Kinin-induced prolongation of action-potential duration in right ventricular muscle from rat: involvement of B1 and B2 receptors.

Previous work has shown that, in rat ventricular muscle, bradykinin (BK) causes a dose-dependent increase in action potential duration (APD), an action that may be responsible for APD prolongation by captopril (kininase II). To determine which kinin receptor might be involved in APD prolongation, we studied the effects of B1- and B2-receptor agonists, as well as those of antagonists and mergepta (a kininase I inhibitor) added during BK superfusion. Action potentials were recorded by using the standard glass microelectrode technique in rat ventricular muscle preparations. Action-potential characteristics were compared between preparations superfused with peptide/drug-free Tyrode's solution (control group) and preparations superfused with peptide/drug-containing solution. APD was significantly longer in preparations superfused with BK (10(-8) M) than in the control group. The APD prolongation induced by BK, a known B2-receptor agonist, was significantly reduced by Hoe 140 (a B2 antagonist) and also by Lys[Leu8]des-Arg9-BK (a B1 antagonist), an action presumably related to inhibition of B1 receptor stimulation by the BK metabolite des-Arg9-BK. When mergepta was added in the presence of BK, APD prolongation by BK was significantly reduced, an effect that could have been related to reduced B1-receptor stimulation after inhibition of the endogenous generation of des-Arg9-BK by kininase I. Sar4-[d-Phe8]des-Arg9-BK, a B1-receptor agonist that is not degraded by kininase II, also prolonged APD. We conclude that both B1 and B2 receptors may be involved in APD prolongation induced in rat ventricular muscle preparations.

Class III antiarrhythmic effects of ceruloplasmin on rat heart.

Recently it has been shown that ceruloplasmin presents a protective action against reperfusion-induced arrhythmias in the isolated perfused rat heart, an effect that is lost when the protein is denaturated by heat. The present study was carried out to see whether ceruloplasmin can alter electrophysiological properties such as ventricular effective refractory periods, conduction time, and action potential duration calculated at 50, 75, and 90% levels of repolarization (APD50, APD75, APD90). To check the specificity of the electrophysiological effects of ceruloplasmin, we have also compared them with those of heat-denatured ceruloplasmin, superoxide dismutase, catalase, deferoxamine, and albumin. In isolated rat hearts, ceruloplasmin (0.25-3 microM) (n = 8 for each concentration) was shown to increase the effective refractory period in a concentration-dependent manner by 26 to 89%. Conduction time was not significantly altered. Heat-denatured ceruloplasmin (0.50-3 microM) (n = 8 for each concentration) increased the effective refractory period by 33 to 70% and did not affect the conduction time. In contrast, superoxide dismutase (1-4 microM), catalase (1-2 microM), deferoxamine (500 microM-1 mM), and albumin (1-4 microM) (n = 8 for each substance and for each concentration) had no significant effect on effective refractory period and conduction time at any dose, suggesting that the ceruloplasmin effect might be specific. In rat ventricular preparations, ceruloplasmin (1 microM) also induced a constant prolongation of APD50 (52%), APD75 (64%), and APD90 (41%) after 15 min of infusion (n = 6). The prolongation of effective refractory period and of action potential duration, by native and heat-denatured ceruloplasmin, suggests that this substance has specific class III effects, although this cannot entirely account for its antifibrillatory action at reperfusion in isolated rat hearts.

Prolongation by captopril of action potential duration in the normal and hypertrophied rat ventricle: direct action or inhibition of the local angiotensin converting enzyme?

OBJECTIVE: The aims were: (1) to study the acute effects of captopril on the action potential characteristics of ventricular fibres from the normal rat, (2) to compare the effects of captopril with those of perindoprilat, a non-thiol angiotensin I converting enzyme (ACE) inhibitor, (3) to determine the electrophysiological properties of the peptide substrates of converting enzyme, bradykinin and angiotensin I, and (4) to investigate whether the effects of captopril occurring in the healthy heart also occur in two models of ventricular hypertrophy. METHODS: Action potentials were recorded with the standard glass microelectrode technique in right ventricular preparations excised from rat hearts and superfused under baseline conditions and with drug containing or peptide containing Tyrode solution. Ventricular hypertrophy was induced in response to hypertension (unilaterally nephrectomised, DOCA-salt model) or 4 week old left ventricular infarction. RESULTS: In preparations from normal rat hearts, captopril increased action potential duration in a concentration dependent fashion [EC50 = 3.5 x 10(-8) M; maximum effect = 44(SEM 5.1)% prolongation at 10(-5) M for action potential duration at 90% repolarisation, APD90]. Perindoprilat similarly caused a dose dependent increase in action potential duration, but with 100 times greater potency [EC50 = 3.1 x 10(-10) M; maximum effect = 71(11)% prolongation at 10(-5) M for APD90]. SQ 14,534, a stereoisomer of captopril with one hundredth the ACE inhibitor potency, had no significant effect on action potential duration at 10(-5) M. Angiotensin I and bradykinin caused concentration dependent prolongation of action potential, but angiotensin II (10(-6) M) had no effect. Captopril (10(-5) M) had no significant effect in the hypertrophied right ventricle from DOCA-salt hypertensive rats, but significantly increased APD90 [39(4.9)%] in right ventricular preparations from rats with 4 week old anterior left ventricular infarction. CONCLUSIONS: In the rat, captopril prolongs action potential duration, an effect possibly due to local accumulation of bradykinin and angiotensin I.