Life Sciences, Vol . 23, pp . 2539-2542 Printed in the U .S .A .
Pergamon Press
MINIREVIEW BETA-ADRENERGIC BLOCKADE IN ACUTE MYOCARDIAL INFARCTION Robert J .~Lee Department of Pharniacology Arnar-Stone Laboratories McGaw Park, Illinois
There is considerable evidence that cardiac power failure, and thus mortality, following acute myocardial infarction is directly related to the ultimate size of the infarct, i .e ., the amount of damaged myocardium (1,2) . Since blood flow to the region of the infarct is greatly reduced, the rate at which oxygen is consumed by the myocardium (MV0 2 ) becomes an important factor in the development of the infarct . Following experimental occlusion of a major coronary artery, evidence of myocardial ischemia is present within seconds (2) . Available oxygen supplies are rapidly reduced in the central zone of the infarct and contractile function of myocardium in this area quickly ceases . If this is analogous to the clinical situation following acute rt~yocardial infarction (AMI), therapeutic interventions that favorably alter the relationship between oxygen supply and demand in the ischemic area surrounding the central zone of the infarct should result in the salvage of viable myocardium and minimize final infarct size (3) . The pain and anxiety present after acute myocardial infarction leads to an increase in circulating catecholamines (4,5) . In addition, Mueller (6) has shown that following coronary artery ligation, norepinephrine content in coronary venous blood increased, indicating catecholamine release by the ischemic myocardium . This high catecholamine milieu has positive chronotropic and inotropic effects that wastefully increase MV02 (7) leading to extension of infarct size . Furtherniore, the potential for the induction of reentrant ventricular arrhythmias is enhanced 6y increased catecholamine concentration (8) . It seems reasonable, therefore, that blockade of beta-adrenergic receptors in the acutely infarcted heart would be beneficial from the point of view of decreasing MY02 as well as for the antiarrhythmic protection such intervention would confer . Experimental Findings The major determinants of MV02 are heart rate, contractile state and wall tension (9) . Heart rate and myocardial contractile force are decreased by the administration of beta-adrenergic blocking doses ôf propranolol . These effects are, presumably, due to blockade of the stimulant effects of the intrinsic catecholamine concentration . Higher doses of propranolol cause a further direct depression of myocardial contractility and increase in wall tension (10) . Intravenous administration of beta-adrenergic blocking doses of proprano101 (0 .5 - 2 mg/kg, i .v .) to anesthetized, open-chest dogs reduced the heart rate from 130 + 6 to 111 + 4 beats/min, and decreased the average S-T segment elevation, recôrded from several epicardial sites, during coronary artery 0300-9653/78/1225-253902 .00/0 Copyright (c) 1978 Pergamon Press
2540
Acute Myocardial Infarction
Vol . 23, No . 26, 1978
occlusion (3) . Average S-T segment elevation measured in this fashion is an indication of the degree of underlying myocardial ischemia and its reduction during coronary artery occlusion must be due either to decreased MV02 or to redistribution of blood flow into the ischemic area (11,12) via increased collateral flow (13,14) . There is experimental evidence that the favorable effect of propranolol on the oxygen supply/demand ratio may be due to both of these mechanisms (9,15) . The beneficial effects of decreasing heart rate and myocardial contractility would seem to outweigh the possible detrimental effect of increased wall tension since MV02 decreases after propranolol administration (6) . Furthermore, the prolongation of diastole permits a greater time for subendocardial perfusion to occur . This, plus the fact that propranolol may reverse ischemia-induced increases in ventricular diastolic compliance (6), brings about a redistribution of coronary flow from subepicardial to more ischemic, subendocardial regions . The net result of the decrease in MV02 and redistribution of blood flow following propranolol is an increase in p02 in the ischemic region (12), preservation of the microvasculature (16), improvement of ventricular function ( .17) and decreased loss of myocardial CPK (3) . That these hemodynamic effects of propranolol administration may have a practical application in acute myocardial infarction was suggested by the work of Sommers and Jennings (18) . They reported that intravenous administration of propranolol (5 mg/kg) prior to coronary artery occlusion lasting 20 or 25 min markedly decreased the incidence of myocardial necrosis in surviving dogs . Clinical Findings The usefulness of beta-adrener is blockade in the therapy of angina pectoris has been well established 19,20,21) . The major beneficial effect of such therapy is the reduction in cardiac work and, thus, MV02, both at rest and during activity . This reduces the incidence of stress-induced myocardial ischemia in susceptible areas, e .g ., subendocardium, supplied by compromised coronary arteries . The potential of such therapeutic interventions in the salvage of viable ischemic myocardium in AMI is obvious from a theoretical point of view . When the hemodynamic state of the patient with AMI is taken into account, however, there are potential disadvantages to the administration of beta-adrenergic blocking drugs . A reduction in overall ventricular function exists, the extent of which is related to the size of the infarct . In this situation, maintenance of marginal cardiac performance may depend upon comIf this is removed by blockade of the pensatory adrenergic stimulation (22~ . In addition, beta receptors in the heart, congestive heart failure may result . beta-adrenergic blocking agents such as propranolol possess quinidine-like effects which directly depress myocardial contractility and represent further potential hazards . Controversy exists as to whether or not the potential for inducing heart failure precludes the use of pro~ranolol in AMI . The earliest reports of clinical trials of this drug in AMI indicated that propranolol treatment de creased mortality (23,24) . Of particular interest in these studies was the fact that fewer patients in the propranolol-treated group developed heart failure than in the control group although this was not a significant difference . Later studies failed to confirm a reduction in mortality due to propranolol in AMI (25,26 and one, in which critically ill patients were not excluded, reported a. greater tendency toward heart failure in the treated group (25) . These studies demonstrate that propranolol does not increase mortality in AMI nor does it increase the incidence of heart failure except possibly in the critically ill patient . They fail to show, however, whether or not propranolol reduces the extent of myocardial damage in surviving patients .
Vol . 23, No . 26, 1978
Acute Myocardial Infarction
2541
Using a 35-lead serial precordial electrocardîographic technique (an extension of the epicardial mapping technique mentioned above), Maroko et al . (27) reported that propranolol reduced the magnitude of S-T segment elevat~n in patients with uncomplicated infarcts, presumably reflecting a decrease in the degree of ischemia in the area of the infarct . Gold, et al . (28) later confirmed the reduction of S-T segment elevation in Infarctpatients without excessive depression of myocardial function . The results of an extensive hemodynamic study of the effects of intravenous propranolol in AMI (6) showed that the drug improved oxygenation of ischemic myocardium . Decrease in heart rate and myocardial contractility, improvement of ventricular diastolic relaxation and probably a decrease in catecholamine release by ischemic myocardium were the main factors involved in this beneficial effect . The spectre of congestive heart failure due to direct Myocardial depression following propranolol administration in AMI led to experimental studies with practolol, a cardioselective beta-adrenergic blocking agent with intrinsic sympathamtmetic effects . This agent decreased the extent and severity of myocardial ischemic injury, as manifest by epicardial S-T segment elevation, after acute coronary artery occlusion in dogs without depressing ventricular function (29) . Clinical studies utilizing practolol in AMI demonstrate a decrease in precordial S-T segment elevation (30), a decrease in the occurrence of chest pain (31) and a decrease in heart work without signs of manifest heart failure (32) . Recent reports of serious side-effects after prolonged administration of practolol make it unlikely that this agent will be available for future clinical use . All beta-adrenergic receptor blocking agents that have been tested clinically in the treatment of angina pectoris have proven to be effective (33) . The compounds tested include representatives of all five groups classified by Fitzgerald (34) on the basis of associated properties such as selectivity, membrane stabilization and intrinsic sympathomimetic action . Thus, the antianginal efficacy of these agents is due primarily, if not solely, to their beta-adrenergic blocking properties . In conclusion, it seems clear that the decrease in MV02 and the favorable hemodynamic changes following beta-adrenergic blockade în AMI results in the salvage of ischemic myocardium and the reduction of ultimate infarct size . These agents should be used only with extreme caution in patients with borderline congestive heart failure who rely on adrenergic stimulation for adequate myocardial performance . References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10 .
J .N . CORN . Bull . N .Y . Acad . Med . 50 (3), 328-340 (1974 Z . W .B . HOOD, JR . In : Innovations in the dia nosis and mana gnent of acute m ocardial infarction . . rest, L . ener, E .K . C ung an aspar an, e s . 9-278 . F .A . Davis Company, Philadel Phia (1975) . P .R . MAROKI, J .K . KJEKSHUS, B . E . SOBEL, T . WATANABE, J .W . COVELL, J . ROSS, JR ., and E . BRAUNWALD . Circulation 43, 67-82 (1971) . P .C . GAZES, J .A . RICHARDSON, and E .F~4100DS, Circulation 19, G57-661 (1959) . C . VALORI, M . THOMAS, and J . SHILLINGSFORD . Amer . J . Ca r~o1 . 20, 605-617 (1967) . H . MUELLER . Acta . Med . Scand . S u 1 . 587, 177-183 (1976) . W . RAAB, Cardiologia 52, 306-31 A .L . WIT, B . F . HOFFMAI~and M .R . ROSEN . Amer . Heart J . 90, 521-533 (1975) . E .H . SONNENBLICK and C .L . SKELTON . Mod . Conc : Cardiovasc . Dis . _40, 9-16 (1971) . R .J . LEE and S .H . BAKY . Fed . Proc . 35(3), 349 (1976)_ .
2542
11 . 12 . 13 . 14 : 15 . 16 . 17 . 18 . 19 . 20 . 21 . 22 . 23 . 24 . 25 . 26 . 27 . 28 . 29 . 30 . 31 . 32 . 33 . 34 .
Acute Myocardial Infarction
Vol . 23, No . 26, 1978
W .M . FAM and M . McGREGOR . Circ . Res . 22, 649-659 (1968) . M .M . WINBURY, J,R . WEISS and B .B .' HOWE- Eur . J . Pharmacol . 16, 271-277 (1971) . S .F . VATNER, H . BAIG, W .T . MANDERS, H . OCHS and M . PAGANI . J . Clin . Invest . 60, 353-360 (1977) . M .M . RASAIfSSEN, K . A . REIMER, R . A . KLONER and R .B . JENNINGS . Circulation 56, 794-798 (1977) . L-C . BECKER, N .J . FORTUIN and B . PITT, Circ . Res . .28, 263-269 (1971) . R .A . KLONER, M .C . FISHHEIM, R .S . COTRAN, E . BRAUNWALb and P .R . MAROKO . Circulation 56, 872-880 (1977) . Amer . J . Cardiol . _32, 930-936 P .R, MAROKO, P. LIBBY and E . BRAUNWALD . (1973) . H .M, SOMMERS and R .B . JENNINGS . Arch . Intern . Med . 128, 780-789 (1972) . Clin . Med . 29-3 7 Sept . (1970) . R .E, GIANELLY and D .C . HARRISON . B .N,C . PRICHARD and P .M .S . GILLAM . Brit . Heart J . _33, 473-480 (1971) . D .J . COLTART . Brit . Hear t J . 33, 62-64 (1971) . In : Circulator effects and clinical D .C . HARRISON and E .L . ALDERMAF. - 5 Excerpta uses of beta-adrener is blockin dru s . D . . arr son, ster am Me ca, P .J .D . SNOW . Lance t _2, 551-553 ( . 1965) . P .J .D . SNOW . Amer . J Cardiol . 18, 458-459 (1966) . Lancet _2, 917-920 R . BALCON, D .E . JEWITT, J .P,J . DATIIES and S . GRAM . (1966) . J . CALUSEN, M . FELSBY, F .S . JORGENSEN, B .L . NIELSEN, J . ROIN and B . STRANGE . Lancet 2, 920-924 (.1966) . P .R . MAROKO, P . LIBBf(, J .W . COVELL, B .E . SOBEL, J . ROSS, JR . and E . BRAUNWALD . Amer . J . Cardiol . 38, 223-230 (1972) . H .K .GOLD, R .C . LEINBACH and P .R . F4~ROK0 . Amer . J . Cardiol _38, 689-695 (1976) . P . LIBBY, P .R . MAROKO, J .W . COVELL, C .I . MALLOCH, J . ROSS, JR . and Cardiovasc . Res . 7 167-173 (1973) . E . BRAUNWALD . M . THOMAS . Acta Med . Scand . Su ~ . 587, 185-188 (1976) . cta Med . Scand . Suppl . 587 , 201-207 F . WAAGSTEIN and A .C . HJALMARS . (1976a) . F . WAAGSTEIN and A .C . HJALMARSON . Acta Med . Scand . Suppl . 587 , 193-200 (1976b) . Drug s 7, 55-84 (19741 . B .N .C . PRICHARD . Clin . Pharmacol . Therap . 10, 292-306 (1969) . J .D . FITZGERALD .
Pergamon Press
MINIREVIEW BETA-ADRENERGIC BLOCKADE IN ACUTE MYOCARDIAL INFARCTION Robert J .~Lee Department of Pharniacology Arnar-Stone Laboratories McGaw Park, Illinois
There is considerable evidence that cardiac power failure, and thus mortality, following acute myocardial infarction is directly related to the ultimate size of the infarct, i .e ., the amount of damaged myocardium (1,2) . Since blood flow to the region of the infarct is greatly reduced, the rate at which oxygen is consumed by the myocardium (MV0 2 ) becomes an important factor in the development of the infarct . Following experimental occlusion of a major coronary artery, evidence of myocardial ischemia is present within seconds (2) . Available oxygen supplies are rapidly reduced in the central zone of the infarct and contractile function of myocardium in this area quickly ceases . If this is analogous to the clinical situation following acute rt~yocardial infarction (AMI), therapeutic interventions that favorably alter the relationship between oxygen supply and demand in the ischemic area surrounding the central zone of the infarct should result in the salvage of viable myocardium and minimize final infarct size (3) . The pain and anxiety present after acute myocardial infarction leads to an increase in circulating catecholamines (4,5) . In addition, Mueller (6) has shown that following coronary artery ligation, norepinephrine content in coronary venous blood increased, indicating catecholamine release by the ischemic myocardium . This high catecholamine milieu has positive chronotropic and inotropic effects that wastefully increase MV02 (7) leading to extension of infarct size . Furtherniore, the potential for the induction of reentrant ventricular arrhythmias is enhanced 6y increased catecholamine concentration (8) . It seems reasonable, therefore, that blockade of beta-adrenergic receptors in the acutely infarcted heart would be beneficial from the point of view of decreasing MY02 as well as for the antiarrhythmic protection such intervention would confer . Experimental Findings The major determinants of MV02 are heart rate, contractile state and wall tension (9) . Heart rate and myocardial contractile force are decreased by the administration of beta-adrenergic blocking doses ôf propranolol . These effects are, presumably, due to blockade of the stimulant effects of the intrinsic catecholamine concentration . Higher doses of propranolol cause a further direct depression of myocardial contractility and increase in wall tension (10) . Intravenous administration of beta-adrenergic blocking doses of proprano101 (0 .5 - 2 mg/kg, i .v .) to anesthetized, open-chest dogs reduced the heart rate from 130 + 6 to 111 + 4 beats/min, and decreased the average S-T segment elevation, recôrded from several epicardial sites, during coronary artery 0300-9653/78/1225-253902 .00/0 Copyright (c) 1978 Pergamon Press
2540
Acute Myocardial Infarction
Vol . 23, No . 26, 1978
occlusion (3) . Average S-T segment elevation measured in this fashion is an indication of the degree of underlying myocardial ischemia and its reduction during coronary artery occlusion must be due either to decreased MV02 or to redistribution of blood flow into the ischemic area (11,12) via increased collateral flow (13,14) . There is experimental evidence that the favorable effect of propranolol on the oxygen supply/demand ratio may be due to both of these mechanisms (9,15) . The beneficial effects of decreasing heart rate and myocardial contractility would seem to outweigh the possible detrimental effect of increased wall tension since MV02 decreases after propranolol administration (6) . Furthermore, the prolongation of diastole permits a greater time for subendocardial perfusion to occur . This, plus the fact that propranolol may reverse ischemia-induced increases in ventricular diastolic compliance (6), brings about a redistribution of coronary flow from subepicardial to more ischemic, subendocardial regions . The net result of the decrease in MV02 and redistribution of blood flow following propranolol is an increase in p02 in the ischemic region (12), preservation of the microvasculature (16), improvement of ventricular function ( .17) and decreased loss of myocardial CPK (3) . That these hemodynamic effects of propranolol administration may have a practical application in acute myocardial infarction was suggested by the work of Sommers and Jennings (18) . They reported that intravenous administration of propranolol (5 mg/kg) prior to coronary artery occlusion lasting 20 or 25 min markedly decreased the incidence of myocardial necrosis in surviving dogs . Clinical Findings The usefulness of beta-adrener is blockade in the therapy of angina pectoris has been well established 19,20,21) . The major beneficial effect of such therapy is the reduction in cardiac work and, thus, MV02, both at rest and during activity . This reduces the incidence of stress-induced myocardial ischemia in susceptible areas, e .g ., subendocardium, supplied by compromised coronary arteries . The potential of such therapeutic interventions in the salvage of viable ischemic myocardium in AMI is obvious from a theoretical point of view . When the hemodynamic state of the patient with AMI is taken into account, however, there are potential disadvantages to the administration of beta-adrenergic blocking drugs . A reduction in overall ventricular function exists, the extent of which is related to the size of the infarct . In this situation, maintenance of marginal cardiac performance may depend upon comIf this is removed by blockade of the pensatory adrenergic stimulation (22~ . In addition, beta receptors in the heart, congestive heart failure may result . beta-adrenergic blocking agents such as propranolol possess quinidine-like effects which directly depress myocardial contractility and represent further potential hazards . Controversy exists as to whether or not the potential for inducing heart failure precludes the use of pro~ranolol in AMI . The earliest reports of clinical trials of this drug in AMI indicated that propranolol treatment de creased mortality (23,24) . Of particular interest in these studies was the fact that fewer patients in the propranolol-treated group developed heart failure than in the control group although this was not a significant difference . Later studies failed to confirm a reduction in mortality due to propranolol in AMI (25,26 and one, in which critically ill patients were not excluded, reported a. greater tendency toward heart failure in the treated group (25) . These studies demonstrate that propranolol does not increase mortality in AMI nor does it increase the incidence of heart failure except possibly in the critically ill patient . They fail to show, however, whether or not propranolol reduces the extent of myocardial damage in surviving patients .
Vol . 23, No . 26, 1978
Acute Myocardial Infarction
2541
Using a 35-lead serial precordial electrocardîographic technique (an extension of the epicardial mapping technique mentioned above), Maroko et al . (27) reported that propranolol reduced the magnitude of S-T segment elevat~n in patients with uncomplicated infarcts, presumably reflecting a decrease in the degree of ischemia in the area of the infarct . Gold, et al . (28) later confirmed the reduction of S-T segment elevation in Infarctpatients without excessive depression of myocardial function . The results of an extensive hemodynamic study of the effects of intravenous propranolol in AMI (6) showed that the drug improved oxygenation of ischemic myocardium . Decrease in heart rate and myocardial contractility, improvement of ventricular diastolic relaxation and probably a decrease in catecholamine release by ischemic myocardium were the main factors involved in this beneficial effect . The spectre of congestive heart failure due to direct Myocardial depression following propranolol administration in AMI led to experimental studies with practolol, a cardioselective beta-adrenergic blocking agent with intrinsic sympathamtmetic effects . This agent decreased the extent and severity of myocardial ischemic injury, as manifest by epicardial S-T segment elevation, after acute coronary artery occlusion in dogs without depressing ventricular function (29) . Clinical studies utilizing practolol in AMI demonstrate a decrease in precordial S-T segment elevation (30), a decrease in the occurrence of chest pain (31) and a decrease in heart work without signs of manifest heart failure (32) . Recent reports of serious side-effects after prolonged administration of practolol make it unlikely that this agent will be available for future clinical use . All beta-adrenergic receptor blocking agents that have been tested clinically in the treatment of angina pectoris have proven to be effective (33) . The compounds tested include representatives of all five groups classified by Fitzgerald (34) on the basis of associated properties such as selectivity, membrane stabilization and intrinsic sympathomimetic action . Thus, the antianginal efficacy of these agents is due primarily, if not solely, to their beta-adrenergic blocking properties . In conclusion, it seems clear that the decrease in MV02 and the favorable hemodynamic changes following beta-adrenergic blockade în AMI results in the salvage of ischemic myocardium and the reduction of ultimate infarct size . These agents should be used only with extreme caution in patients with borderline congestive heart failure who rely on adrenergic stimulation for adequate myocardial performance . References 1. 2. 3. 4. 5. 6. 7. 8. 9. 10 .
J .N . CORN . Bull . N .Y . Acad . Med . 50 (3), 328-340 (1974 Z . W .B . HOOD, JR . In : Innovations in the dia nosis and mana gnent of acute m ocardial infarction . . rest, L . ener, E .K . C ung an aspar an, e s . 9-278 . F .A . Davis Company, Philadel Phia (1975) . P .R . MAROKI, J .K . KJEKSHUS, B . E . SOBEL, T . WATANABE, J .W . COVELL, J . ROSS, JR ., and E . BRAUNWALD . Circulation 43, 67-82 (1971) . P .C . GAZES, J .A . RICHARDSON, and E .F~4100DS, Circulation 19, G57-661 (1959) . C . VALORI, M . THOMAS, and J . SHILLINGSFORD . Amer . J . Ca r~o1 . 20, 605-617 (1967) . H . MUELLER . Acta . Med . Scand . S u 1 . 587, 177-183 (1976) . W . RAAB, Cardiologia 52, 306-31 A .L . WIT, B . F . HOFFMAI~and M .R . ROSEN . Amer . Heart J . 90, 521-533 (1975) . E .H . SONNENBLICK and C .L . SKELTON . Mod . Conc : Cardiovasc . Dis . _40, 9-16 (1971) . R .J . LEE and S .H . BAKY . Fed . Proc . 35(3), 349 (1976)_ .
2542
11 . 12 . 13 . 14 : 15 . 16 . 17 . 18 . 19 . 20 . 21 . 22 . 23 . 24 . 25 . 26 . 27 . 28 . 29 . 30 . 31 . 32 . 33 . 34 .
Acute Myocardial Infarction
Vol . 23, No . 26, 1978
W .M . FAM and M . McGREGOR . Circ . Res . 22, 649-659 (1968) . M .M . WINBURY, J,R . WEISS and B .B .' HOWE- Eur . J . Pharmacol . 16, 271-277 (1971) . S .F . VATNER, H . BAIG, W .T . MANDERS, H . OCHS and M . PAGANI . J . Clin . Invest . 60, 353-360 (1977) . M .M . RASAIfSSEN, K . A . REIMER, R . A . KLONER and R .B . JENNINGS . Circulation 56, 794-798 (1977) . L-C . BECKER, N .J . FORTUIN and B . PITT, Circ . Res . .28, 263-269 (1971) . R .A . KLONER, M .C . FISHHEIM, R .S . COTRAN, E . BRAUNWALb and P .R . MAROKO . Circulation 56, 872-880 (1977) . Amer . J . Cardiol . _32, 930-936 P .R, MAROKO, P. LIBBY and E . BRAUNWALD . (1973) . H .M, SOMMERS and R .B . JENNINGS . Arch . Intern . Med . 128, 780-789 (1972) . Clin . Med . 29-3 7 Sept . (1970) . R .E, GIANELLY and D .C . HARRISON . B .N,C . PRICHARD and P .M .S . GILLAM . Brit . Heart J . _33, 473-480 (1971) . D .J . COLTART . Brit . Hear t J . 33, 62-64 (1971) . In : Circulator effects and clinical D .C . HARRISON and E .L . ALDERMAF. - 5 Excerpta uses of beta-adrener is blockin dru s . D . . arr son, ster am Me ca, P .J .D . SNOW . Lance t _2, 551-553 ( . 1965) . P .J .D . SNOW . Amer . J Cardiol . 18, 458-459 (1966) . Lancet _2, 917-920 R . BALCON, D .E . JEWITT, J .P,J . DATIIES and S . GRAM . (1966) . J . CALUSEN, M . FELSBY, F .S . JORGENSEN, B .L . NIELSEN, J . ROIN and B . STRANGE . Lancet 2, 920-924 (.1966) . P .R . MAROKO, P . LIBBf(, J .W . COVELL, B .E . SOBEL, J . ROSS, JR . and E . BRAUNWALD . Amer . J . Cardiol . 38, 223-230 (1972) . H .K .GOLD, R .C . LEINBACH and P .R . F4~ROK0 . Amer . J . Cardiol _38, 689-695 (1976) . P . LIBBY, P .R . MAROKO, J .W . COVELL, C .I . MALLOCH, J . ROSS, JR . and Cardiovasc . Res . 7 167-173 (1973) . E . BRAUNWALD . M . THOMAS . Acta Med . Scand . Su ~ . 587, 185-188 (1976) . cta Med . Scand . Suppl . 587 , 201-207 F . WAAGSTEIN and A .C . HJALMARS . (1976a) . F . WAAGSTEIN and A .C . HJALMARSON . Acta Med . Scand . Suppl . 587 , 193-200 (1976b) . Drug s 7, 55-84 (19741 . B .N .C . PRICHARD . Clin . Pharmacol . Therap . 10, 292-306 (1969) . J .D . FITZGERALD .
