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Electrophysiological actions of calcium antagonists in normal heart and in mild and severe acute myocardial ischemia
J Mol Cell Cardiol 21 (Supplement
II) (1989)
1
THE EFFECT OF Kc 23-6152/001 (R) AND OILTIAZEM (D) ON BLOOD PKESSURE (BP) AND HEART RATE (HP,) IN THE CONSCIOUS SPONTANEOUSLY HYPERTENSIVE RAT (SHR). G. Hirkaler, S. G. Cavallo and J. Wenger. Department of Pharmacology and Chemotherapy, Urbano, Hoffmann-La Roche, Nutley, New Jersey, USA. H, a novel napthothidzepinone calcium antagonist, was compared to D for its effects on BP and HR in conscious SHR. A computer assisted continuous direct BP monitoring system was used (Fed. Proc. 41:1668, 1982). Both compounds were tested at oral doses of 10, 50, and 100 mg/kg. At 10 mg/kg neither compound had any effect on BP. D had At 50 mg/kg D produced a no effect on tiR, while K produced a slight initial increase. significant decrease in BP which persisted for 6 hours. Peak decrease was 24 mmtig at 1 hour. At this dose K produced a significant decrease in BP which persisted for 9 D produced a decrease followed by an hours. Peak decrease was 40 mnHg at 3-7 hours. increase in HR while R had no effect on HR. At the 100 mg/kg dose D produced a significant decrease in BP for up to seven hours following dosing. Peak decrease was K produced a significant decrease in BP which lasted for up to 24 46 mmtig at 1 hour. hours following dosing. A peak decrease of 45 mmHg was maintained for 16 hours following dosing. HR changes mimicked those seen at the 50 mg/kg dose. D produced an initial decrease followed by an increase, while R had essentially no effect. In conR aemonstrates a significant advantage over D in the SHR because of the clusion, longer duration of its antihypertensive effect without significant changes in heart rate.
2
EFFECTS OF ANTIHYPERTENSIVE MONOTHERAPY WITH OXPRENOLOL, NITRENDIPINE OR CLONIDINE ON INDICES OF SYMPATHETIC ACTIVATION DURING PSYCHOPHYSIOLOGICAL STRESS TESTING. G. L. Todd, M. Peters, R. Schmieder, H. Ruddel. Department of Anatomy, University of Nebraska Medical Center, Omaha, NE, U.S.A. and Department of Medicine, University of Bonn, Bonn, F.R.G. Certain forms of hypertension are believed mediated through increased sympathetic nervous system stimulation but there are disagreements on how this can be adequately assessed in the clinical diagnosis and treatment. Plasma catecholamine and heart rate changes were examined following the long term antihypertensive monotherapy with a beta-blocker, oxprenolol (n=21), a calcium antagonists, nitrendipine (n=19), or a sympatholytic drug, clonidine (n=12), in previously undiagnosed hypertensive subjects. Baseline responses were measured before therapy, after at least 3 months of effective blood pressure control, and after psychophysiological stress testing. All three drugs similarly reduced blood pressure. Oxprenolol was able to attenuate the stress-induced heart rate increases but not the stressinduced increases in plasma norepinepbrine. Nitrendipine had ao effect on plasma catecholamines and exhibited the highest resting heart rate. Clonidiae had no effect 011 hemodynamic changes during stress but was the only drug that did not lead to a significant increase in plasma norepinephrine during the stress test. The results clearly indicate the importance of utilizing more than a single index of sympathetic system involvemeat and the role of stress testing in differentiating the mechanisms of pharmacological therapy.
3 ELECTROPHYSIOLOGICAL
ACTIONS OF CALCIUM ANTAGONISTS IN NORPIAL HEART AND IN MILD AND SEVERE ACUTE MYOCARDIAL ISCHEMIA. A. VBgh, L. Szekeres, &. Udvary. Department of Pharmacology Albert Szent-GyBrgyi Medical University, Szeged, Hungary The aim of the present study was to evaluate the effect of verapamil (V), diltiazem (D), nifedipine (N) and fendiline (F) on "in situ" electrophysiological parameters in intact anesthetized, open chest dogs and on the basis of these results to estimate their antiarrhythmic effects in mild and severe myocardial ischemia. In normal hearts the electrophysiological parameters (CSNRT, AFRP, VFRP, AV-ERP) were determined by using computer controlled electrical stimulations, whereas in mild and severe ischemia (occlusion of LAD alone and combined with LCX constriction) the antiarrhythmic and antiischemic actions of the drugs were characterized by measuring the inhomogeneity of electrical activation, ST-segment elevation, ES-activity and the incidence of VF. As a result, N and F had slight effects on the electrophysiological parameters in both normal and ischemic hearts, however, their antiischemic effect was significant. V and D exerted the most pronounced actions on the electrophysioloqical parameters in normal hearts and significantly reduced the ST-segment elevation as well as the number of ES and the incidence of VF in mild and severe myocardial ischemia. s.l
II) (1989)
1
THE EFFECT OF Kc 23-6152/001 (R) AND OILTIAZEM (D) ON BLOOD PKESSURE (BP) AND HEART RATE (HP,) IN THE CONSCIOUS SPONTANEOUSLY HYPERTENSIVE RAT (SHR). G. Hirkaler, S. G. Cavallo and J. Wenger. Department of Pharmacology and Chemotherapy, Urbano, Hoffmann-La Roche, Nutley, New Jersey, USA. H, a novel napthothidzepinone calcium antagonist, was compared to D for its effects on BP and HR in conscious SHR. A computer assisted continuous direct BP monitoring system was used (Fed. Proc. 41:1668, 1982). Both compounds were tested at oral doses of 10, 50, and 100 mg/kg. At 10 mg/kg neither compound had any effect on BP. D had At 50 mg/kg D produced a no effect on tiR, while K produced a slight initial increase. significant decrease in BP which persisted for 6 hours. Peak decrease was 24 mmtig at 1 hour. At this dose K produced a significant decrease in BP which persisted for 9 D produced a decrease followed by an hours. Peak decrease was 40 mnHg at 3-7 hours. increase in HR while R had no effect on HR. At the 100 mg/kg dose D produced a significant decrease in BP for up to seven hours following dosing. Peak decrease was K produced a significant decrease in BP which lasted for up to 24 46 mmtig at 1 hour. hours following dosing. A peak decrease of 45 mmHg was maintained for 16 hours following dosing. HR changes mimicked those seen at the 50 mg/kg dose. D produced an initial decrease followed by an increase, while R had essentially no effect. In conR aemonstrates a significant advantage over D in the SHR because of the clusion, longer duration of its antihypertensive effect without significant changes in heart rate.
2
EFFECTS OF ANTIHYPERTENSIVE MONOTHERAPY WITH OXPRENOLOL, NITRENDIPINE OR CLONIDINE ON INDICES OF SYMPATHETIC ACTIVATION DURING PSYCHOPHYSIOLOGICAL STRESS TESTING. G. L. Todd, M. Peters, R. Schmieder, H. Ruddel. Department of Anatomy, University of Nebraska Medical Center, Omaha, NE, U.S.A. and Department of Medicine, University of Bonn, Bonn, F.R.G. Certain forms of hypertension are believed mediated through increased sympathetic nervous system stimulation but there are disagreements on how this can be adequately assessed in the clinical diagnosis and treatment. Plasma catecholamine and heart rate changes were examined following the long term antihypertensive monotherapy with a beta-blocker, oxprenolol (n=21), a calcium antagonists, nitrendipine (n=19), or a sympatholytic drug, clonidine (n=12), in previously undiagnosed hypertensive subjects. Baseline responses were measured before therapy, after at least 3 months of effective blood pressure control, and after psychophysiological stress testing. All three drugs similarly reduced blood pressure. Oxprenolol was able to attenuate the stress-induced heart rate increases but not the stressinduced increases in plasma norepinepbrine. Nitrendipine had ao effect on plasma catecholamines and exhibited the highest resting heart rate. Clonidiae had no effect 011 hemodynamic changes during stress but was the only drug that did not lead to a significant increase in plasma norepinephrine during the stress test. The results clearly indicate the importance of utilizing more than a single index of sympathetic system involvemeat and the role of stress testing in differentiating the mechanisms of pharmacological therapy.
3 ELECTROPHYSIOLOGICAL
ACTIONS OF CALCIUM ANTAGONISTS IN NORPIAL HEART AND IN MILD AND SEVERE ACUTE MYOCARDIAL ISCHEMIA. A. VBgh, L. Szekeres, &. Udvary. Department of Pharmacology Albert Szent-GyBrgyi Medical University, Szeged, Hungary The aim of the present study was to evaluate the effect of verapamil (V), diltiazem (D), nifedipine (N) and fendiline (F) on "in situ" electrophysiological parameters in intact anesthetized, open chest dogs and on the basis of these results to estimate their antiarrhythmic effects in mild and severe myocardial ischemia. In normal hearts the electrophysiological parameters (CSNRT, AFRP, VFRP, AV-ERP) were determined by using computer controlled electrical stimulations, whereas in mild and severe ischemia (occlusion of LAD alone and combined with LCX constriction) the antiarrhythmic and antiischemic actions of the drugs were characterized by measuring the inhomogeneity of electrical activation, ST-segment elevation, ES-activity and the incidence of VF. As a result, N and F had slight effects on the electrophysiological parameters in both normal and ischemic hearts, however, their antiischemic effect was significant. V and D exerted the most pronounced actions on the electrophysioloqical parameters in normal hearts and significantly reduced the ST-segment elevation as well as the number of ES and the incidence of VF in mild and severe myocardial ischemia. s.l