1 The inhibitory eects of cilnidipine and various organic Ca 2+ channel blockers on high voltage-activated Ba 2+ currents (HVA I Ba ) in rat sympathetic neurones were examined by means of the conventional whole-cell patch-clamp recording mode under voltage-clamped conditions. 2 HVA I Ba was classi®ed into three dierent current components with subtype selective peptide Ca 2+ channel blockers. No o-Agatoxin IVA-sensitive (P-type) or o-conotoxin MVIIC-sensitive (Q-type) current components were observed. Most (485%) I Ba was found to consist of o-conotoxin GVIAsensitive N-type components. 3 The application of cilnidipine inhibited HVA I Ba in a concentration-dependent manner. The K d value for cilnidipine was 0.8 mM. Cilnidipine did not shift the current-voltage (I-V) relationship for HVA I Ba , as regards the threshold potential and peak potential where the amplitude reached a maximum. 4 High concentrations of three hypotensive Ca 2+ channel blockers, nifedipine, diltiazem and verapamil, all inhibited HVA I Ba in a concentration-dependent manner. The K d values for nifedipine, diltiazem and verapamil were 131, 151 and 47 mM, respectively. A piperazine-type Ca 2+ channel blocker,¯unarizine, showed a relatively potent blocking action on I Ba . The K d value was about 3 mM. 5 These results thus show that cilnidipine potently inhibits the sympathetic Ca 2+ channels which predominantly consist of an o-Cg-GVIA-sensitive component. This blockade of the N-type Ca 2+ channel, as well as the L-type Ca 2+ channel by cilnidipine suggests that it could be used therapeutically for treatment of hypersensitive sympathetic disorders associated with hypertension.
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 fre quency (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 ƒÊg/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 ƒÊg/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.
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.
We examined the effects of FRC-8653, a novel dihydropyridine calcium Calcium antagonists possess potent vasodila tive activity, and their therapeutic usefulness in the treatment of essential hypertension and several types of angina pectoris has been well established (1, 2). Various compounds with a 1,4-dihydropyridine structure have been de veloped with the intent of improving the hy potensive activity of nifedipine, the prototype calcium antagonist. FRC-8653 is a new dihy dropyridine calcium antagonist synthesized by Fujirebio Inc. (3) that has a strong and long lasting action (4). In accordance with the clini cal data, in vitro depolarization experiments using rat arterial preparations have demon strated that the calcium antagonistic activity of FRC-8653 is longer lasting than those of nife dipine and nicardipine (M. Hosono et al., un published data). In the present communica tion, we examined whether the long-lasting calcium antagonistic activity of FRC-8653 was also seen in rat mesenteric arterial prepara tions and whether FRC-8653 had a long-last ing inhibitory activity on the calcium influx through cell membranes.Superior mesenteric arteries from male Splague-Dawley rats (250-350g) were cut into helical strips under a binocular micro scope. Preparations were mounted in an organ bath and incubated at 37°C in oxygenated (95% 02, 5% CO,) physiological salt solution (PSS) of the following composition: 135 mM NaCI, 1 mM MgCl-,, 5 mM KCI, 2 mM CaCl,, 15 mM NaHCO3, and 1 mM glucose (5). The contraction elicited by raising the K+ concen tration to 65 mM was isometrically recorded using a force transducer (TB651T, Nihon Kohden, Tokyo, Japan). Tension was initially set at 0.8 g, and the tissues were equilibrated for 1 hr, after which they were re-tensioned at 0.8 g. Mesenteric arterial preparations were initially contracted by 65 mM KCI as a control response. After removing the high potassium solution, the preparations were treated for 1 hr with one of the following calcium antago nists dissolved in PSS: 1 X 10_9 M, FRC 8653, 5 X 109 M, nifedipine, 3 X 10-10 M
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