Cecilia A. Muller

Adrenaline-induced “oxygen-wastage” and enzyme release from working rat heart. Effects of calcium antagonism, β-blockade, nicotinic acid and coronary artery ligation

Adrenaline in a high dose (10−6 m) caused the following harmful effects on mechanical and biochemical parameters of the isolated working rat heart: (i) loss of efficiency of mechanical work from 4.48 ± 0.20 to 3.24 ± 0.13 joules per ml O2 (P < 0.001), so that much more oxygen was required to do the same amount of work (“oxygen-wastage”); (ii) a decreased cardiac output despite increased power production (from 14.2 ± 0.7 to 18.9 ± 0.8 mW/g, (P < 0.001); (iii) a marked release of lactate dehydrogenase (value 10 min after adrenaline: 558 ± 113 mU/g/min; vs control: 16 ± 2); and (iv) a decreased myocardial content of ATP. Interventions to counter the deleterious effects of adrenaline were: calcium antagonism, β-blockade, an antilipolytic agent, and a combination of calcium antagonism and an antilipolytic agent. From this, two separate aspects emerged. First, mechanical function as measured by cardiac output and power production was markedly improved by calcium antagonism which completely reversed the impairment of function caused by the high dose of adrenaline. β-blockade had also a less marked protective effect on mechanical function. Secondly, enzyme release was most effectively inhibited by the combination of calcium antagonism and inhibition of lipolysis or by propranolol. The inefficiency of work (“oxygen-wastage”) was β-mediated and Ca2+-dependent, whereas enzyme release was predominantly Ca2+-dependent and partially dependent on lipolysis. Hence the effects of β-blockade in inhibition of the adrenaline-provoked enzyme release could be ascribed to a combination of calcium-antagonism and inhibition of lipolysis.

Effects of mibefradil, a novel calcium channel blocking agent with T-type activity, in acute experimental myocardial ischemia: maintenance of ventricular fibrillation threshold without inotropic compromise☆

OBJECTIVES We tested whether mibefradil, a selective T-type calcium channel blocking agent, could differentially inhibit experimental ventricular arrhythmogenesis more than contractility during acute regional ischemia and reperfusion compared with that during L-channel blockade by verapamil. BACKGROUND T-type calcium channels are found in nodal and conduction tissue and in vascular smooth muscle, but in much lower density in contractile myocardium. The potential role of mibefradil in ventricular arrhythmogenesis remains unclear. METHODS Mibefradil (Ro 40-5967, 1 mg/kg body weight intravenously [i.v.]) was given as a bolus 30 min before anterior descending coronary artery ligation, followed by 2 mg/kg per h i.v. during 20 min of ischemia and 25 min of reperfusion in open chest pigs. In a second group, mibefradil was given in a dose twice as high. A third group received verapamil (0.3 mg/kg i.v.), followed by an infusion of 0.6 mg/kg per h. RESULTS During the ischemic period, the low (clinically relevant) dose of mibefradil prevented the fall of the ventricular fibrillation threshold, without depressing the maximal rate of pressure development of the left ventricle (LVmax dP/dt). This low dose increased left ventricular blood flow, whereas peripheral arterial pressure remained unchanged. The higher dose of both mibefradil and verapamil was antiarrhythmic during ischemia, at the cost of depressed contractile activity. During reperfusion, only the higher dose of mibefradil and verapamil was antiarrhythmic but both depressed contractile activity. CONCLUSIONS Mibefradil is antiarrhythmic, without inotropic compromise. Speculatively, both T-type and L-type calcium channel blockade are involved in these effects.

Critical role of dose in protection by propranolol against ventricular fibrillation in a pig model of acute myocardial ischemia

We hypothesized that the antiarrhythmic efficacy of propranolol during acute myocardial ischemia could be dose related. Propranolol was administered in two equally divided doses 30 min before and 10 min after ligation of the anterior descending coronary artery (CAL) in anesthetized open-chest pigs. Only the lowest dose of propranolol, i.e., 0.1 mg/kg intravenously (i.v.) (plasma level 22 ± 2 ng/ml) decreased the incidence of ventricular fibrillation (VF), i.e, 3 of 12 versus 16 of 20 in control group (p < 0.01). VF incidence with propranolol 0.5 or 3 mg/kg was 4 of 6 and 8 of 9, respectively (both NS vs. control group). Propranolol 0.1 mg/kg did not change left ventricular (LV) blood flow. Propranolol 3 mg/kg reduced blood flow in the peripheral ischemic myocardium to 13.2 ± 1.2 versus 19.2 ± 1.4 ml/100 g/min in control group (p < 0.01), and in the midischemic zone to 4.4 ± 0.5 versus 7.0 ± 0.9 ml/100 g/min in control group (p < 0.001). Propranolol 0.1 mg/kg prevented a disparity of levels of cyclic AMP from arising between ischemic and non-ischemic myocardium, whereas propranolol 3.0 mg/kg did not. Furthermore, LV mechanical function was suppressed by propranolol 3 mg/kg. Only the lowest dose of propranolol (i.e., 0.1 mg/kg) decreased the incidence of VF in this model.

Bucindolol, a beta blocker, decreased ventricular fibrillation and maintained mechanical function in a pig model of acute myocardial ischemia

SummaryBucindolol is a new beta blocker with marked vasodilatory properties and intrinsic sympathomimetic activity. We tested its potential effect against ventricular fibrillation (VF), in a pig model of acute myocardial ischemia. Bucindolol 6 mg/kg IV was administered in two equally divided doses, the first 30 minutes prior to, and the second 10 minutes after, ligation of the anterior descending coronary artery (CAL) in anesthetized open-chest pigs. Bucindolol decreased the incidence of VF to 1/11 versus 14/16 in the control group (p<0.005). Bucindolol also decreased the duration of ventricular tachycardia, 15±8 seconds versus 104±32 seconds in the control group (p<0.01). Bucindolol maintained LVmaxdP/dt at predrug and pre-CAL values, whereas LVmaxdP/dt was decreased by CAL in the control group. Bucindolol decreased arterial pressure and heart rate. Bucindolol increased blood flow in the peripheral ischemic zone (24.6±1.8% versus 16.2±1.7% (percent of pre-CAL value) in controls, p<0.002), as well as in the nonischemic zones (perlischemic zone: 126.4±6.1% versus 96.7±4.8% in the control group, p<0.0005; remote nonischemic zone: 126.6± 7.1% versus 87.1±4.3% of pre-CAL value in the control group, p<0.0001). Bucindolol had marked antiarrhythmic effects that were associated with beneficial effects on the mechanical function of the left ventricle and on blood flow to the ischemic myocardium.

Antiarrhythmic and metabolic effects of indoramin during acute regional ischemia and reperfusion in isolated rat heart.

The antiarrhythmic effect of α1-adrenbceptor antagonists during myocardial ischemia and reperfusion remains controversial. The potential antiarrhythmic properties of indoramin, an α1-antagonist, were assessed in the isolated perfused rat heart during regional ischemia and during sustained reperfusion. Coronary artery ligation (CAL) decreased the ventricular fibrillation threshold (VFT) of control hearts from 9.1 ± 1.3 (pre-CAL, mean ± SEM) to 2.1 ± 0.5 mA 15 min post-CAL (p < 0.0001). Perfusion with indoramin 10−8 M (α1-receptor antagonistic concentration) started 5 min prior to CAL did not prevent the fall in VFT after CAL. Indoramin 10−6 M prevented the fall in VFT after CAL relative to the control group. Indoramin 10−5 M markedly increased the VFT before CAL from 9.9 ± 1.0 to 28.6 ± 2.9 mA (p < 0.0001) and prevented the fall in VFT after CAL. During reperfusion, indoramin 10−5 M decreased the incidence of spontaneous ventricular fibrillation (VF) to 1 of 6 vs. 6 of 6 in the control group (p < 0.02). Indoramin 10−5 M preserved adenosine triphosphate in the reperfused myocardium: 2.82 ± 0.06 vs. 2.16 ± 0.21 μmol/g in the control group (p < 0.05). Specific α1-antagonist properties of indoramin did not appear to be involved in the antiarrhythmic effects.

Combination of a Calcium Antagonist, Verapamil, with an Angiotensin Converting Enzyme Inhibitor, Trandolapril, in Experimental Myocardial Ischemia and Reperfusion: Antiarrhythmic and Hemodynamic Effects of Chronic Oral Pretreatment

The combination of a calcium antagonist with an angiotensin-converting enzyme (ACE) inhibitor is increasingly used in the therapy of hypertension, but there are no experimental data supporting the use of this combination in acute myocardial ischemia and reperfusion. We tested the effects of oral pretreatment in a pig model, paying special attention to arrhythmias and adverse hemodynamic effects. Pigs received verapamil 240 mg + trandolapril 4 mg, verapamil 240 mg, or placebo orally once daily for 10 days, after which a coronary artery was ligated for 20 minutes and then allowed to reperfuse. The ventricular fibrillation threshold (VFT) was measured during ischemia to assess the vulnerability of the heart to ventricular fibrillation, whereas spontaneous tachyarrhythmias were monitored during reperfusion. Regional left ventricular (LV) blood flow was measured with radioactive microspheres. During the ischemic period, both the combination of verapamil plus trandolapril, and verapamil alone, prevented a fall in the VFT, indicating antiarrhythmic activity. The combination maintained LV contractile activity and cardiac output (CO) at preligation levels, whereas verapamil alone decreased cardiac output. During reperfusion, verapamil plus trandolapril prevented spontaneous ventricular tachyarrhythmias and increased blood flow in the reperfused zone. In contrast, verapamil was not antiarrhythmic and decreased CO. Thus the addition of the ACE inhibitor trandolapril to the calcium antagonist verapamil resulted in antiarrhythmic activity during ischemia and reperfusion, and produced a better hemodynamic profile.