Peter S. Wolf

Vasoconstrictor Role of Vasopressin and Angiotensin in Experimental Aortic Stenosis in the Rat

The roles of vasopressin and angiotensin II in the regulation of peripheral vascular tone were investigated in control rats and in rats with chronic (15 weeks) aortic stenosis, by intravenous application of a specific antagonist to the vascular receptors of vasopressin and the angiotensin-converting enzyme inhibitor teprotide. The application of a Silver clip (0.6 mm) on the aorta ascendens produced a hemodynamically effective aortic stenosis with an increase in left ventricular weight (38%), a reduction in mean arterial pressure, cardiac index, and stroke volume index, and an increase in peripheral vascular resistance. In both groups of rats, a bolus injection of 30 micrograms of the vasopressin inhibitor d (CH2) 5 Tyr (Me) arginine vasopressin (AVP) showed an agonistic effect by increasing arterial pressure by 11 and 15 mm Hg, respectively, and no antagonistic effect in the control animals. In the rats with chronic aortic stenosis we observed a significant fall in blood pressure (4.1 +/- 5.5 mm Hg; p less than 0.05) and a reduction in peripheral vascular resistance of 6.3% (p less than 0.02). Stroke volume index and heart rate did not change. Most of the animals with aortic stenosis had inappropriately elevated plasma levels of vasopressin and increased levels of plasma renin concentration. The rats with aortic stenosis and inappropriately increased values of vasopressin showed significantly lower plasma osmolality, cardiac index, and stroke volume index and increased peripheral vascular resistance compared with the stenosed rats with a normal osmoregulation of vasopressin.(ABSTRACT TRUNCATED AT 250 WORDS)

Celiprolol, a Compound Which Attenuates Myocardial Acidosis and Improves Regional Segmental Function following Ischemia in Dogs: a Comparison with Propranolol

Celiprolol, propranolol or saline were administered to separate groups (n = 5-6) of anesthetized dogs in which a critical stenosis was applied to the circumflex coronary artery for 90 min and then reperfused for 30 min. Test drugs were administered at 30 min poststenosis and the effects on pH, regional function and endocardiogram were monitored. A reduction in coronary flow of 54 +/- 2% (n = 27) yielded marked increases in hydrogen ion concentration (H+) of 17 +/- 2 X 10(-8) and ischemic endocardial ST segment of 6 +/- 1 mV while ischemic segmental shortening decreased 75 +/- 9%. Heart rate, arterial pressure and normal regional function were not altered. Celiprolol 0.1 and 1 mg/kg, i.v., reversed the alterations in H+ and ischemic ST segment to prestenosis values while improving ischemic segmental shortening 20 and 38%, respectively, and not affecting heart rate. Propranolol 0.1 and 1 mg/kg, i.v., reversed the alterations in H+ and ischemic ST segment to prestenosis values while further decreasing ischemic segmental shortening 66 and 30%, respectively. Upon reperfusion, ischemic segmental shortening returned to prestenosis values in the group treated with celiprolol 1 mg/kg, i.v., while the propranolol- and saline-treated groups further decreased. It is concluded that celiprolol is efficacious in normalizing myocardial function and ischemia-induced electrophysiological changes following coronary artery stenosis.

Measurement of oxygen tension in the ischemic myocardium using encased polargraphic oxygen electrodes

The ability to continuously monitor the delicate balance between blood flow and oxygen consumption would be a great asset in the study of myocardial ischemia. The present study was performed, in anesthetized dogs, to validate the use of encased polargraphic oxygen electrodes in the study of myocardial ischemia. Polargraphic oxygen electrodes were placed in the area to be rendered ischemic at fixed tissue depths of 3 mm (epicardium) and 9 mm (endocardium). Endocardial and epicardial oxygen tensions as well as the ratio of endocardial to epicardial oxygen tension and left circumflex coronary flow were monitored. Ischemia was induced by decreasing left circumflex coronary flow by 50%. Upon completion of a 20-min poststenotic period, endocardial pO2, endocardial/epicardial ratio, and coronary flow were significantly decreased (59 +/- 7, 52 +/- 7, and 55 +/- 4%, respectively) whereas epicardial pO2 was slightly decreased. Nitroglycerin (10 micrograms/kg, i.v.) markedly increased endocardial pO2 and endocardial/epicardial ratio above poststenotic control (13 +/- 5 mmHg and 64 +/- 10%, respectively) whereas epicardial pO2 was not significantly decreased. The increases in endocardial pO2 occurred at a point where coronary flow and mean arterial pressure were not significantly changed. Conversely, dipyridamole (125 micrograms/kg, i.v.) significantly increased coronary flow (26 +/- 2 ml/min/100 g) although it did not appreciably alter endocardial or epicardial pO2. It is concluded that encased polargraphic oxygen electrodes provide a quantitative method for determination of oxygen tension in the ischemic myocardium.

Effects of Nitroglycerin, Dipyridamole, Nifedipine, Verapamil and Diltiazem on Canine Coronary Arterial Rings Contracted with 5-Hydroxytryptamine and Anoxia

Anoxia has been shown to potentiate the constrictor effects of 5-hydroxytryptamine (5HT) in isolated vascular tissue. In the present study, canine coronary arterial rings were incubated with various treatments and exposed to 5HT (4 X 10(-7) M) and anoxia (95% N2 and 5% CO2). Developed tension was increased by 250 +/- 40 mg by 5HT alone and 2,000 +/- 90 mg by 5HT and anoxia. Calcium (5 mM) potentiated, while inorganic (lanthanum, 10(-2) M) and organic calcium antagonists (nifedipine, verapamil and diltiazem; IC50 = 7 X 10(-9), 7.3 X 10(-8) and 2.4 X 10(-7) M, respectively) blocked the anoxic potentiation. Anoxia alone decreased resting tension (RT). Methysergide 3 X 10(-5) M inhibited both the 5HT- and anoxia-potentiated responses. Nitroglycerin decreased RT and inhibited the anoxic response (IC50 = 7.6 X 10(-6) M), while dipyridamole decreased RT and did not affect the anoxic response. These data suggest that the potentiation of 5HT contraction by anoxia is dependent upon extracellular calcium influx and is linked to a 5HT receptor. In addition, inhibition of the anoxic response can be achieved at other sites and is not a property common to all coronary vasodilators.

The emergence of drugs which block calcium entry

Calcium Entry Blockers (CEBs) are a new class of drugs which have been pushing back the frontiers of science and medicine for almost two decades. This report reviews some of the wealth of chemical, biological and clinical data describing the discovery and development of these compounds. The scientific importance, therapeutic benefit and marketing potential of these compounds have caused an explosion of scientific literature describing their effects in many preclinical and clinical settings. The definitional characteristics of these compounds suggest a certain predictability of their biological profile but their therapeutic usefulness varies widely dependent upon their physical properties, net hemodynamic effects, duration of action and incidence of side effects. CEBs appear uniquely suited to the treatment of the underlying complexity of cardiovascular disease. The CEBs of the future may live up to the expectations of pathophysiologically based therapeutics and allow the heart and blood vessels to outlive the cells which they support. The development of CEBs is an evolving story of epic proportions and represents the cooperative efforts of individuals in all areas of science.

Current Calcium Entry Blocker

The principle examples of the “first generation” of CEBs are verapamil, nifedipine and diltiazem. These three compounds are the reference standards against which new (and many older) compounds are compared. Each is a potent, and to varying degrees a selective CEB and, importantly, each has a distinct chemical structure. The differences in chemical structure give rise to differences in physical or chemical properties, distribution and metabolism, tissue binding characteristics and net biological effects. It is therefore not surprising that the therapeutic efficacy or tolerance of these agents may also be quite different (Sect. 4–5).

Introduction: Calcium Entry Blockers (CEBs)

The following review relates the cardiovascular new drug discoveries of the organic chemicals called calcium entry blockers 1) of the recent past, to the present development of additional agents with similar mechanisms of action, and to the understanding of calcium metabolism which holds the key to meaningful future new drug discovery. CEBs are a special group of chemicals because they 1) can display dramatic therapeutic efficacy (e.g. in vasospastic angina), 2) demonstrate very potent biological activity preclinically, 3) share a common mechanism of action — a mechanism that supports other new therapeutic indications and 4) provide important tools by which to characterize calcium metabolism and its relationship to excitation-contraction or excitation-secretion coupling. There is widespread interest in CEBs as evidenced by the rapidly expanding scientific literature and the number of excellent reviews that have been published (see individual sections below).

Perspectives: CEB New Drug Discovery

New drug, and particularly CEB new drug, discovery will continue as long as there are cardiovascular diseases to be treated. In the next few years, maybe even decades, the drugs will be designed to relieve the symptoms of disease. At sometime in the not too distant future, however, cardiovascular drugs will be designed to prevent or cure disease. Current drugs have had an important role in decreasing cardiovascular morbidity and mortality 1096, 1392, 1393, 1394, 1395, 1396) and will continue to do so as even more effective drugs are introduced. As the population lives longer the kinds of drugs which are developed may change. As we deal with a finite life expectancy it is assumed that each cardiovascular organ/tissue has a fixed life expectancy with genetic factors determining the upper limits and diet, exercise (or work), stress (physical, mental or chemical) and injury determining the lower limits. It is also reasonable to assume that life encompasses a continuance of change, first maturative then degenerative, which is limited by failure of the weakest link (organ or tissue). Cardiovascular drugs which will prolong life (limited by cardiovascular failure) will necessarily address the weakest link, and then the next and so on. Ultimately, with ideal therapeutic support, the pump (heart) and the conduits (blood vessels) responsible for the delivery of oxygen and removal waste will outlive the cells they are supporting. Until that time, new drug discovery scientists must address the practical problems of where to look for useful new drugs with somewhat more modest expectations.

Effects of Celiprolol in Anesthetized Dogs with Reduced Myocardial Function

Celiprolol HCl is a new cardioselective beta adrenoceptor antagonist with both mild propranolol-sensitive partial agonist activity and propranolol-insensitive cardiostimulatory properties. The purpose of the present investigation was to assess the significance of this unique pharmacological profile in a study of the effects of celiprolol in anesthetized dogs with depressed myocardial function. Dogs were acutely instrumented to directly monitor myocardial contractile force (CF), arterial pressure (AP), heart rate (HR), and ECG limb lead II. Mecamylamine 1 mg/kg i.v., and verapamil, 0.5 mg/kg i.v., reduced CF (80 +/- 6 g), HR (76 +/- 4 beats/min), and AP (59 +/- 8 mm Hg). Celiprolol (3 mg/kg i.v.) did not produce any further decrement in myocardial function. There were no appreciable ECG changes. These data suggest that celiprolol may be the drug of choice in patients receiving verapamil, since it should not further compromise myocardial function.