In vivo antiarrhythmic profile of AP-792 assessed in different canine arrhythmia models.

The antiarrhythmic effects of a novel antiarrhythmic drug AP-792, 4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-[4-cyclohexylbutyl]piperidine hydrochloride, were analyzed using the epinephrine-, digitalis- and two-stage coronary ligation-induced canine ventricular arrhythmia models. Intravenous administration of AP-792 (0.3 or 1.0 mg/kg) effectively suppressed each of the ventricular arrhythmias, an action that resembles that of a typical cardioselective Ca2+ channel blocker, AH-1058. The antiarrhythmic action of AP-792 was slow in onset and longer-lasting than those in our previous studies using more than 50 antiarrhythmic drugs, including Na+ and Ca2+ channel blockers. These results suggest that AP-792 can become a unique long-acting antiarrhythmic drug.

Utilization of telemetry system to assess the cardiovascular profile of AH-1058, a new cardioselective Ca2+ channel blocker, in conscious dogs.

Cardiovascular effects of a new Ca2+ channel blocker AH-1058, 4-(5H-dibenzo[a,d]cyclo-hepten-5-ylidene)-1-[(E)-3-(3-methoxy-2-nitro)phenyl-2-propenyl]piperidine hydrochloride, were assessed in conscious dogs using a new telemetry system. AH-1058 (0.03, 0.1 and 0.3 mg/kg, i.v.) reduced systolic blood pressure and the maximal upstroke velocity of the left ventricular pressure and increased the heart rate in a dose-dependent manner without affecting the diastolic blood pressure; each of these responses lasted for several hours. These results support the previous knowledge that AH-1058 is a long-lasting cardiodepressive drug. The telemetry system provided important information for predicting favorable clinical effects of AH-1058.

Cardiovascular action of a cardioselective Ca(2+)channel blocker AH-1058 in conscious dogs assessed by telemetry.

AH-1058, 4-(5H-Dibenzo[a,d]cyclohepten-5-ylidene)-1-[(E)-3-(3-methoxy-2-nitro)phenyl-2-propenyl]piperidine hydrochloride, is a novel Ca(2+)channel blocker exerting cardioselective action in isolated or anesthetized canine heart preparations. To clarify the cardiac and hemodynamic action of AH-1058 in conscious dogs, we assessed the effects of the drug on the hemodynamic parameters continuously recorded by telemetry in conscious unrestrained beagle dogs, and its cardiovascular effects were compared with those of verapamil, disopyramide and atenolol. Oral administration of AH-1058 (0.15, 0.3 and 0.6 mg/kg) reduced the systolic blood pressure and maximal upstroke velocity of the left ventricular pressure (LVdP/dt(max)), increased heart rate and prolonged the QA interval in a dose-dependent manner whereas the drug did not affect diastolic blood pressure. Verapamil at 10 mg/kg reduced systolic and diastolic blood pressure with little effect on heart rate, LVdP/dt(max) and QA interval. Disopyramide at 20 mg/kg increased systolic and diastolic blood pressure, decreased LVdP/dt(max) and prolonged the QA interval with little changes in heart rate. Atenolol at 10 mg/kg decreased LVdP/dt(max) and prolonged the QA interval with little changes in systolic blood pressure, diastolic blood pressure and heart rate. The time course of the cardiohemodynamic action of AH-1058 was longer than those of the other drugs. These results suggest that AH-1058 is a long-acting cardiodepressive drug, and its hemodynamic profile is obviously different from that of disopyramide and atenolol. This unique cardiovascular profile may be beneficial for the treatment of certain pathological processes in which selective inhibition of the ventricular Ca(2+)channels would be the target of drug therapy.

Effects of a dual L/N-type Ca(2+) channel blocker cilnidipine on neurally mediated chronotropic response in anesthetized dogs.

We investigated the effects of an L-type and N-type Ca(2+) channel blocker, cilnidipine, on neurally mediated chronotropic responses to clarify the anti-autonomic profile of cilnidipine in anesthetized dogs. Pretreatment with cilnidipine (0.3, 1.0 and 3.0 microg/kg, i.v.), which decreased mean blood pressure by 5 to 31 mm Hg, inhibited the changes in heart rate and plasma norepinephrine concentration induced by bilateral carotid artery occlusion, whereas it had no effect on vagal nerve stimulation-induced bradycardia. These results suggest that antihypertensive and antisympathetic doses of cilnidipine fail to influence chronotropic responses mediated by parasympathetic nerve activation in the in vivo canine heart.

Electrophysiological and cardiohemodynamic effects of AH-1058, a new type calcium channel blocker, assessed by the in vivo canine model.

AH-1058 (4-(5H-dibenzo[a, d]cyclohepten-5-ylidene)- 1-[(E)-3-(3-methoxy-2-nitro)phenyl-2-propenyl]piperidine hydrochloride) is a novel calcium channel blocker whose chemical structure is quite different from those of typical calcium channel blockers. In this study, electrophysiological and hemodynamic effects of AH-1058 were assessed in the halothane-anesthetized, closed-chest canine model. Intravenous administration of a canine antiarrhythmic dose of 100 microg/kg of AH-1058 (n = 6) did not affect the cardiovascular variables, except that the cardiac output was decreased at 30 min after the drug administration. Additional administration of 200 microg/kg of AH-1058 (n = 6) suppressed the sinus nodal automaticity, AV nodal conduction and ventricular contraction and decreased the mean blood pressure, cardiac output and double product. The effects gradually appeared, while no change was detected in the intraventricular conduction, ventricular repolarization period, ventricular effective refractory period, preload to the left ventricle and total peripheral vascular resistance during the observation period of 30 min. The cardiosuppressive effects of AH-1058 can be explained by its calcium channel blocking action demonstrated in a previous in vitro experiment, while the lack of the effect on the vascular resistance would suggest that AH-1058 may become a slow-acting cardioselective calcium channel blocker.

Antiarrhythmic and cardiohemodynamic effects of a novel Ca(2+) channel blocker, AH-1058, assessed in canine arrhythmia models.

The antiarrhythmic profile and cardiohemodynamic effect of a novel Ca(2+) channel blocker, 4-(5H-Dibenzo[a, d]cyclohepten-5-ylidene)-1-[(E)-3-(3-methoxy-2-nitro)phenyl-2-p ropeny l]piperidine hydrochloride (AH-1058), were analyzed using the epinephrine-, digitalis- and two-stage coronary ligation-induced canine ventricular arrhythmia models. Intravenous administration of AH-1058 (100 microg/kg) effectively suppressed each of the ventricular arrhythmias accompanied by weak hypotensive effects. The results contrast well with those of a typical Ca(2+) channel blocker, verapamil, which suppresses only the epinephrine-induced ventricular arrhythmia with severe hypotension. These results indicate that AH-1058 may possess a more selective inhibitory action on Ca(2+) channels in the heart than on those in the vessels. Furthermore, the antiarrhythmic actions of AH-1058 were slower in onset and longer-lasting, than those in our previous studies using other antiarrhythmic drugs, including Na(+) and Ca(2+) channel blockers. The antiarrhythmic effects of AH-1058 did not correlate with its plasma concentrations when administered either intravenously or orally. These results suggest that AH-1058 can become a long-acting Ca(2+) channel blocker with unique antiarrhythmic properties, and that AH-1058 may be used in certain pathological processes, for which selective inhibition of the cardiac Ca(2+) channels is essential.

Comparison of cardiovascular effects of a new calcium channel blocker AH-1058 with those of verapamil assessed in blood-perfused canine heart preparations.

The cardiovascular effects of AH-1058, a novel calcium channel blocker, were examined in comparison with those of verapamil using canine isolated, blood-perfused papillary muscle, atrioventricular node, and sinoatrial node preparations. Intravenous administration of AH-1058 (20, 50, and 100 microg/kg) or verapamil (20, 50, and 100 microg/kg) to the blood-donor dog induced negative inotropic, dromotropic, and chronotropic effects and a coronary vasodilator action in cross-circulated isolated heart preparations, simultaneously inducing the same cardiac effects in the blood-donor dog. The order of potency of the effects of AH-1058 was ventricular contraction > coronary blood flow >> atrioventricular conduction > sinoatrial automaticity, whereas that of verapamil was coronary blood flow >> atrioventricular conduction >> sinoatrial automaticity > ventricular contraction. The cardiosuppressive effects of AH-1058, especially on ventricular contraction, were slower in onset and longer lasting than those of verapamil. These results suggest that this unique cardiovascular profile of AH-1058 may become beneficial for the treatment of certain pathologic processes, in which selective inhibition of ventricular calcium channels would be essential for drug therapy.

Effects of AH-1058, a new antiarrhythmic drug, on experimental arrhythmias and cardiac membrane currents.

AH-1058 is a newly synthesized antiarrhythmic agent. We investigated the antiarrhythmic and electrophysiological effects of AH-1058 in experimental arrhythmia models and isolated cardiomyocytes. In the ouabain-induced arrhythmia model of the guinea pig, pretreatment with AH-1058 (0.1-0.3 mg/kg, i.v.) delayed the appearance of premature ventricular complex (PVC) and ventricular fibrillation (VF) induced by intravenous infusion of ouabain. However, disopyramide (10 mg/kg, i.v.) delayed only that of PVC, and verapamil (1 mg/kg, i.v.) failed to affect the ouabain-induced ventricular arrhythmias. In the reperfusion-induced arrhythmia model of the rat, in which 5-min coronary occlusion and 10-min reperfusion were produced, AH-1058 (0.1-0.3 mg/kg, i.v.) inhibited the incidence of both ventricular tachycardia (VT) and VF, whereas disopyramide (5 mg/kg, i.v.) inhibited only reperfusion-induced VF. On the other hand, a higher dose of AH-1058 (1 mg/kg, i.v.) did not affect the aconitine-induced arrhythmias in rats, which were inhibited by disopyramide (5 mg/kg, i.v.). We also confirmed oral activity of AH-1058 in the reperfusion-induced arrhythmia model of the rat. AH-1058, at doses of 2-4 mg/kg, dose-dependently inhibited VT and VF. Electrophysiological experiments with patch-clamp techniques revealed that AH-1058 potently suppressed the L-type Ca2+ currents in isolated cardiomyocytes of the guinea pig. These results suggest that AH-1058 is a potent antiarrhythmic drug having a Ca2+ channel-blocking action. The antiarrhythmic profile of AH-1058 is different from that of disopyramide and verapamil.

Cilnidipine attenuates renal nerve stimulation-induced renal vasoconstriction and antinatriuresis in anesthetized dogs.

We examined the effects of cilnidipine, which is an L- and N-type Ca2+ channel blocker, on adrenergically regulated renal functions in anesthetized dogs. Renal nerve stimulation (RNS) at high frequency (3-7 Hz) decreased renal blood flow (RBF) without changes in systemic blood pressure. The RBF response was inhibited by intrarenal arterial (i.r.a.) infusion of cilnidipine at 0.1-0.3 microgram/kg/min. Low-frequency RNS (0.5-1 Hz) reduced absolute and fractional urinary sodium excretion. These responses were attenuated during i.r.a. infusion of cilnidipine at 0.3 microgram/kg/min. An increase in norepinephrine secretion rate induced by low-frequency RNS was also attenuated during cilnidipine infusion. These results suggest that cilnidipine can suppress norepinephrine release from the renal nerve endings and thereby interfere with the neural control of renal functions.

Blockade of N-type Ca2+ current by cilnidipine (FRC-8653) in acutely dissociated rat sympathetic neurones.

1 The inhibitory effects of cilnidipine (FRC-8653) and various organic Ca2+ channel blockers on high voltage-activated Ba2+ currents (HVA IBa) in rat sympathetic neurones were examined by means of the conventional whole-cell patch-clamp recording mode under voltage-clamped conditions. 2 HVA IBa was classified into three different current components with subtype selective peptide Ca2+ channel blockers. No omega-Agatoxin IVA-sensitive (P-type) or omega-conotoxin MVIIC-sensitive (Q-type) current components were observed. Most (> 85%) IBa was found to consist of omega-conotoxin GVIA-sensitive N-type components. 3 The application of cilnidipine inhibited HVA 1Ba in a concentration-dependent manner. The Kd value for cilnidipine was 0.8 microM. Cilnidipine did not shift the current-voltage (I-V) relationship for HVA IBa, as regards the threshold potential and peak potential where the amplitude reached a maximum. 4 High concentration of three hypotensive Ca2+ channel blockers, nifedipine, diltiazem and verapamil, all inhibited HVA IBa in a concentration-dependent manner. The Kd values for nifedipine, diltiazem and verapamil were 131, 151 and 47 microM, respectively. A piperazine-type Ca2+ channel blocker, flunarizine, showed a relatively potent blocking action on IBa. The Kd value was about 3 microM. 5 These results thus show that cilnidipine potently inhibits the sympathetic Ca2+ channels which predominantly consist of an omega-Cg-GVIA-sensitive component. This blockade of the N-type Ca2+ channel, as well as the L-type Ca2+ channel by cilnidipine suggests that it could be used therapeutically for treatment of hypersensitive sympathetic disorders associated with hypertension.

[Antihypertensive effects of repeated oral administration of cilnidipine, a novel calcium antagonist, in 2K1C renal hypertensive dogs].

Antihypertensive effects of repeated oral administration of cilnidipine in 2K1C renal hypertensive dogs were compared with those of nicardipine. On the first day, oral administration of cilnidipine (3 mg/kg) or nicardipine (3 mg/kg) markedly lowered both systolic and diastolic blood pressure 1 hr after administration. The hypotensive effects of cilnidipine were longer compared with those of nicardipine. Both drugs elevated the heart rate and plasma renin activity. On the 8th and 15th days, similar responses were obtained by repeated administrations of cilnidipine and nicardipine. After withdrawal of these drugs, no rebound phenomena in blood pressure were observed. The changes in mean blood pressure were correlated with plasma cilnidipine or nicardipine concentrations that were obtained at each time of blood pressure measurement (r = -0.598; P < 0.001 and r = -0.594; P < 0.001, respectively). These results suggest that stable and long-acting antihypertensive effects of cilnidipine for 15 consecutive days in renal hypertensive dogs are related to the change in plasma drug concentrations.

In vitro and ex vivo Ca-antagonistic effect of 2-methoxyethyl(E)-3-phenyl-2-propen-1-yl(+/-)-1,4-dihydro-2,6-dimethyl- 4-(3- nitrophenyl)pyridine-3,5-dicarboxylate (FRC-8653), a new dihydropyridine derivative.

The characteristics of calcium antagonism and vascular effect of 2-methoxyethyl(E)-3-phenyl-2-propen-1-yl(+/-)-1,4-dihydro-2,6-dime thyl-4-(3- nitrophenyl)pyridine-3,5-dicarboxylate (FRC-8653) were investigated. FRC-8653 inhibited an increase in intracellular free calcium concentration during membrane depolarization in PC12 cells. FRC-8653 also inhibited the specific binding of 3H-nitrendipine to cardiac membranes, in a similar manner to nifedipine and nicardipine. FRC-8653 inhibited KCl- and CaCl-induced contractions in isolated rabbit aorta, but failed to affect norepinephrine-induced contraction. The vasorelaxing effect of FRC-8653 in rabbit aorta developed more slowly than those of nifedipine and nicardipine. In ex vivo experiment, the inhibitory effect of orally administered FRC-8653 against KCl-contraction in rat aorta lasted longer than that of nifedipine. These findings suggest that FRC-8653 dilates blood vessels by blocking calcium influx via dihydropyridine-sensitive, voltage-dependent calcium channels and that the vascular effects are slow in development and long in duration.

Effects of a new dihydropyridine derivative, FRC-8653, on blood pressure in conscious spontaneously hypertensive rats.

Antihypertensive effects of FRC-8653, a new 1,4-dihydropyridine derivative, and its combined effects with an angiotensin converting enzyme (ACE) inhibitor, a diuretic, and a beta-adrenergic blocking agent were examined in conscious spontaneously hypertensive rats (SHR). When administered intravenously to SHR (10, 30 micrograms/kg), FRC-8653 lowered blood pressure more slowly and sustained it longer than nifedipine and nicardipine. Consecutive once-daily administrations of FRC-8653 to SHR (3 mg/kg, p.o.) produced a stable reduction of blood pressure throughout the experimental period of 29 d. When blood pressure was continuously measured for 24 h in conscious unrestricted SHR, orally administered FRC-8653 produced a long-lasting reduction in blood pressure. When concomitantly used with atenolol (30 mg/kg, p.o.), the antihypertensive effect of FRC-8653 was augmented in both potency and duration. However, simultaneous administration of captopril (30 mg/kg, p.o.) or hydrochlorothiazide (2.5 mg/kg, p.o.) did not modify the antihypertensive effect of FRC-8653.

Prolonged inhibition of vascular contraction and calcium influx by the novel 1,4-dihydropyridine calcium antagonist cinaldipine (FRC-8653).

We examined the effects of FRC-8653, a novel dihydropyridine calcium antagonist, on the contraction of an arterial preparation and the calcium influx into vascular smooth muscle cells to clarify the long-lasting hypotensive activity of this drug. Inhibition by FRC-8653 persisted for more than 7 hr after its removal, whereas nifedipine and nicardipine exhibited shorter durations of suppressive activity. These results suggest that prolonged inhibition of calcium influx through L-channels contributes to the long-lasting vasodilative and antihypertensive activity of FRC-8653.

Synthesis and in vitro affinity for dopamine D-2 receptor of N-fluorine-substituted analogs of eticlopride.

With the aim of developing fluorinated benzamides that may be useful as radioligands for positron emission tomography, fluorine analogs of eticlopride, in which the N-ethyl group was replaced by 2-fluoroethyl, 3-fluoropropyl and p-fluorobenzyl groups, were synthesized. These derivatives were tested for their ability to displace [3H]spiperone from its specific dopamine D-2 receptor. Their potencies were decreased when compared with eticlopride, but the two fluoroalkylated analogs were in the same order of magnitude as that of haloperidol.