaps by shunting blood away from
`unstable myocardial ischemia, including unstable an-
`zones of jeopardized myocardial blood flow. There-
`fore, nitroprusside cannot be recommended to treat
`gina and myocardialinfarction. Nitrate hemodynamic
`effects have been long known. They are primarily
`myocardial ischemia; intravenousnitroglycerin should
`modulated through a decrease in myocardial work
`be used in this context.
`that results from smaller cardiac chambers operating
`{Am J Cardiol 1996;77:31C-37C)
`INGtroetycenn (NTG) and the long-acting ni-
`trates are used by physicians for a variety of
`cardiovascular conditions (Table I). The primary
`role of these drugsis in the prophylaxis and treat-
`ment of myocardial ischemia in subjects with cor-
`onary atherosclerosis. Less well knownis their ef-
`ficacy in ameliorating the signs and symptomsof
`congestive heart failure and left ventricular dys-
`function. In intravenous formulation, NTG is used
`to treat severe hypertension and to control blood
`pressure in the operating room during certain sur-
`gical procedures. Important advantages of the ni-
`trates relates to their many mechanismsof action;
`their proven efficacy in many cardiovascular dis-
`eases; and their reassuring safety and adverseef-
`fect profile. The dominant negativesofnitrate ther-
`apy include headache and nitrate tolerance. The
`latter is discussed in detail elsewhere in this sym-
`posium. Table II outlines the various mechanisms
`
`of action ofthe nitrates as they relate to the clinical
`syndromes for which these agents are used.
`
`NITRATES AND MYOCARDIAL
`ISCHEMIA
`The initial utilization of NTG in medicine wasfor
`acute attacks of angina pectoris. This indication re-
`mains the most importantrole for these agents. Thus,
`sublingual or oral spray NTG or,
`less commonly,
`sublingual isosorbide dinitrate (ISDN) remain the
`worldwide gold standards for relief of anginal chest
`pain. Intelligent preadministration of these drugs be-
`fore anticipated physical activity or emotional stress
`is an important but infrequently utilized approach to
`the prevention of angina. Most of the known mech-
`anismsofnitrate action can be invoked as being im-
`portant in preventing or eliminating myocardial isch-
`emia.It is likely that different actions are more (or
`less) importantin individual patients, in whom there
`are a variety of ways for myocardial ischemia to be
`triggered. Several recent reports of transdermal NTG
`in patients with chronic stable angina demonstrate
`the potency and efficacy of nitrates in alleviating
`exercise
`
`Human Power of N Company
`EX1019
`Page | of 7
`
`From the Department of Medicine (Cardiclogy), University of New
`Mexico School of Medicine, Albuquerque, New Mexico.
`Addressfor reprints: jonathan Abrams, MD, Department of Med-
`icine, University cf New Mexico School of Medicine, 2211 Lomas
`Boulevard NE, Albuquerque, New Mexico 87131.
`
`©1996 by Excerpta Medica, Inc.
`All rights reserved.
`
`Human Power of N Company
`EX1019
`Page 1 of 7
`
`

`

`Beneficial Actiohs of Nitrates in Cardiovascular Disease Jonathan Abrams, MD Nitroglycerin and the long-acting nitrates have been used in cardiovascular medicine for > 100 years. Nitrates are widely utilized for the various angina1 syndromes and are also used in congestive heart fail- ure and patients with left ventricular dysfunction. The potential mechanisms for relief of myocardial isch- emia with nitrates are multiple. The nitrovasodilators are a related group of drugs that result in the forma- tion of nitric oxide (NO) within vascular smooth mus- cle cells. NO stimulates the enzyme guanylate cyclase, which results in increases in cyclic guanosine mono- phosphate and vasodilation. In the presence of ath- erosclerosis, endothelial dysfunction is ubiquitous and associated with decreased NO availability, probably due to increased destruction of NO by free radical anions. Nitrovasodilators, including the nitrates, sup- ply exogenous NO to the vascular wall and improve the vasodilator state. When nitrates are administered, endothelial-dependent stimuli cause relaxation rather than constriction in the setting of endothelial dys- function. Nitrates also have antiplatelet effects, and recent evidence confirms that these drugs decrease platelet aggregation and thrombosis formation. This may play an important role in the therapy of acute unstable myocardial ischemia, including unstable an- gina and myocardial infarction. Nitrate hemodynamic effects have been long known. They are primarily modulated through a decrease in myocardial work that results from smaller cardiac chambers operating with lower systolic and diastolic pressures. These changes are caused by a redistribution of the circu- fating blood volume away from the heart to the ve- nous capacitance system, with a fall in venous return to the heart. The afterload or arterial effects of nitrates are also useful in decreasing myocardial oxygen con- sumption. Considerable evidence confirms a variety of mechanisms whereby nitrates increase coronary blood flow, including epicardial coronary artery di- lation, stenosis enlargement, enhanced collateral size and flow, improvement of endothelial dysfunction, and prevention or reversal of coronary artery vaso- constriction. These effects help increase nutrient cor- onary blood flow to zones of myocardial ischemia. Recent data with the nitroglycerin patch confirm that myocardial ischemia is decreased after nitrate admin- istration. Nitroprusside, another nitrovasodilator, is a commonly used intravenous agent for lowering arte- rial pressure and left ventricular filling pressure. This drug is highly effective for the treatment of acute or severe hypertension and congestive heart failure. However, there are data suggesting that nitroprusside may be deleterious in the presence of acute myocar- dial ischemia, perhaps by shunting blood away from zones of jeopardized myocardial blood flow. There- fore, nitroprusside cannot be recommended to treat myocardial ischemia; intravenous nitroglycerin should be used in this context. (Am J Cardiol 1996;77:3 1 C-37C) N itroglycerin (NTG) and the long-acting ni- trates are used by physicians for a variety of cardiovascular conditions (Table I). The primary role of these drugs is in the prophylaxis and treat- ment of myocardial ischemia in subjects with cor- onary atherosclerosis. Less well known is their ef- ficacy in ameliorating the signs and symptoms of congestive heart failure and left ventricular dys- function. In intravenous formulation, NTG is used to treat severe hypertension and to control blood pressure in the operating room during certain sur- gical procedures. Important advantages of the ni- trates relates to their many mechanisms of action; their proven efficacy in many cardiovascular dis- eases; and their reassuring safety and adverse ef- fect profile. The dominant negatives of nitrate ther- apy include headache and nitrate tolerance. The latter is discussed in detail elsewhere in this sym- posium. Table II outlines the various mechanisms From the Department of Medicine [Cardiology), University of New Mexico School of Medicine, Albuquerque, New Mexico. Address for re icine, University o P rints. Jonathan Abrams, MD, Department of Med- New Mexico School of Medicine, 22 1 1 lomas Boulevard NE, Albuquerque, New Mexico 8713 1. 0 1996 by Excerpto Medica, Inc. All rights reserved. of action of the nitrates as they relate to the clinical syndromes for which these agents are used. NITRATES AND MYOCARDIAL ISCHEMIA The initial utilization of NTG in medicine was for acute attacks of angina pectoris. This indication re- mains the most important role for these agents. Thus, sublingual or oral spray NTG or, less commonly, sublingual isosorbide dinitrate (ISDN) remain the worldwide gold standards for relief of angina1 chest pain. Intelligent preadministration of these drugs be- fore anticipated physical activity or emotional stress is an important but infrequently utilized approach to the prevention of angina. Most of the known mech- anisms of nitrate action can be invoked as being im- portant in preventing or eliminating myocardial isch- emia. It is likely that different actions are more (or less) important in individual patients, in whom there are a variety of ways for myocardial ischemia to be triggered. Several recent reports of transdermal NTG in patients with chronic stable angina demonstrate the potency and efficacy of nitrates in alleviating exercise-induced myocardial ischemia.“* Although 0002.9149/96/$15.00 31c PII SOOO2-9149(96)00186-5
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`Page 1 of 7
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`TABLE I Clinical Indications for Nitrates Condition l Acute attacks of angino pectoris l Prophylaxis of chronic stable angina l Unstable ongino l Acute myocardial infarction -Control of chest pain and ischemia -Hypertension, acute heart failure -Routine 24-48 hour infusion of intravenous NTG l Post-MI left ventricular remodeling l Chronic congestive heart failure l Acute heart failure/pulmonary edema l Hypertension Comments Highly effective Comparable efficacy to calcium and beta blockers. Tolerance o problem Intravenous nitroglycerin (NTG) very useful Often effective: use sublingual, intravenous NTG. Caution to avoid hypotension Very useful; intravenous or high-dose topical little positive data; consider in large anterior myocordial infarction (MI) Limited positive data. Uncertain benefits Useful adjunct to angiotensinconverting enzyme (ACE) inhibitors-can use with hydrolozine. Consider for all symptomatic subjects on ACE inhibitors and digitalis Highly effective-especially intravenous NTG Useful in intravenous formulation. limited positive doto in systolic hypertension of the elderly in oral formulotion TABLE II Mechanism of Action of Nitrates: Relationship to Clinical Indications* Acute attacks and prophylaxis of stable angina pectoris Decreased myocordiol oxygen consumption -Decreased LV dimension -Decreased LV filling pressure -Decreased LV systolic pressure -Decreased vascular impedence Increased coronary blood supply -Epicardial coronary artery dilation -Coronary stenosis enlorgement Unstable angina Acute myocardial infarction Congestive heart failure Systolic dysfunction -Improved coronary endotheliol function -Dilaton of coronary collaterals or small distal coronary vessels Same OS above, plus ontiplotelet antithrombotic action Same as above, plus antiplatelet ontithrombotic action Decreased LV and RV dimensions (few data in congestive heart failure) Decreased LV and RV filling pressure Decreased orterial pressure Decreased systemic vascular resistance Decreased PA and RA pressure Improved endothelial function Diastolic dysfunction Hypertension Coronary artery disease patients: increased coronary blood flow Decreased mitral regurgitation Decreased LV filling pressure Decreased systolic blood pressure Decreased systemic vascular resistance Decreased LV prelood, uncertain importance * LV = left ventricular; PA = pulmonary artery; RA = right otrial; RV = right ventricular. these studies do not provide insight as to the pre- cise mechanisms of NTG action in reducing myo- cardial ischemia in a given subject, they carefully document and quantitate the magnitude of im- provement in ischemia reduction that is induced by the drug (Figure l).’ Another recent study con- firms earlier work suggesting that nitrates improve nutrient coronary blood flow to regional zones of myocardial ischemia.3 MECHANISMS OF ACTION OF THE NITROVASODIIATORS The nitrovasodilators are a related group of drugs that result in the formation and release of nitric oxide (NO) from the parent molecule (Table III). A va- riety of metabolic or biochemical steps exist for these agents; some (the organic nitrates) are enzymatically converted to NO. Nitroprusside and molsidomine form NO directly. Many new NO donors are cur- rently under investigation. This discussion will em- phasize NTG, nitroprusside, ISDN, and isosorbide- 5mononitrate (ISMN) . Cellular mechanisms: NTG, as the prototype com- pound, is a short-lived agent with a half-life of sev- eral minutes. It is rapidly converted to NO at or near the plasma membrane of the vascular smooth muscle cell. For years it was believed that NTG goes through a stepwise denitration process re- sulting in the release to NO, but it appears that NTG directly forms either NO itself or a nitrosy- lated entity known as a nitrosothio14 (Figure 2). The conversion of NTG (and the other nitrates) to NO is enzymatic. The enzyme has been partially characterized; of potential importance, a thiol moi- ety forms part of the enzyme structure.” Nitrate ox- ide or nitrosothiols formed from NTG activate the cytoplasmic enzyme guanylate cyclase (Figure 2). This catalyzes the formation of cyclic guanosine monophosphate from guanosine diphosphate. Cy- 32C THE AMERICAN jOURNA1 OF CARDIOLOGY@ VOL. 77 MAY 30, 1996
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`clic guanosine monophosphate, a second messen- ger, induces a shift in intracellular calcium within the sarcoplasmic reticulum, resulting in a transient fall in intracellular calcium and subsequent vaso- relaxation.6 Nitroprusside and molsidomine pro- duce NO in a nonenzymatic fashion; nitrate toler- ance does not appear to be a problem with these compounds. Endothelial function: It has been known for some time that arterial vasomotor function is predomi- nantly related to phasic release of a NO-like sub- stance from endothelial cells. NO itself (or a close intermediate) is produced in endothelial cells in response to vascular shear stress or a variety of receptor-mediated stimuli (e.g., serotonin, thrombin, histamine). This process, which is mediated by a putative endothelium-derived relaxing factor (EDW, ’ is responsible for vasodilation of large arteries and the microcirculation. Prostacyclin, a cyclic adenosine monophosphate-mediated vaso- dilator, is also involved in endothelial cell regu- lation of vasodilation. EDRF (NO) is involved in other important functions of the endothelium, including antiplate- let and antithrombotic activity and processes that impede or suppress smooth muscle cell prolifera- tion and atherosclerosis. Although most available data regarding EDRF involves its vasodilating ac- tions, many believe that normal or abnormal EDRF production or degradation is intimately related to fundamental characteristics of the vascular wall it- self, including smooth muscle cell function and atherogenesis.’ Endothelial dysfunction and nitrates: Abnormal en- dothelial function has been well documented in cor- onary atherosclerosis. Most of this research involves endothelial modulation of vasomotor function and documents impaired vasodilator responses to a va- riety of stimuli in the presence of abnormal endothe- lial function in atherosclerotic blood vessels. The dominant finding in such studies is a derangement of maximal or normal dilator capacity. In the presence of overt atherosclerosis, and also in apparently nor- mal arteries in subjects with diabetes, high choles- terol, hypertension, or heart failure, endothelial va- sodilator capacity is impaired.’ The administration of NTG or other nitrates results in normal or near- normal vasodilation, presumably because the nitrate directly supplies NO to the vascular endothelium and smooth muscle in the media.*-” It is believed that endothelial dysfunction in humans is often caused by accelerated destruction of EDRF and NO, prob- ably due in part to the presence of excess oxygen- free radical activity.” Patients with an elevated low density cholesterol, hypertension, or a history of smoking often have an impairment of endothelial vasodilator responsive- ness. Further, the presence of overt atherosclerosis is an important marker that endothelial dysfunction is present; the greater the severity of the atheroscle- rotic process, the more the impairment of endothe- lial-modulated vasodilation. Abnormal responses to FIGURE 1. Nitroglycerin patch efficacy in reducing exercise-in- duced ischemia in patients with angina. Mean and individual po- tient changes in exercise-induced left ventricular (1~) perfusion defects from study 1 (baseline placebo patch) to study 2 (active nitrate versus cantly reduc fxr lacebo patch). Nitroglycerin patch therapy signifi- the mean quantitative thallium perfusion defect size compared with placebo therapy (‘p = 0.04). Bold lines indi- cate the 7 patients receiving active patch therapy who reduced their perfusion defect size by 2 10% (absolute). (Reprinted with permission from I Am Co// Car&o/.‘) I SmJDvl mJDY2 mum1 muDv2 TABLE III Nitrovasodilators Exogenous Currently available in the United States Nitroglycerin lsosorbide dinitrate Isosorbide5mononitrate Sodium nitroprusside Not available or approved in the United States Nicorandil (also a K’ channel blocker) Molsidomine (converted to SIN-l, the active moiety, in the liver) Nitrosothiols [research only) Endogenous Endothelium-derived relaxing factor (nitric oxide or closely related compound) exogenous endothelial-dependent stimuli (e.g., ace- tylcholine, reactive hyperemia) are proportional to the degree of atherosclerosis. Coronary stenosis con- striction is an advanced form of endothelial dys- function; it is likely that transient decreases in the caliber of atherosclerotic lesions are important trig- gers of myocardial ischemia. Nitrates, through their capacity to provide NO di- rectly to the arterial media, are categorized as en- dothelial independent vasodilator agents.‘-” Thus, NTG, nitroprusside, and the other organic nitrates result in predictable near-normal coronary vasodi- lation in the presence of endothelial dysfunction. This has led to the concept that nitrates act as ex- ogenous EDRF-like agents, supplying or replenish- ing NO to the vessel wall when normal NO avail- ability is diminished by disease processes.*-” This construct points to the potentially unique role of ni- trovasodilators in patients with vascular disease, hy- pertension, or heart failure, states often associated A SYMPOSIUM: NITRATES IN HEART FAllURE 33C
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`ENOOTHELIUM VASCULAR SMOOTH MUSCLE 1 NO S-nitrosothiol’ RSH ,I J (RSNO) - RSNO:: . . Endothelium -dependent *EDRF vosodi lotors I / * FIGURE 2. Nitrovasodilators, endo- thelium-dependent vasodilators, and vascular smooth muscle relaxation. EDRF = endothelium-derived relaxing factor; GC = guanylate cyclase; GTP = guanosine triphosphate; NO = ni- tric oxide; R’SH and RSH = 2 distinct pools of intracellular sulfhydryl groups; R’SSR’ = disulfide roups. (Re rinted with permission !r om Ko- wa uk E, Fung H-L. Pharmacology P and phannacokinetics of nitrates. In: Abrams J, Pepine C, Thadani U, eds. Medical Therapy of lschemic Heart Disease: Nitrates, Beta Blockers, and Calcium Antagonists. Boston: Little, Brown, 1992: 152.) with NO penia. Of interest, in the presence of normal or intact endothelial function, NTG appears to have a lessened vasodilator capability, perhaps in part re- lated to continuous basal release of NO by the en- dothelial cell layer decreasing the potential maximal vasorelaxation induced by nitrate-derived NO. In any case, the concept of exogenous EDRF (NO) supplied by NTG and the organic nitrates, is useful, and helps explain the efficacy of these rather old-fashioned drugs in patients with vascular abnor- malities. 8-‘“,‘2,13 Prevention or reversal of coronary artery and atherosclerotic lesion vasoconstriction, l3 or overt coronary spasm, are more readily explained in the context of NO supplementation from an ex- ogenous pharmaceutic NO donor. Nitrates and thrombosis: It has been long recog- nized that NTG and other organic nitrates have an antiaggregatory effect on platelet function. The re- sults of early experiments were controversial, how- ever, and the actual importance of nitrate antiplatelet action has been clouded by uncertainty. In recent years, however, considerable evidence has become available supporting a robust role for these agents in interfering with platelet function and subsequently decreasing platelet thrombotic activity. A variety of animal and human studies have confirmed important nitrate antiplatelet actions in this regard.14-17 Although it is difficult to attribute a beneficial contribution of nitrates in chronic stable angina re- lated to platelet and antithrombotic actions, it is ob- vious that a significant anti-platelet-thrombotic ef- fect could be important in patients with unstable angina or acute myocardial infarction. These so- called syndromes of acute myocardial ischemia are associated with focal and perhaps generalized en- dothelial dysfunction; platelets help initiate the thrombotic cascade leading to intraluminal or mural thrombus and ongoing platelet-thrombin activation, which would be favorably affected by nitrate anti- platelet. activity. Such nitrate actions would lead to decreased coronary artery spasm or vasoconstriction, particularly at or near the site of intimal disruption. These nitrate effects, in addition to a nitrate related decrease in myocardial oxygen consumption and in- crease in nutrient coronary blood flow, should be salutary in such patients. HEMODYNAMIC ACTIONS Nitrates dilate veins, arteries, and arterioles through the previously described cascade of intra- cellular events leading to NO production and acti- vation of cyclic guanosine monophosphate (Figure 2). In the smaller, distal vessels of the microcircu- lation, NTG and the organic nitrates appear to have little vasodilator capacity, perhaps because the en- zyme responsible for nitrate bioconversion to NO is not present in these vessels.9 Veins take up nitrates more avidly than arteries, and venodilation is pro- nounced at lower plasma concentration of nitrate. Nitroprusside is a potent vasodilator; at relatively low infusion rates, nitroprusside is more active than NTG in dilating arteries and arterioles. Further, ni- troprusside relaxes the microcirculation and is more likely to decrease coronary resistance than NTG (see below ) . The classic view of nitrate hemodynamic actions relates to pronounced venodilation with an increase in blood volume in the venous capacitance beds. In effect, nitrates induce an autotransfusion of blood away from the heart and lungs to the splanchnic and peripheral circulations. Less blood returns to the right heart; preload falls, and cardiac output and stroke volume typically decrease. NTG is a potent and reliable agent for decreasing left and right ven- tricular filling pressure in the normal heart, as well as in subjects with congestive heart failure and high pulmonary capillary pressure. Concomitant nitrate actions on pulmonary and aortic compliance and im- pedance result in decreases in systolic pressure in the central circulations. Thus, pulmonary artery and aor- 34C THE AMERICAN JOURNAL OF CARDIOLOGY@ VOL. 77 MAY 30, 1996
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`FIGURE 3. Hemodynamic changes (A) in hemodynamic variables after bolus intravenous nitroglycerin in normal (group 1) (n = 9; E./E, < 1) (solid bars), hypertensive ( roup 2a) (n = 9; E,/E,,> 1; ejection L ction >40%) (hatched bars), and heart fail- ure (group 2b) (n = 9; E./E.,> 1; ejection fraction <40%) (open bars) subiects. Prelood changes, defined OS o decrease in end-diastolic volume (EDV) ore greatest in roup 1 and in- termediate in group 2 % . Afterload changes defined OS a decrease in ef- fective aerial elastance (E,), are greatest in groups 20 and 2b. In- creases in stroke volume (Sv) consis- tent with predominant afterlwd effects ore seen in groups 2a and 2b. Systo L llic blood pressure (BP) decreased in all groups but to a lesser extent in group 2b. *p ~0.05 versus group 1. tp <0.05 versus group 20. (Reprinted with permission from J Am co// Cardio/,‘q tic systolic pressure falls with a relatively small de- cline in diastolic pressures. Peripheral arterial vaso- dilation contributes to an overall reduction in arterial impedance and blood pressure. In the normal heart decreased left and right ventricular preload contrib- ute to the decrease in cardiac output and blood pres- sure. Nitroprusside is more potent in the arterial cir- culation than NTG on a per milligram basis and de- creases arterial pressure to a greater degree than NTG. At high infusion rates and plasma concentra- tions, however, intravenous NTG becomes more po- tent as a dilator of arteries and arterioles, and the drug’s hemodynamic effects become comparable to nitroprusside. The decreases in left ventricular and right ventricular preload and afterload translate into smaller ventricular chamber size, with lower intra- cardiac systolic and diastolic pressures. These mul- tiple actions result in decreased diastolic and systolic left ventricular wall stress, and lower myocardial en- ergy demands.” In the presence of normal left ven- tricular systolic function, stroke volume and cardiac output usually decline following NTG administra- tion. However, in the setting of left ventricular sys- tolic compromise, increased systemic vascular resis- tance, or an elevated afterload, nitrates allow the left ventricle to empty more efficiently, and stroke vol- ume may increase due to nitrate “unloading” ef- fects. I9 Nitroprusside is even more potent in this re- gard. A recent study suggests that the effects of NTG on left ventricle dimensions and stroke volume may be, in part, determined by the underlying state of the circulation. Thus, nitrate hemodynamic actions in the normal heart are different from that in the impaired left ventricle with contractile dysfunction, or in hy- pertensive patients who have an increased resting af- terload (Figure 3 ) . l9 Several differences in nitrate hemodynamic ef- fects are demonstrable in different physiologic states (Table IV). It is important for the clinician to be aware of the diversity of nitrate actions related to the underlying status of the circulation. Further, the rel- evance of nitrate therapy in congestive heart failure becomes quite clear when one recognizes the im- portant physiologic effects of nitrates in this condi- tion. Nitrates are beneficial in heart failure, although large amounts of these drugs are usually necessary to achieve desired hemodynamic goals. CORONARY BLOOD SUPPLY NTG, and presumably the other nitrates, have sig- nificant actions on the coronary circulation (Table II). These are less well recognized than nitrate ef- fects on peripheral veins and arteries. The coronary vasodilating actions of the nitrates probably play a significant role in the prevention and relief of myo- cardial ischemia in many patients with coronary ar- tery disease. Although epicardial coronary artery va- sodilation has been long recognized, and beneficial nitrate effects on coronary collateral size and flow are well known, several mechanisms of action of ni- trates in the coronary bed have only recently been confirmed. These include the salutary effects on cor- onary endothelial dysfunction, discussed before,8-‘0 coronary atherosclerotic stenosis dilation or enlarge- ment, I3 and increased regional coronary blood flow to viable myocardium downstream from a total cor- onary artery obstruction via collateral and distal ves- sel vasodilation.*’ It is quite difficult if not impossible to dissect out the benefits of NTG vis-a-vis decreased myocardial ox- ygen consumption versus increased regional or nutrient myocardial blood flow in a given patient with coronary TABLE IV Hemodynamic Effects of Nitrates in the Normal Circulation and in Congestive Heart Failure with Left Ventricular Contractile Dysfunction Normal LV CHF Blood pressure Decrease No change or modest decrease Heart rate Increase No change LV filling pressure Decrease Decrease Stroke volume Decrease No change or modest increase CHF = congestive heart failure; LV = left ventricular. A SYMPOSIUM, NITRATES IN HEART FAILURE 35c
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`Late Treatment --O--O--,,’ 70 ’ ’ ’ ’ ’ ’ ’ ’ ’ ’ ’ ’ ’ 0 I 2 3 4 5 6 7 6 9 IO II 12 13 WEEKS FIGURE 4. Intravenous nitroprusside in acute myocardial infarc- tion. Approximately 400 patients in each group, nitroprusside versus placebo. Cumulative percentage of patients surviving after early treatment (within 9 hours of onset of acute myocardial in- farction) and late treatment (later than 9 hours). (Reprinted with permission from N Engl I Med.25) artery disease. Perhaps both actions come into play in most subjects. Nevertheless, the recognition that ni- trates improve coronary blood flow to regions of myo- cardium subtended by a coronary stenosis or obstruc- tion represents an enhanced understanding of these valuable agents. Prevention or reversal of coronary ep- icardial artery and microcirculatory vasoconstriction as well as stenosis vasodilation may be quite important in certain individuals. INTRAVENOUS NITRATES: NITROGLYCERIN AND NITROPRUSSIDE Sodium nitroprusside is a more potent arterial va- sodilator than NTG, and nitroprusside has an impor- tant dilating effect on the coronary microcirculation. Although the hemodynamic profile of nitroprusside helps explain its greater efficacy in lowering blood pressure or in the therapy in decompensated conges- tive heart failure, 2’ serious questions have been raised as to whether nitroprusside is completely safe in the presence of coronary artery disease. It is pos- sible that the dilator actions of nitroprusside on the resistance vessels of the coronary circulation may allow for an unwanted diversion of coronary blood flow away from zones of potential or actual myo- cardial ischemia subtended by a tight coronary ste- nosis. This concept has some basis in older animal and human data during acute infarction.22-24 Further, a multicenter trial in acute myocardial infarction demonstrated an increased mortality in patients given a 48-hour nitroprusside infusion, treated within the first 9 hours (Figure 4) .25 Another trial, however, demonstrated a survival benefit with an early nitroprusside infusion in acute infarction.26 Al- though this issue is not resolved, many experts be- lieve that nitroprusside should be avoided in the set- ting of acute myocardial ischemia so as to ii revent a possible “coronary steal” phenomenon27l2 Present guidelines do not include nitroprusside as an anti- ische