Guppy, Leon J.

The chapter, "Targeting ischemic ventricular arrhythmias" was written by the listed authors including Leon J. Guppy (Douglas College Faculty). Methods in Pharmacology and Toxicology publishes cutting-edge techniques, including methods, protocols, and other hands-on guidance and context, in all areas of pharmacological and toxicological research. Each book in the series offers time-tested laboratory protocols and expert navigation necessary to aid toxicologists and pharmaceutical scientists in laboratory testing and beyond. With an emphasis on details and practicality, Methods in Pharmacology and Toxicology focuses on topics with wide-ranging implications on human health in order to provide investigators with highly useful compendiums of key strategies and approaches to successful research in their respective areas of study and practice. The revolution in molecular medicine makes it imperative to integrate the classical and molecular approaches to drug development for the treatment of heart disease, the number one killer in North America and Europe. In the Cardiac Drug Development Guide, basic medical researchers, clinicians, and pharmacologists join forces to comprehensively survey the most recent breakthroughs in molecular cardiology and review the latest drug discoveries in cardiac and cardiovascular medicine. Topics range from novel molecular targets for cardiac drug development, to functional endpoints for evaluating cardiac drug activity, to clinical aspects of cardiovascular therapeutics. The authors describe the most advanced procedures in cardiovascular pharmacology, including in vivo and in vitro whole animal studies, the electrophysiological methods used to study pacemaker cells, and the application of biochemical principles and technologies to novel therapeutic agents. Also discussed are the methods used to express the ion channels involved in cardiovascular pharmacology, adenoviral vector delivery for cardiovascular gene therapy, pharmacometrics in cardiovascular drug development, gender differences in heart failure, and angiogenesis therapies for coronary heart disease. Each chapter concisely illustrates the concepts described and includes comprehensive background information, detailed figures and tables, and an up-to-date list of the most important references. Comprehensive and easy-to-understand, the Cardiac Drug Development Guide offers pharmacologists, cardiologists, and physiologists not only a gold-standard survey of the many different methods being used to develop new heart drugs, but also details powerful new ways in which cardiovascular disease is targeted, from the whole organ to the genetic level. The purpose of this chapter is to ask why there has been so little success in developing new antiarrhythmic drugs and what can we do to increase our chances of success. Failure has been a fairly common theme in attempts to produce new antiarrhythmic drugs, particularly for lethal ventricular arrhythmias. The chapter considers old and new ways of finding novel drugs for lethal ventricular arrhythmias as a result of myocardial ischemia and infarction and describes new compounds selective for ischemia-induced ventricular tachycardia and fibrillation. --From publisher description.

Male Sprague-Dawley rats were made physically dependent on ethanol by exposure to ethanol vapour in inhalation chambers for 6–10 days. Animals were sacrificed immediately after removal from the chambers. After sacrifice, membrane preparations from cerebral cortex, heart, vas deferens and thigh skeletal muscle were prepared and studied to determine the characteristics of [3H]-nitrendipine binding. In membranes from cerebral cortex, the number of binding sites (Bmax) was increased 40% in preparations from ethanol-dependent rats compared to controls. Similar results were obtained in heart (Bmax increased 125%). vas deferens (Bmax increased 50%) and skeletal muscle (Bmax increased 33%). Binding affinity (Kd) in all these tissues was unchanged. Membranes from cortex and heart were studied more extensively. Displacement studies using other dihydropyridines and the effects of ionic composition on [3H]-nitrendipine binding provided no evidence to suppose that the binding sites induced by the development of ethanol dependence were from a population different from those in ontrol tissues. The results suggest a generalised ‘up-regulation’ of the dihydropyridine-sensitive subclass of voltage operated calcium channels in excitable tissues from ethanol-dependent rats.

Physical dependence was induced by ethanol inhalation in male Sprague-Dawley rats and, in parallel experiments, in two lines of mice (WSR and WSP) genetically selected for differential severity of ethanol withdrawal. In dependent rats [3H]nitrendipine binding sites were significantly increased in cerebral cortex, cardiac and smooth muscle (vas deferens). Cerebral cortical membranes were the first to show an increase, the Bmax for nitrendipine binding rising sharply after 3–4 days of ethanol administration, whereas binding sites in the other tissues increased after 5–6 days. Nitrendipine binding affinity in all tissues was consistently reduced immediately preceding the rise in Bmax to a new steady state, but then returned to control values. Between 6 and 10 days of ethanol exposure there was no further increase in the Bmax for nitrendipine binding, and on removal of ethanol, the numbers of nitrendipine binding sites fell precipitously to control levels within 24 h of withdrawal. In the genetically selected mice, the up-regulation of nitrendipine binding sites in cardiac membranes was significantly greater in the WSP line. This correlates with severity of physical signs of withdrawal and parallels previous results obtained in brain. The results are consistent with an increase in the synthesis and membrane insertion of dihydropyridine sensitive calcium channel proteins in several tissues during the induction of ethanol dependence and suggest that in the brain this change may play a role in the ethanol withdrawal syndrome.

In this study we examined the cardiovascular and possible antiarrhythmic actions of anipamil, a long acting analog of verapamil. Initial dose-response studies for anipamil (0.25-6.0 mg/kg, i.v.) in pentobarbitone-anesthetized pigs (n = 4) were conducted to determine the effects of the drug on EKG and hemodynamic measures. In this initial study anipamil was found to produce a dose-dependent reduction in blood pressure, left-ventricular pressure and its derivative (dP/dtmax), cardiac output, and increase in heart rate. These results were used as a basis from which to choose doses for a second study to assess antiarrhythmic actions of anipamil against arrhythmias induced by regional myocardial ischemia. The antiarrhythmic effects of the two doses were compared with verapamil when the latter was given at a dose producing cardiovascular effects mid-way between those produced by the two doses of anipamil. Anesthetized pigs were randomly assigned to receive one of three drug treatments, or vehicle control, prior to occlusion of the left-anterior descending coronary artery. Antiarrhythmic effectiveness of low (1.0 mg/kg + 0.10 mg/kg/min infusion, n = 8) and high (5.0 mg/kg + 0.50 mg/kg/min infusion, n = 12) dose anipamil was compared to that of verapamil (0.5 mg/kg + 0.60 mg/kg/min infusion, n = 8) in a vehicle controlled study (n = 15). Arrhythmic events (VPB, VT and VF incidence) were monitored and grouped according to their time of occurrence after occlusion. Thus phase 1a arrhythmias occurred 0-5 min after initiation of occlusion, phase 1b, 5-30 min, and phase 2, 0.5-4 hr after occlusion. This study showed that during phase 1a there was a low incidence of arrhythmias in all groups except the one receiving 5 mg/kg anipamil where the group incidence of VT was 58% as compared to 20% in controls (n = 15). Most ventricular arrhythmias occurred in all groups during phase 1b. In this phase verapamil abolished VF and reduced VT, as compared with controls. Anipamil (high and low doses) tended to reduce VT but not VF. In the period 0.5 to 4 hours post occlusion (phase 2) all three drug treatments were associated with fewer arrhythmias but this only reached statistical significance with verapamil. Thus verapamil was more efficacious than anipamil at providing antiarrhythmic protection against both early and late onset arrhythmias. Anipamil may have been proarrhythmic in the early phase of arrhythmias and only moderately antiarrhythmic, if at all, in the later phase.(ABSTRACT FROM AUTHOR)

The experiments reported in this study constitute a preliminary investigation into the possible hypotensive effect of the Jamaican Cho-Cho (Sechium edule). Experiments were conducted in a random and blind fashion on two sub species of Sechium edule. Both the pulp and the peel were examined for hypotensive activity. Water-soluble extracts were prepared from these components of the fruit and injected into anaesthetised rats. Various cardiovascular parameters were measured including heart rate, mean arterial pressure (MAP) and several ECG intervals. We report that all extracts tested produced a fall in blood pressure with little change in ECG intervals. Extract B produced the least change in heart rate with a fall in MAP of approximately 23 mmHg. Changes in heart rate with all extracts appeared to be minimal as an ED25 value could only be determined for extract A, and ED10 values could not be evaluated for extracts C and D. The mechanism(s) by which these extracts produce their hypotensive effects could not be determined in these preliminary experiments. However, it appears not to involve direct effects on cardiac tissue. This conclusion is based on the finding that it took a minimum of 10 to 15 seconds for the hypotensive action to manifest post bolus. Future experiments will be aimed at delineating the mechanism(s) involved in decreasing MAP.

A new model of regional ischaemia using blood-perfused isolated rat hearts is reported in this issue. This model has potential value in pharmacology to test the actions of drugs against the arrhythmias that arise early period (0-30 min) after induction of ischaemia. Unfortunately, the severity of arrhythmias in this new model is reduced, when compared to other models, in both the early and the late period (1-4 h) of coronary artery occlusion. This commentary compares the new model with previous models, and comments on the possible mechanisms of arrhythmias induced by ischaemia.

This study investigated the possibility that previously reported marked upregulation of binding sites for the dihydropyridine calcium channel antagonist nitrendipine in heart tissue during the development of ethanol dependence in the rat may represent functional L-type voltage-operated calcium channels (L-VOCCs). Isolated hearts obtained from adult Sprague-Dawley rats, which received intoxicating concentrations of ethanol for 6-10 days, by inhalation, were perfused with Krebs-Henseleit solution in the Langendorff mode. Basic measurements of cardiac function were compared with hearts from control rats not exposed to ethanol vapor. In another study, concentration-response curves were constructed for nitrendipine at concentrations in the range of 10−10-10−6M for hearts obtained from control and ethanol-exposed animals. Changes in measured cardiac parameters such as R-wave amplitude, heart rate, diastolic and systolic pressure, and (+)dP/dtmax and coronary flow were recorded. All comparisons were made between preparations set to a similar left ventricular end-diastolic pressure. Under these conditions, there were no significant differences in R-wave amplitude, but isolated hearts from ethanol-dependent rats showed significantly greater indices of myocardial contraction than did controls. These included increased systolic and developed ventricular pressure and increased (+)dP/dtmax. Coronary flow also was significantly greater in hearts from ethanol-dependent rats compared with controls. Heart rate was higher in the alcohol-exposed group, but this difference did not achieve significance. When nitrendipine was added to the perfusate at concentrations between 10−10 and 10−6M, hearts from ethanol-dependent animals showed a greater sensitivity to the effects of the drug on heart rate and systolic pressure. Effects on R-wave amplitude and (+)dP/dtmax were less clear but also suggested a greater sensitivity to nitrendipine in hearts from ethanol-exposed rats. Effects on coronary flow were small and did not differ significantly between preparations from control and ethanol-dependent rats. The results suggest that the increase in Bmax of DHP binding previously observed in hearts from ethanol-dependent animals might represent an increase in L-VOCCs, which alters physiologic function, and pharmacologic responses in the isolated heart. These changes may represent the exposure of an adaptive mechanism designed to overcome the generally depressant effects of ethanol on cardiac function in vivo.