Open-chest Dog Heart Research Articles

Antiarrhythmic Effects of Bisaramil on Triggered Arrhythmias Produced by Intracoronary Injection of Digitalis and Adrenaline in the Dog

Antiarrhythmic effects of bisaramil were examined by using new in vivo triggered arrhythmia models, and they were compared with those of other antiarrhythmic drugs. Bisaramil (3–10 μg, i.e.) suppressed triggered ventricular arrhythmias that were produced during pauses between trains of rapid ventricular stimulation (cycle length: 250 msec, train number: 15) in anesthetized open-chest dog hearts administered with subtoxic doses of digitalis or adrenaline to the anterior descending coronary artery. The potencies of bisaramil, disopyramide, lidocaine and flecainide suppressing digitalis-induced triggered ventricular arrhythmias were similar to those suppressing adrenaline-induced ones. The potency of verapamil for suppressing digitalis-induced triggered ventricular arrhythmias were weaker than that for suppressing the adrenaline-induced ones. Bisaramil was the most effective among the antiarrhythmic drugs used in the present experiment. Since bisaramil has been reported to be effective in suppressing other canine automatic ventricular arrhythmias, and the triggered ventricular arrhythmias occur in clinical situations, bisaramil may become a useful drug for the treatment of clinical arrhythmias.

Effects of iloprost, a PGI2 derivative, on ischemic myocardial energy and carbohydrate metabolism in dogs.

Effects of iloprost, which is a stable prostacyclin analogue, on the ischemic myocardium were examined in the open-chest dog heart in terms of biochemical parameters. Ischemia was initiated by ligating the left anterior descending coronary artery. When the coronary artery was ligated for 3 min, the levels or glycogen, fructose-1,6-diphosphate (FDP), adenosine triphosphate and creatine phosphate decreased, and the levels of glucose-6-phosphate (G6P), fructose-6-phosphate (F6P), lactate, adenosine diphosphate and adenosine monophosphate increased. During ischemia, therefore, energy charge potential was significantly decreased from 0.89 +/- 0.01 to 0.82 +/- 0.01, and ([G6P] + [F6P])/[FDP] and [lactate]/[pyruvate] ratios were significantly increased from 1.75 +/- 0.30 to 29.05 +/- 5.70 and 13 +/- 3 to 393 +/- 112, respectively. Iloprost (0.1, 0.3, or 1 microgram.kg-1) was injected intravenously 5 min before the onset of ischemia. Iloprost (0.1, 0.3, and 1 micrograms.kg-1) reduced the ischemia-induced decrease in energy charge potential to 94, 74, and 86%, respectively, the increase in ([G6P] + [F6P])/[FDP] to 38, 29, 32%, respectively, and the increase in [lactate]/[pyruvate] to 67, 45, 65%, respectively. These results suggest that iloprost lessens the myocardial metabolic derangements produced by ischemia, and the most potent effect was obtained at the dose of 0.3 microgram.kg-1.

Denopamine (beta1-selective adrenergic receptor agonist) and isoproterenol (non-selective beta-adrenergic receptor agonist) equally increase heart rate and myocardial oxygen consumption in dog heart.

The effects of denopamine (a beta 1-selective adrenergic receptor agonist) and isoproterenol (a non-selective beta-adrenergic receptor agonist) on heart rate, left ventricular contractility, and left ventricular oxygen consumption (VO2) at the same left ventricular volume were compared in excised cross-circulated dog hearts. Denopamine and isoproterenol increased heart rate and VO2 to a comparable extent at a comparably increased contractility. Moreover, the oxygen cost of contractility which quantifies VO2 for excitation-contraction coupling was the same between the two agents. These findings contradict the previously reported smaller increases in heart rate and VO2 by denopamine than by isoproterenol in open-chest dog hearts, which have been mainly attributed to the beta 1-selectivity of denopamine. Our results suggest that in isolated and denervated hearts, the degree of beta 1-selectivity of a beta-agonistic agent does not directly determine the relative potencies of its inotropic and chronotropic effects and the oxygen cost of contractility.

Interaction between adenosine and beta-adrenoceptors.

Interaction between adenosine and isoproterenol (ISP) on myocardial inotropic action was studied in open-chest dog hearts. The local myocardial force and the left ventricular (LV) dP/dt were measured as indices of myocardial contractility. Isoproterenol [ISP, 9.47 microM (2 micrograms/ml)] was infused into the left circumflex coronary artery at rates of 0.05 ml/min (low dose ISP) or 0.2 ml/min (high dose ISP). Two mM adenosine or 0.5 mM N6-phenylisopropyl-adenosine (PIA) were infused into the coronary artery at rates of 0.2 (4 x 10(-7) mol/min), 0.5 (1 x 10(-6) mol/min) and 10 ml/min (2 x 10(-5) mol/min) in the presence of either a low or a high dose of ISP. Adenosine infusion at a rate of 0.2 ml/min did not modify myocardial contractility in the presence of the both doses of ISP. The larger doses of adenosine, 0.5 ml/min and 10 ml/min, decreased myocardial-developed tension and LVmax dP/dt dose-dependently. However, the dose of adenosine which affected myocardial contractility was inphysiologically high in comparison with the concentration in the ischemic myocardium. PIA, a potent agonist of adenosine A1-receptor, attenuated an increase in myocardial contractility in a dose-dependent manner which was caused by intracoronary ISP infusion. This indicates that A1-adenosine receptors exist, but a functional adenosine-catecholamine antagonism does not play a significant role in the canine left ventricle.

Effect of flunarizine on ischemic myocardial metabolism in dogs

The effect of flunarizine, a calcium entry-blocker, on the ischemic myocardial metabolism of the open-chest dog heart was examined and compared to that of diltiazem. During ischemia, initiated by ligating the left anterior descending coronary artery, the metabolism of the myocardium switched from aerobic to anaerobic; the levels of glycogen, fructose-1,6-diphosphate (FDP), adenosinetriphosphate and creatinephosphate decreased, and the levels of glucose-6-phosphate (G6P), fructose-6-phosphate (F6P), lactate, adenosine diphosphate and adenosine monophosphate increased during 3 min of ischemia. The calculated energy charge potential decreased, and the ([G6P] + [F6P]/[FDP] ratio and the lactate/pyruvate ratio were increased by ischemia. Flunarizine (0.3 or 1 mg/kg) or diltiazem (0.1 mg/kg) was injected i.v. 5 min before the start of ischemia. Pretreatment with either flunarizine or diltiazem reduced the decrease in the energy charge potential and the increase in the ([G6P] + [F6P])/[FDP] ratio during ischemia. Flunarizine (1 mg/kg) and diltizem (0.1 mg/kg) reduced the accumulation of lactate due to ischemia, leading to a decrease in the lactate/pyruvate ratio. Flunarizine and diltiazem may lessen the influence of ischemia on the myocardial tissue.

Inhibitors of adenosine catabolism improve recovery of dog myocardium after ischemia.

The effects of inhibitors of adenosine catabolism on contractile function and metabolites were assessed during 15 minutes of ischemia followed by 30 minutes of reperfusion in the open-chest dog heart. As compared to sham treatment, pretreatment with erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA) and dipyridamole (DP) protected contractile function during ischemia, and improved recovery of high energy phosphate content and contractile function during reperfusion following ischemia. Testing EHNA and DP in a free-radical generating system indicated both compounds have some scavenging ability, suggesting the effect of EHNA + DP may not be on adenosine nucleotide metabolism alone. Comparison of end diastolic segment lengths to contractile function indicated the results were not affected by changes in preload resulting from peripheral vasodilation.

Different effects of interventions suppressing free fatty acid metabolism on myocardial ischemia.

We studied the effects of different metabolic interventions, which stimulate oxidative myocardial carbohydrate metabolism, on ischemic stress during repeated coronary occlusions of three minutes in open-chest dog hearts. Increase of glucose concentration in plasma and decrease of peripheral lipolysis by glucose-insulin-potassium (n = 6) had no substantial beneficial effects on myocardial damage indicated by hemodynamic, electrocardiographic, and metabolic parameters. Infusion of lactate and pyruvate (10 mM, n = 6) was detrimental. Only activation of pyruvate dehydrogenase by dichloroacetate (n = 6) without influence on plasma osmolality reduced epicardial ST-segment elevations (-42%) and myocardial release of potassium (-36%), phosphate (-58%), and lactate (-39%). Elevations of plasma osmolalities by 10 and 20 mOsm with the metabolically inert mannitol increased ECG changes, functional loss and release of potassium, phosphate, and lactate during ischemia in our model. It is suggested, that the oxygen-saving potency of metabolic interventions can exert univocal beneficial effects in experimental and in clinical conditions only when systemic hyperosmolality and hypervolemia are avoided.

Temporal and spatial characteristics of evolving cell injury during regional myocardial ischemia in the dog: The “border zone” controversy

An open chest dog heart with multiple coronary ligations was used to define the temporal and spatial characteristics of injury evolving during regional ischemia. With the use of a multiple (40 sample) biopsy device, adjacent transmural biopsy specimens were obtained from the transition zone between normal and ischemic tissue after 5, 30, 45, 60 and 120 minutes of ischemia. The first 1.8 mm of epicardial tissue was taken for the analysis of flow and metabolites. The results confirmed the existence of a sharp interface of flow and metabolism in the epicardial lateral plane at the boundary of the ischemic zone. There was no significant zone of intermediate injury (flow and metabolism being depressed uniformly throughout the ischemic area). Comparison of the distribution of flow determined by radiolabeled gadolinium-153 at onset of ischemia with that indicated by radiolabeled tin-113 microspheres given at the end of various periods of ischemia revealed no change in the position or steepness of the flow interface at any time during the first 2 hours of ischemia. This observation, together with the absence of any major redistribution or enhancement of residual flow to the ischemic zone, indicated that there was little or no significant collateralization between 5 and 120 minutes. Analysis of the adenosine triphosphate (ATP) content revealed a rapid depletion during the first 5 minutes of ischemia; the content then remained essentially unchanged until 30 minutes, after which time a second phase of accelerated ATP depletion was observed until 45 minutes. ATP content then remained relatively constant up to 2 hours.

A new model for testing therapeutic interventions during myocardial ischemia.

An open-chest dog heart model is presented which shows highly reproducible hemodynamic, electrophysiologic, and metabolic changes during and after short-term coronary occlusions. We repeatedly performed 3-min coronary ligations of the proximal ramus interventricularis anterior followed by reperfusion periods of 45 min. Thus, hemodynamic, metabolic, and electrophysiologic parameters of myocardial damage were fully reversible. The experimental model presented seems well suited to evaluate interventions which aim at influencing the extent and damage of myocardial ischemia without needing a large number of separate experiments.

Estimation of local myocardial stress

Two formulas are presented for estimating local average circumferential stress in the left ventricle from the cavity pressure and various quantities, available from the angiogram, which characterize the size and shape of the cavity and ventricular wall. The advantages of these formulas are as follows: 1) they are based on thick-wall shell theory; 2) they are intended for application at positions in the ventricular wall other than the base; and 3) they are based on a more general representation of ventricular geometry than a sphere, cylinder, or ellipsoid. Except for one location, both formulas predict average circumferential stresses that agree to within 25% with the corresponding stresses in a finite element model of an aneurysmal ventricle. In addition, at the equator of a thick-wall ellipsoid, the formulas are identical in form to a previously derived formula that has been shown to predict stresses that are in fair to good agreement with measured stresses in the open-chest dog heart.

Effect of ventricular premature beats on idioventricular pacemaker activity

The effect of ventricular premature beats on idioventricular pacemaker activity was studied in open-chest dog hearts with a surgically induced block in the His bundle. While the ventricle was paced by basic stimuli at a given rate, the pacing was interrupted for about 2.5 seconds following every twelfth basic beat (V 1) in order to obtain the interval between V 1 and the first escape beat (V e) or the basic escape interval (V 1V e). Ventricular premature beats (V 2) were then introduced at various coupling intervals (V 1V 2) and the effect of these premature beats on the postextrasystolic escape interval (V 1V e) was observed. The plot of V 2V e against V 1V 2 intervals showed that the V 2V e interval was shortest at shorter V 1V 2 intervals, and it increased gradually with the increase in V 1V 2 intervals. The V 2V e intervals at shorter coupling intervals were much shorter than the basic escape interval (V 1V e), indicating enhanced automaticity after early premature beats. The V 2V e at longer coupling intervals were much longer than the basic escape intervals, indicating suppressed automaticity after late premature beats. The similar response to ventricular premature beats was noted during spontaneous idioventricular rhythm. The suppression was more pronounced at faster pacing rates and following two successive premature beats, probably due to the phenomenon of overdrive suppression. The same phenomena of altered automaticity after premature beats could be observed under the influence of ouabain, epinephrine, lidocaine, and propranolol, although these agents either decreased or increased the average escape intervals. The results may explain the clinically observed alteration of the idioventricular pacemaker rate following ventricular premature beats.