The action of DCI upon the aconitine-induced arrhythmia was studied using the isolated perfused rabbit heart. It has been demonstrated that DCI does not inhibit the aconitine-induced ectopic focus. However, in the presence of DCI the rate of ectopic discharge is increased. This effect has been shown to be unrelated to the intrinsic sympathomimetic activity of DCI. In addition to DCI, the effects of acetyicholine, acetylstrophanthidin, Ca++ and K+ ions upon the aconitine arrhythmia have been investigated. The actions of these agents are discussed. It has been noted that the calcium and potassium ions have opposite effects upon the aconitine-induced pacemaker. In addition the activity of DCI appears to be dependent upon a suitable concentration of the potassium ion. It has been suggested that DCI may exert its effects by altering the ionic permeability of the myocardial cell.
The effects of the dimethyl quarternary analog of propranolol, UM-272, on myocardial infarct volume were studied in the canine heart. Myocardial infarction was produced by occlusion of the left circumflex coronary artery for 60 minutes followed by reperfusion and quantitation of infarct volume 24 hours later. Groups of dogs were either untreated or pretreated with UM-272 with an initial loading dose of 5.0 mg/kg (group A) or 2.5 mg/kg (group B) 30 minutes before occlusion of the left circumflex coronary artery. Both group A and group B animals received additional doses of 2.5 mg/kg of UM-272 every 90 minutes for a period of 6 hours so that the total respective doses were 15 and 12.5 mg/kg. Control animals received comparable volumes of 0.9% sodium chloride solution. All animals were followed throughout the 6-hour procedure with continuous electrocardiographic recordings which were used to assess the effects of acute myocardial ischemia upon disturbances in cardiac rhythm and the effects of drug treatment. Dogs which survived the procedure were given tetracycline i.v. the next day and sacrificed 1 hour later by an overdose of pentobarbital sodium. The hearts were removed and the left ventricle was sliced and examined first under ultraviolet light to localize the ischemic zone by noting the tetracycline fluorescence. The ventricular slices were next incubated in nitro blue tetrazolium which stains normal myocardial tissue, thus allowing one to quantitate the volume of infarcted myocardium by excising and weighing the nonstained and stained muscle separately. The untreated control group had an infarct volume of 23.8 +/- 3.2 g/100 g of left ventricle. The treated animals in groups A and B had respective infarct volumes of 2.3 +/- 0.8 g/100 g (P less than .001) and 7.0 +/- 3.3 g/100 g (P less than .025) of left ventricle. During the acute phase of ischemia and reperfusion, arrhythmias and alterations in the ST-segment, R-wave amplituted and development of pathologic Q-waves were more prominent in the untreated animals and almost totally absent in the treated animals. UM-272 produced a dose-dependent decrease in heart rate as well as a decrease in developed isometric tension. Pretreatment with UM-272 did not prevent the derangement of function in the ischemic zone nor did it permit a return of function upon reperfusion, even though it reduced the degree of cellular damage resulting from 60 minutes of regional ischemia. A possible mechanism for the protective effect of UM-272 may be through its ability to reduce myocardial contractility and heart rate, both of which would reduce myocardial oxygen consumption and thus produce a more favorable balance between myocardial oxygen supply and myocardial oxygen demand.
The electrophysiologic changes produced by amiodarone were examined in the isolated buffer-perfused rabbit heart. Long-term amiodarone administration (20 mg/kg/day for 28 days) depressed the intrinsic sinus heart rate and prolonged the PR and QT intervals of the electrocardiogram (P less than .05 vs. control). Ventricular refractoriness and the AH interval of the His-bundle electrogram were prolonged (P less than .05 vs. control) without a prolongation of the HV or QRS intervals. The electrophysiologic actions observed with long-term amiodarone treatment were reversed by the simultaneous administration of triiodothyronine (T3). No differences were noted in the electrophysiologic parameters measured in hearts removed from control and long-term amiodarone- plus T3-treated rabbits. The perfusion of the normal rabbit hearts with a buffer solution containing 1 microgram/ml of amiodarone hydrochloride failed to mimic the electrophysiologic changes produced by long-term amiodarone administration. Only a prolongation of the AH and PR intervals occurred with acute drug administration. The long-term administration of amiodarone was accompanied by decreased plasma T3 concentrations and increased concentrations of the less active thyroxine and reverse T3 species. The present data demonstrate the reversal of the electrophysiologic effects of long-term amiodarone administration by T3 administration. The data also suggest that the electrophysiologic actions of long-term amiodarone administration may be due in part to an antagonism of the actions of thyroid hormones.
COX-2 is an important mediator of cardiovascular protection after ischemia and reperfusion. It is known that COX-2 has a role in ischemic preconditioning (IP). The beneficial actions of COX-2 appear to be mediated by the synthesis of PGE2 and/or PGI2. Little is known about the actions of COX-1 in IP. This study was designed to determine the effects of COX-1 inhibition on infarct size after IP. Male New Zealand white rabbits were administered SC-560 (0.3 mg/kg or 1 mg/kg), nimesulide (5mg/kg), or vehicle intravenously prior to IP, 30 minutes of ischemia and 4 hours of reperfusion. IP reduced myocardial infarct size (10.5+/−2.6% vs. control 40.4+/−2.6%; p < 0.001) whereas treatment with the COX-2 inhibitor nimesulide abolished the protective effects of IP (40.3+/−3.1% p < 0.001 vs. IP). Treatment with the COX-1 inhibitor SC-560 reduced the protective effects of IP at a dose of 1 mg/kg (30.2+/−2.8%; p < 0.01), but not at 0.3 mg/kg (23.7+/−3.1%). The data suggest that endothelial COX-1 may also play a role in IP. It is likely that COX-2 plays a larger role because of its inducible activation, but the ability of COX-1 to produce protective PGE2 and/or PGI2 should not be overlooked. A recent study (Mitchell et al. 2006) suggests that endothelial COX-1, a source of PGI2, is more susceptible to inhibition by selective COX-2 inhibitors than is platelet COX-1. This would explain the reduced efficacy of IP by both the selective COX-1 and COX-2 inhibitors.
The antiarrhythmic and antifibrillatory actions of the CK-3579 and sematilide, two new class III antiarrhythmic drugs, administered in a multiple-dose regimen were evaluated in conscious dogs 3-5 days after anterior myocardial infarction. The study population consisted of three groups of 10 dogs each, in which all animals entered into the final protocol developed nonsustained or sustained ventricular tachycardia in response to programmed electrical stimulation using one, two or three premature stimuli. Each drug was administered intravenously in a dose of 3.0 mg/kg every 3 h for a total of six doses. Sematilide significantly suppressed the induction of ventricular tachyarrhythmia by programmed electrical stimulation in six of 10 postinfarcted dogs, whereas CK-3579 suppressed the induction of tachyarrhythmia in only two of 10 animals. Despite its ineffectiveness in preventing electrical induction of tachycardia, CK-3579 produced a significant increase in the cycle length of the induced ventricular rhythm. The administration of each drug was associated with an increase in the ventricular refractoriness and in the paced QT interval, suggesting that class III electrophysiologic properties contribute to the antiarrhythmic action of each drug. In addition, CK-3579 was shown to have beta 1-adrenoceptor blocking properties. The subsequent induction of an acute ischemic event in a region remote from the infarct-related artery was associated with a high incidence (80%, eight of 10 postinfarcted dogs) of ventricular fibrillation within the first hour after the onset of myocardial ischemia in the vehicle-treated control group.(ABSTRACT TRUNCATED AT 250 WORDS)
