Preclinical assessment of antiarrhythmic drugs.

The morbidity statistics for the United States alone would suggest that there are 400,000 victims each year who succumb to sudden coronary death, which suggests that there is a need for the development of pharmacological interventions capable of preventing ventricular fibrillation (VF) in patients identified as being at high risk. A major deficiency in this area of experimental investigation is the lack of an animal model that would permit preclinical studies to identify potentially useful therapeutic agents. We have developed an experimental canine model of sudden coronary death in which VF occurs in the chronically injured heart that is subjected to a period of transient ischemia in a coronary region remote from the site of a previous myocardial infarction.

Facilitation of lethal ventricular arrhythmias by therapeutic digoxin in conscious post infarction dogs.

The proarrhythmic potential of digoxin, administered in a therapeutic dosage regimen, was evaluated in conscious dogs in the subacute phase of myocardial infarction. In this evaluation, digoxin (0.0125 mg/kg/day intravenously) or vehicle were administered to conscious dogs for periods of 5 to 7 days, commencing 4 to 5 days after anterior myocardial infarction.

Protective effects of N-2-mercaptopropionyl glycine against myocardial reperfusion injury after neutrophil depletion in the dog: evidence for the role of intracellular-derived free radicals.

Reperfusion of the previously ischemic myocardium is associated with the production of oxygen free radicals and their metabolites, which contribute to the ultimate extent of irreversible myocardial injury. The relative importance of polymorphonuclear leukocytes vs intracellular-derived oxygen metabolites has remained uncertain. We evaluated the effectiveness of a free-radical scavenger, N-2-mercaptopropionyl glycine (MPG), in limiting infarct size after ischemia/reperfusion in dogs that were depleted of neutrophils with specific antisera.

Electrophysiologic, antiarrhythmic and cardiovascular actions of UM301, a quaternary ammonium compound.

The electrophysiologic, antiarrhythmic and cardiovascular actions of UM301 were evaluated in a variety of animal models. UM301 (range, 4.5-10 mg/kg i.

Antiarrhythmic vs. antifibrillatory activity of the basic diphenylhydantoin derivative 3-[3-(4-phenyl-1-piperidyl)propyl]-5-(4-methoxyphenyl)-5-phenylhydantoin hydrochloride.

The effects of 3-[3-(4-phenyl-1-piperidyl)propyl]-5-(4-methoxyphenyl)-5-phenylhydantoin hydrochloride (TR 2985), a basic diphenylhydantoin derivative, were studied in four canine models of experimental cardiac dysrhythmias. In conscious dogs, 48 h after myocardial infarction, TR 2985 significantly reduced the frequency of spontaneous ventricular arrhythmias. However, in anesthetized dogs, TR 2985 produced only a slight and insignificant increase in the ventricular fibrillation threshold.

Reduction of the size of infarction by allopurinol in the ischemic-reperfused canine heart.

This study was performed to assess the effect of allopurinol in a canine preparation of myocardial infarction. Dogs underwent occlusion of the left circumflex coronary artery for 90 min, followed by reperfusion for 6 hr. Three groups were studied: (1) control, (2) dogs receiving 25 mg/kg allopurinol 18 hr before occlusion and 50 mg/kg 5 min before occlusion, and (3) dogs receiving allopurinol as above plus 5 mg/kg superoxide dismutase over 1 hr beginning 15 min before reperfusion.

Platelet-activating factor and the release of a platelet-derived coronary artery vasodilator substance in the canine.

Platelet-activating factor (acetyl-glyceryl-ether-phosphorylcholine; 1-O-alkyl-2-O-acetyl-sn-glycero-3-phosphorylcholine), which is released by stimulated neutrophils and platelets, possesses the ability to alter vascular tone and permeability and to activate various formed blood elements. We have characterized the hemodynamic effects of intracoronary injections of platelet-activating factor and the influences of pharmacological blockade and platelet depletion on its activity. Intracoronary injections of platelet-activating factor produced maximum increases in left circumflex coronary artery blood flow of 55 +/- 8, 52 +/- 8, and 52 +/- 7 ml/min at 0.

Antiarrhythmic and electrophysiologic actions of clofilium in experimental canine models.

Clofilium was studied in three experimental models. In non-ischemic and chronically infarcted canine hearts, clofilium (0.5-2 mg/kg) produced a dose-dependent increase in electrical ventricular fibrillation threshold (VFT), but prolonged the effective refractory period (ERP) of normal myocardium in only the non-ischemic heart.

Antiarrhythmic and electrophysiologic effects of bepridil in chronically infarcted conscious dogs.

The antiarrhythmic and antifibrillatory actions of bepridil, an antianginal agent with cardiac fast and slow channel-blocking activities, were evaluated in conscious dogs 3 to 7 days after anterior myocardial infarction. The i.v.

Augmentation of streptokinase-induced thrombolysis by heparin and prostacyclin.

The ability of heparin and prostacyclin to improve streptokinase-induced recanalization was examined in open-chest dogs subjected to thrombotic occlusion of the left circumflex coronary artery. Vessel injury was produced by electrical stimulation of the intimal surface at the site of a noncircumferential fixed stenosis. Animals were divided into three treatment groups as follows: group 1 received intracoronary streptokinase alone (75,000 units/80 min starting 30 min postocclusion; n = 8); group 2 received streptokinase plus heparin (300 units/kg i.

The independent effects of oxygen radical scavengers on canine infarct size. Reduction by superoxide dismutase but not catalase.

Previous studies demonstrated a significant reduction of ultimate infarct size in the canine heart by the combined administration of superoxide dismutase plus catalase. This study was performed to assess the independent effects of each enzyme on ultimate infarct size due to ischemia/reperfusion. Dogs received 2-hour infusions of superoxide dismutase, catalase, or albumin (controls) via the left atrium beginning 15 minutes before and ending 15 minutes after a 90-minute occlusion of the left circumflex coronary artery.

Platelet depletion in experimental myocardial infarction.

Accumulation of platelets in the microvasculature after acute myocardial ischemia may exacerbate tissue injury through the formation of microthrombi and by the release of vasoactive substances. To assess the role of platelets in myocardial ischemic injury and infarction, circulating platelets were reduced by 94 +/- 2% (mean +/- S.E.

Prevention of ventricular fibrillation by dextrorotatory sotalol in a conscious canine model of sudden coronary death.

The antiarrhythmic and antifibrillatory actions of the dextrorotatory isomer of sotalol, administered in a multiple-dose regimen, were evaluated in conscious dogs 3 to 5 days after anterior myocardial infarction. The intravenous administration of d-sotalol, four 8 mg/kg doses over a 24-hour treatment period, suppressed the induction of ventricular tachycardia by programmed electrical stimulation in six of nine dogs tested, slowed the rate of the induced tachyarrhythmia in two of the remaining three dogs, and provided significant protection (5 of 8 d-sotalol vs 0 of 8 vehicle control) against the development of ventricular fibrillation in response to ischemia at a site distant to a previous myocardial infarction. Increases in ventricular myocardial refractoriness and in QTc and paced QT intervals suggest that class III electrophysiologic actions contribute to the antiarrhythmic properties of dextrorotatory sotalol in this animal model.

Do catecholamines play a physiologic role in regulating corpus luteum function in the pseudopregnant rabbit?

In these studies the beta-adrenergic receptor antagonist propranolol was administered to estrogen-treated hypophysectomized pseudopregnant rabbits in vivo, and serum progesterone concentrations were measured to monitor luteal function. In Experiment 1, which was designed to determine an effective dose of propranolol, 1 mg/(kg X h) s.c.

Antifibrillatory actions of bepridil and butyl-MDI, two intracellular calcium antagonists.

The antifibrillatory and electrophysiologic actions of bepridil and butyl-methylenedioxyindene (BU-MDI), two intracellular calcium antagonists, were examined in anesthetized dogs. The administration of bepridil (1.0-10.

The antiarrhythmic actions of intravenous and oral UM424 in postinfarction canine myocardium.

The electrophysiologic and antiarrhythmic effects of oral and intravenous UM424 were studied in canine models of acute and chronic myocardial injury. In the first phase of this study, reentrant ventricular tachyarrhythmias and/or ventricular fibrillation were initiated by programmed electrical stimulation techniques in seven dogs 48-120 h after myocardial infarction. The cycle length of these reentrant ventricular beats was 176 +/- 16 ms, and they were accompanied by fractionated asynchronous epicardial electrical activity in the injured region that bridged the diastolic interval, i.

Protective effects of AICAriboside in the globally ischemic isolated cat heart.

The effects of a purine precursor, AICAriboside (5-aminoimidazole-4-carboxamide riboside), on postischemic recovery of myocardial function and adenine nucleotides have been studied in the isolated blood-perfused cat heart. The isolated hearts received either AICAriboside or saline prior to 60 min of global ischemia and during 60 min of subsequent reperfusion. After 60 min of global ischemia and reperfusion, left ventricular function of the AICAriboside-treated hearts approached preischemic values, whereas contractile function of the saline-treated hearts remained depressed.

Postinfarction sudden death: significance of inducible ventricular tachycardia and infarct size in a conscious canine model.

The relationship between inducible ventricular tachycardia in the convalescent phase of myocardial infarction and subsequent spontaneous ventricular fibrillation is uncertain. Thirty conscious instrumented dogs underwent programmed ventricular stimulation 5 days after anterior infarction; 15 had inducible ventricular tachycardia and 15 were noninducible. Following programmed ventricular stimulation, the application of a 150 uA current to the intima of the proximal circumflex artery initiated intimal damage, thrombosis, and acute ischemia of the posterolateral wall.

Free radicals in ischemic myocardial injury.

Myocardial ischemia causes release of chemotactic factors, migration of neutrophils, peroxidation of lipids, and depletion of free radical scavengers. The invading neutrophils may injure the myocardial vasculature and sarcolemma by generating oxygen free radicals. Several agents that affect neutrophils or oxygen radicals were evaluated in a canine model of regional myocardial ischemia and reperfusion.

Effects of bepridil on regional and global myocardial ischemia/reperfusion-induced injury.

The effectiveness of the calcium entry blocker bepridil in protecting the myocardium from ischemic injury, was assessed in a canine model of regional ischemia and in a feline model of global ischemia. Bepridil administration (5 mg/kg or 15 mg/kg/24 h intravenously) did not reduce ultimate infarct size as assessed in anesthetized, open-chest dogs subjected to 90 min of occlusion of the left circumflex coronary artery and 24 h of reperfusion. Bepridil (5 mg/kg administered intravenously to a blood donor cat) did not provide any protection of the isolated blood-perfused cat heart from 90 min of normothermic global ischemia and 60 min of reperfusion.

Identification of hydrogen peroxide and hydroxyl radicals as mediators of leukocyte-induced myocardial dysfunction. Limitation of infarct size with neutrophil inhibition and depletion.

Neutrophil infiltration of the myocardium is an important component of such diverse disease entities as myocarditis, ischemia, and ischemia-reperfusion injury. We have hypothesized that activated neutrophils are capable of disrupting myocardial function via an oxygen free-radical mechanism. Human neutrophils activated with phorbol myristate acetate disrupted calcium transport by canine cardiac sarcoplasmic reticulum, and this process was inhibited by a combination of superoxide dismutase and catalase.

Experimental coronary artery thrombosis in the absence of thromboxane A2 synthesis: evidence for alternate pathways for coronary thrombosis.

The actions of the thromboxane synthetase inhibitor, U-63557A, were evaluated in vivo in anesthetized open-chest dogs by inducing left circumflex coronary artery (LCCA) thrombosis with low amperage electrical stimulation (100 microA for 6 h) of the intimal surface of the vessel, and ex vivo by assessing platelet aggregation and TXB2 production. U-63557A, 10 mg/kg + 5 mg/kg/h i.v.

Streptokinase thrombolysis in experimental coronary artery thrombosis: pattern of reflow and effect of a stenosis.

We studied recanalization of an obstructed left circumflex coronary artery by streptokinase in open-chest anesthetized dogs. Thrombotic occlusion was induced by a 100 microA anodal current selectively delivered to the intimal surface of the vessel. Intracoronary streptokinase (50,000 U) or saline was infused over a 50-min period beginning at either 30 min or 90 min after occlusion.