M. Koltai

Loss of preconditioning in rabbits with vascular tolerance to nitroglycerin.

A preceding right ventricular overdrive pacing (VOP) of 500 b.p.m. for 5 min, markedly reduced the severity of global myocardial ischaemia produced by a subsequent 5‐min VOP in conscious rabbits. This VOP‐induced preconditioning developed in parallel with an increase in cardiac cyclic guanosine 3′: 5′‐monophosphate (cyclic GMP) content. VOP‐induced preconditioning was abolished when the animals had been made tolerant to the vasodilator effect of nitroglycerin (NG). In the heart of the NG‐tolerant rabbits, neither VOP nor preconditioning increased cyclic GMP content. This suggests that changes by NG tolerance of cyclic GMP metabolism may account for the loss of VOP‐induced preconditioning.

Ventricular overdrive pacing-induced preconditioning and no-flow ischemia-induced preconditioning in isolated working rat hearts

To examine preconditioning induced by short periods of ventricular overdrive pacing (VOP) as compared with that induced by no-flow ischemia, we subjected isolated working rat heart to 10-min coronary artery occlusion (test ischemia) followed by 3-min reperfu-sion after three intermittent periods of VOP (10 Hz) or 5-min no-flow ischemia, respectively. In the nonprecon-ditioned group, coronary occlusion decreased aortic flow (AF) from 46.6 ± 2.4 to 13.7 ± 1.7 ml/min and increased left ventricular end-diastolic pressure (LVEDP) from 0.53 ± 0.05 to 2.02 ± 0.07 kPa. Preconditioning by VOP or no-flow ischemia significantly increased AF to 25.1 ± 2.3 ml/min (p < 0.001) and to 27.3 ± 1.4 ml/min (p < 0.001) and decreased LVEDP to 1.38 ± 0.1 kPa (p < 0.001) and to 1.65 ± 0.05 kPa (p < 0.05), respectively, after test ischemia. Glibenclamide 10-7 M which blocked the antiischemic effect of the ATP-sensitive K+-channel (KATP) opener cromakalim, inhibited VOP-induced protection (AF 20.3 ± 2.3 ml/min; LVEDP 1.82 ± 0.15 kPa), but did not affect no-flow ischemia-induced preconditioning [AF 26.6 ± 2.4 ml/min (p < 0.001), LVEDP 1.60 ± 0.07 kPa (p < 0.01)]. VOP and no-flow ischemia precondition heart, however their cardioprotective mechanisms may be different in terms of KATP activation in rats.

Effect of Cicletanine on Reperfusion-induced Arrhythmias and Ion Shifts in Isolated Rat Hearts

Isolated hearts from normotensive (NT) and spontaneously hypertensive (SH) rats, subjected to normothermic global ischemia, were used to study whether cicletanine (a new antihypertensive drug) treatment exerts an antiarrhythmic effect against reperfusion-induced arrhythmias. The effect of the drug on myocardial ion contents (Na+, K+, Ca2+, and Mg2+) during ischemia and reperfusion was also determined. Using the optimal doses of cicletanine (30 and 100 mg/kg orally for 14 days), the incidence of reperfusion-induced ventricular fibrillation (VF) and ventricular tachycardia (VT) was reduced from their control values of 91 and 100% (after 30 min of ischemia) to 41 (p < 0.05), 50 (p < 0.05) and 41 (p < 0.05), 58% in the NT group, while the corresponding value in the SH group for VF and VT were 17 (p < 0.001), 33 (p < 0.01) and 17 (p < 0.001), 25% (p < 0.001), respectively. The results obtained indicate that the cardioprotective effect of cicletanine was greater in the SH group than in the NT group. Cicletanine significantly reduced the ischemia- and reperfusion-induced myocardial Na+ and Ca2+ gains and inhibited the loss of myocardial K+ and Mg2+ in both NT and SH groups. The antiarrhythmic effect of cicletanine appears to be correlated with the preservation of myocardial Na+, K+, Ca2+, and Mg2+ contents via an ion transport modulation.

Cicletanine attenuates overdrive pacing-induced global myocardial ischemia in rabbits: possible role of cardiac cyclic nucleotides.

BackgroundThis study examined whether cicletanine, an antihypertensive drug with cGMP phosphodiesterase inhibitory effect, could alleviate ventricular overdrive pacing-induced myocardial ischemia in chronically instrumented rabbits. MethodsAn electrode-catheter implanted into the right ventricle was used for pacing (500 bpm over 5 min) and for measuring intracavital ST-segment elevation and ventricular effective refractory period (VERP). PQ and QT intervals were measured in the chest-lead ECG, and dP/dtmax as well as left ventricular end-diastolic pressure (LVEDP) were recorded through a left intraventricular catheter. In separate groups, mean arterial blood pressure (MABP) was monitored from the right carotid artery. Experiments were performed on conscious rabbits after a week of convalescence. In anesthetized, open-chest rabbits, samples were taken from the left ventricle before and after drug treatment and/or overdrive pacing for determination of cGMP and cAMP contents by radioimmunoassay. ResultsIntravenous cicletanine, 30 mg/kg body weight, did not change resting MABP, dP/dtmax, and LVEDP, but it did reduce heart rate and prolonged PQ and QT intervals and VERP. Overdrive pacing produced intracavital ST-segment elevation, increased LVEDP, and decreased dP/dtmax and MABP. Cicletanine administered 15 minutes before pacing significantly attenuated ST-segment elevation, increased LVEDP, and decreased dP/dtmax and MABP. In anesthetized animals, cicletanine itself slightly increased cardiac cGMP and cAMP contents. Overdrive pacing moderately increased cGMP and profoundly elevated cAMP, and in overpaced rabbits, cicletanine further increased cGMO and markedly attenuated cAMP content increased by overdrive pacing. ConclusionsThese results suggest that in correlation with alterations of cardiac cycle nudeotide contents, cicletanine protects the heart against pacing-induced myocardial ischemia.

Cicletanine improves myocardial function deteriorated by ischemia/reperfusion in isolated working rat hearts

Summary The effect of cicletanine, a novel furopyridine antihypertensive drug was compared with that of nitren-dipine, a dihydropyridine slow calcium channel blocker, on cardiac function and reperfusion-induced ventricular arrhythmias in isolated working rat hearts subjected to 10-min ischemia induced by ligation of the left main coronary artery followed by 10-min reperfusion. Before ischemia, cicletanine and nitrendipine, perfused at concentrations of 3 ± 10-5, 6 ± 10-5, 10-4, and 2 ± 10-4or 10-8 M, respectively, did not influence heart rate (HR), LV developed pressure (LVDP), its first derivative (LVdP/dtmax) and LV end-diastolic pressure (LVEDP), whereas aortic flow (AF) was decreased by 2 ± 10 -4 M cicletanine only. Coronary flow (CF) remained unchanged by various cicletanine concentrations but was slightly increased by nitrendipine. In the concentration range of 3 ± 10-5–10-4 M, cicletanine improved AF either in ischemia or during reperfusion, whereas 2 ± 10 -4 M had no such effect. Nitrendipine slightly attenuated ischemia/reperfusion-induced decrease in AF. Cicletanine and nitrendipine enhanced LVDP during ischemia. Ischemia-induced deterioration of LVdP/dtmax was reduced by cicletanine, during reperfusion, but this parameter was reduced by nitrendipine and the highest cicletanine concentration. Cicletanine decreased LVEDP significantly during ischemia and reperfusion, but nitrendipine had no such effect. All cicletanine concentrations reduced the incidence of irreversible ventricular fibrillation (VF) during reperfusion, an effect roughly concentration dependent in the range of 3 ± 10-5–10-4 M, whereas nitrendipine had no influence on arrhythmias.

Cromakalim and cicletanine against pacing-induced myocardial ischemia in conscious rabbits

Myocardial ischemia assessed by intracavital ST-segment elevation, shortening of ventricular effective refractory period (VERP), and increase in left ventricular end-diastolic pressure (LVEDP) was provoked by ventricular overdrive pacing (VOP) in conscious rabbits. Cromakalim (10 micrograms/kg), an ATP-sensitive K+ channel opener, and cicletanine (30 mg/kg), a cGMP-phosphodiesterase inhibitor, reduced VOP-induced ST-segment elevation and LVEDP-increase. Under resting conditions, cromakalim lowered blood pressure, increased heart rate (HR), and shortened VERP, whereas cicletanine decreased HR, prolonged VERP without changing blood pressure. Co-administration of cromakalim and cicletanine additively reduced VOP-induced ST-segment elevation, shortening of VERP, and LVEDP-increase. Cicletanine did not change cromakalim-induced hypotension but abolished reflexogenic tachycardia. This suggests that VERP shortening is not a prerequisite for the anti-ischemic effect of cromakalim, and the combination of these drugs may afford a potent and safe anti-ischemic effect without affecting hypotension induced cromakalim.