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We examined the effects of the benzoylguanidine derivative HOE 694, an inhibitor of Na(+)-H+ exchange, against veratrine-induced diastolic contractures and action potentials recorded in rat isolated left atria. Concentration-dependent protective effects against veratrine-contractures, in the absence of negative inotropic responses, were observed with HOE 694 (IC50 = 20.1(7.6-27.0) microM, n = 24) and with the chemically related amiloride derivatives DMA, EIPA, HMA and MIA, but not with amiloride itself. Concomitant Na(+)-H+ exchange blockade by a high concentration of amiloride (100 microM) failed to significantly modify the protective effects of HOE 694. HOE 694 decreased Vmax significantly at 10 microM (166.7 +/- 21 vs 154.7 +/- 20 V/s, P < 0.05, n = 6) without any effect on resting potential or action potential duration. High concentrations (100 microM) of HOE 694 further decreased Vmax and increased action potential duration. The protective effects of HOE 694 were compared with three of the class 1 antiarrhythmic agents, quinidine, lidocaine and flecainide against veratrine contracture. These Na+ channel blockers exerted protective effects in the same range of concentrations as HOE 694. Our findings demonstrate that HOE 694 prevents veratrine contractures at concentrations which presumably affect Na(+)-H+ exchange. However, the mechanism by which HOE 694 affords protection is apparently mediated by class 1-type Na+ channel blockade.

Action potential duration (APD) lengthening is believed to underlie the cardiac arrhythmogenicity of ketanserin, a serotonin (5-HT)2A/2C receptor antagonist. We wished to determine (a) whether this activity involves blockade of 5-HT2A/2C receptors and (b) the precise mechanism of ketanserin-induced APD prolongation. APs were recorded in guinea pig isolated papillary muscles by conventional "floating" microelectrodes, and potassium currents in guinea pig isolated myocytes were recorded in the whole-cell configuration. Ketanserin (1-10 microM) increased APD (EC50 value for enhancing APD at 90% repolarization (APD90) 3.1 +/- 2.7 microM, n = 24), without affecting resting potential, maximum upstroke velocity (Vmax) or AP amplitude (APA). Pirenperone (10 microM), a ketanserin congener, similarly increased APD90 from 204 +/- 3 to 241 +/- 7 ms (p < 0.001, n = 6). No increase in APD was observed, however, with ritanserin or ICI 170809, even at high concentrations (10 microM, n = 6, respectively), two 5-HT2A/2C receptor antagonists chemically distinct from ketanserin, thereby excluding the involvement of 5-HT2A/2C receptors in mediating APD lengthening. That APD prolongation was mediated specifically by the benzolyl-piperidine moiety of ketanserin and pirenperone was confirmed by 1-propyl-4(4-fluorobenzoyl)piperidine (PFBP), which evoked APD lengthening effects remarkably similar to those produced by ketanserin and pirenperone (EC50 3.73 +/- 2.6 microM, n = 12). In isolated cardiomyocytes, ketanserin (1-32 microM) selectively and concentration-dependently reduced the IKr component of the delayed outward current (IK) without affecting the inward rectifier current, IK1. Thus, ketanserin (32 microM) significantly reduced IK at a potential value of -20 mV from 813 +/- 65 to 569 +/- 55 pA (p < 0.001, n = 6), whereas at a potential value of -110 mV, IK1 was not significantly affected (730 +/- 103 vs. 603 +/- 143 pA, respectively; n=6). The results demonstrate that APD is prolonged by ketanserin and congeners but not be chemically different 5-HT2A/2C receptor antagonists. The benzoyl-piperidine moiety appears to mediate the APD-prolonging effects of ketanserin and pirenperone specifically. Furthermore, ketanserin-induced APD lengthening does not appear to involve 5-HT2A/2C receptors but is consecutive to direct blockade of myocardial potassium channels.

We hypothesized that the slowly inactivating component of Na+ current, which is an integral part of the Na+ window current, is a major pathway for Na+ loading during myocardial ischemia. The putative protective effects of tetrodotoxin (TTX) and R-56865, at concentrations that selectively blocked the Na+ window current, as assessed by action potential plateau shortening without affecting maximum upstroke velocity (Vmax), were examined in isolated Langendorff-perfused guinea pig hearts subjected to 50 min of normothermic global ischemia and 60 min of reperfusion. In papillary muscles, TTX reduced action potential duration at > or = 10 nM but reduced Vmax only at > or = 1 microM. R-56865 (10 nM-10 microM) failed to affect Vmax but concentration dependently reduced action potential duration. Ischemia-induced cardiac dysfunction, including increases in left ventricular end-diastolic pressure and lactate dehydrogenase and creatine phosphokinase release at reperfusion, was attenuated by TTX and R-56865 (0.1-320 nM). Ischemic contracture (increase in left ventricular end-diastolic pressure) was abolished by drug concentrations as low as 1 nM, whereas higher concentrations (> 10 nM) of TTX and R-56865 were required to restore systolic function at reperfusion. TTX and R-56865 had little or no effect on hemodynamic variables. Evidence is provided of pronounced and direct cardioprotective effects of low concentrations of R-56865 and TTX in cardiac muscle during ischemia.(ABSTRACT TRUNCATED AT 250 WORDS)

An investigation has been made of the putative direct myocardial protective effects of the alpha 1-adrenoceptor antagonists, prazosin and WB4101, against tetanic contractures of rat isolated left atria following modified Na+ channel function and consequent Ca2+ loading elicited by veratrine. Veratrine evoked concentration-dependent, reversible, tetanic contractures which were critically dependent upon the external Ca2+ concentration. Tetrodotoxin (TTX), prazosin, WB 4101 and R 56865 (0.1-10 microM) prevented tetanic contracture elicited by veratrine (100 micrograms/ml) at concentrations which were significantly lower than those which decreased active tension development. The apparent Hill coefficients (nH) obtained for TTX, prazosin, WB 4101 and R 56865 were comparable (range 0.79-0.93), and are consistent with a single site of action. In contrast, the class 1 antiarrhythmic agents, quinidine and lidocaine, elicited no significant inhibition of veratrine-induced contracture at 30 microM, but almost completely abolished the contractures at 100 microM. The nH values for quinidine and lidocaine were found to be significantly greater than unity (3.1 and 2.6, respectively). The L-type Ca2+ channel blockers, diltiazem, nicardipine, nifedipine and verapamil only weakly prevented tetanic contracture, whilst markedly, and concentration-dependently, decreasing active tension development. Neither atropine (10 microM) nor propranolol (1 microM) significantly modified either veratrine-induced contractures or active tension development. In conclusion, evidence is presented of novel, direct protective effects of prazosin and WB 4101 against tetanic contracture following modified Na+ channel function and Ca2+ loading provoked by veratrine. The precise mechanisms involved are unclear at present, but appear to be distinct from blockade of atrial alpha 1-adrenoceptors or L-type Ca2+ channels.(ABSTRACT TRUNCATED AT 250 WORDS)

The cardiovascular effects of oxodipine, a new dihydropyridine calcium channel blocker, were studied after i.v. administration to chloralose-anesthetized dogs, and compared with those of nitrendipine. Nitrendipine produced more marked decreases than oxodipine in both systolic and diastolic blood pressure and in total peripheral resistance. No significant modification of heart rate was observed. Oxodipine decreased cardiac contractility, whereas nitrendipine increased it. This difference originated in reflex modifications, since both drugs, administered at doses of 30 and 60 micrograms/kg, decreased cardiac contractility during studies performed after cardiac autonomic blockade. Under these conditions, nitrendipine decreased heart rate, whereas oxodipine had no effect. The two drugs showed comparable effects on coronary and femoral vascular resistance. However, oxodipine caused a very marked persistent decrease of vertebral vascular resistance. On this local circulation, nitrendipine had a weak effect. The results from the present study indicate that oxodipine predominantly increases vertebral blood flow with a concomitant hypertension which is more moderate than after nitrendipine.

1. The uptake kinetics and pharmacodynamics of lignocaine were studied in isolated perfused heart of the rabbit. 2. Six hearts were perfused with increasing concentrations of lignocaine in a modified Krebs-Henseleit buffer. The effluent concentration together with the increase in QRS duration were measured during lignocaine infusion and during 20 min after cessation of lignocaine infusion. 3. Lignocaine disposition and elimination were best described by a two-compartment open model. Terminal half-life was 11.0 +/- 2.9 min. The unidirectional transfer was slower from central to peripheral compartment than from peripheral to central compartment (T1/2.12 = 42.6 +/- 10.5 min whereas T1/2.21 = 10.7 +/- 2.8 min). The myocardium/perfusate concentration-ratio was 4.7 +/- 0.4. 4. The pharmacodynamic effect was best described in the central compartment by using the Hill equation. Calculated maximum QRS duration (Emax) was 77 +/- 8 ms. Emax was also directly measured in four additional rabbits by infusing ten times the dose of lignocaine used in the main experiment: the value of Emax measured in these conditions was 92.5 +/- 9.6 ms, i.e. a QRS widening of 150%. The steady-state perfusate concentration producing half the effect (C50) was 15.7 +/- 7.6 micrograms ml-1. 6. In conclusion, the specific lignocaine binding leading to increase in QRS duration appeared to be more closely related to the vascular stream than non specific binding leading to a deeper accumulation process.

The cardiac electrophysiological effects of cibenzoline were studied in the conscious dog. Sinus rate, corrected sinus recovery time (CSRT), and Wenckebach point (WP) were measured in six intact dogs. Atrial and ventricular rates, and atrial effective refractory period (AERP) were measured in seven atrioventricular (AV)-blocked dogs. In both groups, blood pressure and cibenzoline plasma concentrations were also monitored. Each dog received three intravenous injections of 0.75, 1.5, and 3 mg base/kg cibenzoline 30 min apart. Cibenzoline increased sinus and atrial rates from the second dose onward, and ventricular rate slightly at the third dose. It lengthened CSRT and decreased WP at the first two doses only, and increased AERP from the first dose onward. In both groups, cibenzoline increased mean blood pressure at each dose. Taken together, these results indicate that in the conscious dog, cibenzoline at low plasma concentrations exhibits electrophysiological effects (lengthening of CSRT and AERP, and decrease in WP) attributable to its antiarrhythmic properties, and that at increasing concentrations it produces effects (increase in sinus rate, no effect on CSRT nor WP) which reflect competition between the effects related to its antiarrhythmic properties and those resulting from its direct vagolytic effect.

The electrophysiologic effects of bepridil (10 mg/kg), verapamil (0.15 mg/kg) and diltiazem (0.6 mg/kg) were studied in the chronically instrumented conscious and pentobarbital-anesthetized dog. Sinus node automaticity assessed by the corrected sinus node recovery time and atrio-ventricular conduction assessed by the Wenckebach phenomenon were evaluated by atrial pacing via electrodes placed in the wall of the right atrium, and exteriorized in the neck region. Nineteen dogs were studied and groups of 6 dogs were used for each experimental session. The calcium channel blocking drugs were administered by slow i.v. infusion (15 min). Effects were measured over 45-60 min and compared with the pretreatment value. In conscious dogs, heart rate was initially markedly increased by bepridil and diltiazem and only slightly increased by verapamil. These chronotropic responses were reversed to bradycardia by diltiazem only. Corrected sinus node recovery time measured at the end of infusion was decreased by verapamil and diltiazem and was unchanged by bepridil. Lengthening of corrected sinus node recovery time was observed with verapamil at the end of the experiment. All 3 calcium channel blocking agents produced negative dromotropic responses. To determine to what extent electrophysiologic effects of pentobarbital were involved in the cardiac responses measured in the anesthetized dog, pentobarbital was administered prior to injection of each calcium channel blocking agent. Pentobarbital produced positive chronotropic and dromotropic effects which were attenuated by the 3 calcium channel blocking agents. The reduction of corrected sinus node recovery time induced by pentobarbital was diminished by bepridil and diltiazem and unchanged by verapamil. Pentobarbital anesthesia thus has important electrophysiologic implications on the effects of calcium channel blocking agents on chronotropic and dromotropic variables on the heart.

The electrophysiologic effects of diproteverine were studied in the conscious nonsedated chronically instrumented dog. Diproteverine at 0.25-0.75 mg/kg (i.e., at plasma levels within the assumed therapeutic range) dose-relatedly decreases heart rate, increases corrected sinus node recovery time, and decreases Wenckebach point. These effects are observed at plasma levels ranging between 16.2 +/- 4.1 and 144.7 +/- 12.5 ng/ml. After cholinergic blockade with N-methylscopolammonium, diproteverine lowers heart rate (greater than or equal to 0.25 mg/kg), increases corrected sinus node recovery time, and decreases Wenckebach point (greater than or equal to 0.5 mg/kg). After propranolol, diproteverine only significantly reduces corrected sinus node recovery time 5 min after the third administration (0.75 mg/kg). After pharmacologic autonomic blockade by N-methylscopolammonium propranolol combination, diproteverine lowers intrinsic heart rate (greater than or equal to 0.25 mg/kg) and Wenckebach point (greater than or equal to 0.5 mg/kg). Diproteverine does not modify mean blood pressure. These results show that diproteverine administered with and without pharmacologic autonomic blockade in the conscious dog causes dose-related depressant effects on sinus node function and atrioventricular conduction without producing significant vasodilatation.