Effect of Diltiazem on Electrical and Mechanical Activity of Isolated Cardiac Ventricular Muscle of Guinea Pig

Nakajima, Hiromichi; Hoshiyama, Masao; Yamashita, Keiko; Kiyomoto, Akio

doi:10.1254/jjp.25.383

Cited by 174 publications

(51 citation statements)

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“…The experimental procedures were similar to those described in the previous papers (1,13 Similar results were also obtained when stimulus of a low frequency (0 .2 Hz) was applied to the preparation at CaC12 concentration ranging from 0.6 to 7.8 mM.…”

Section: Methodssupporting

confidence: 66%

“…It was also suggested that the compound antagonizes calcium ion essential for muscle contraction, thus causing a reduction in the contractile force of the myocardium (1). On the other hand, it has been reported that the slow inward calcium or calcium-sodium current, as well as the fast inward sodium current, is involved in the generation of the action potential of cardiac muscle fibers under normal physiological conditions (4)(5)(6)(7)(8)(9)(10)(11)(12)(13).…”

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confidence: 99%

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Electrical and Mechanical Responses to Diltiazem in Potassium Depolarized Myocardium of the Guinea Pig

Nakajima

Hoshiyama

Yamashita

et al. 1976

Japanese Journal of Pharmacology

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Abstract-Effectsof diltiazem on the electrical and mechanical activities of guinea pig papillary muscle were investigated in K-rich Tyrode's solution (KCI 12.7 mM). The electrical properties of cell membrane in K-rich solution were also examined in the ventricular muscle fibers. It was found that the overshoot as well as the maximum rate of rise (Vm1x) of the action potential were highly sensitive to the extracellular concentration of CaC12 in K-rich solution. Vmax was also affected by NaCI. Diltiazem at a lower concentration (1.1 x 10-' M) caused a reduction in the contractile force of K-depolarized papillary muscle without producing significant changes in the resting and action potentials. In the presence of a higher concentration of diltiazem (1.1 x 10-' M), the contractile force decreased concurrently with the change in the action potential. Addition of CaClz restored the original strength of contraction in parallel to the recovery of the action potential, especially in its overshoot and V~nax. From these results, it is inferred that diltiazem may decrease the contractile force of guinea pig papillary muscle either by interfering with the transmembrane calcium influx or by intracellularly reducing the free calcium ion concentration in the myoplasm.In previous experiments carried out in normal Tyrode's solution (KC1 2.7 mM) (1), it was shown that diltiazem (CRD-401), a new 1,5-benzothiazepine derivative (2) with a potent coronary vasodilating activity (3), has a property which interferes with the excitation contraction coupling in the isolated guinea pig myocardium. It was also suggested that the compound antagonizes calcium ion essential for muscle contraction, thus causing a reduction in the contractile force of the myocardium (1). On the other hand, it has been reported that the slow inward calcium or calcium-sodium current, as well as the fast inward sodium current, is involved in the generation of the action potential of cardiac muscle fibers under normal physiological conditions (4-13).The slow inward calcium current, which is assumed to play an important role in the excitation-contraction coupling in the cardiac muscle (8,12,(14)(15)(16)(17)(18)(19), is disclosed as a result of the inactivation of sodium carrying system when the extracellular concentration of KCI was increased (20)(21)(22)(23) muscle fibers in K-rich solution were also examined. MATERIALS AND METHODSIsolated papillary or ventricular muscle of the guinea pig was used. The experimental procedures were similar to those described in the previous papers (1, 13 Values were obtained 10 min after the concentration of KCI was increased from 2.7 to 12.7 mM. Each value is the mean l--SE of 20 experiments. R.P., resting potential; A.P., amplitude of the action potential; O.S., overshoot; V,,,,,x-, maximum rate of rise of the action potential; duration of A.P., duration of the action potential measured at 50 and 90°o repolarization. Significant difference (paired t-test); *P<0.01.mV (mean+SE of 20 experiments) 10 min after the increase in KCI conce...

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Section: Methodssupporting

confidence: 66%

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confidence: 99%

Electrical and Mechanical Responses to Diltiazem in Potassium Depolarized Myocardium of the Guinea Pig

Nakajima

Hoshiyama

Yamashita

et al. 1976

Japanese Journal of Pharmacology

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“…In isolated myocardium (7,8) and vascular (9)(10)(11)(12) or intestinal (13)(14)(15)(16) smooth muscles, it has been reported that this compound antagonizes calcium ion which is essential for muscle contraction, thus producing a decrease in the contractile force. Such a calcium antagonistic property of diltiazem has been shown in isolated pancreatic B-cell (1): the glucose-induced insulin secretion from the isolated islets of Langerhans from rats was suppressed by diltiazem and this effect was counteracted by increasing extracellular concentration of calcium ion.…”

Section: Discussionmentioning

confidence: 99%

Effect of diltiazem on insulin secretion

Yamaguchi

Akimoto

Nakajima

et al. 1979

Japanese Journal of Pharmacology

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Abstract-Effect of diltiazem on insulin secretion was investigated in the perfused rat pancreas. Experiments were also carried out in anesthetized dogs and conscious rats with and without glucose loading.In the perfused rat pancreas, diltiazem reduced both glucose and tolbutamide-induced insulin secretion and these effects of diltiazem were reversed with removal of the compound. Inhibition of the glucose-induced insulin secretion caused by diltiazem was counteracted by increasing the concentration of calcium ion. In experiments on intact animals, diltiazem at vasoactive doses produced no significant influence on the basal level of plasma insulin or glucose-induced insulin secretion.These data taken together with findings in previously reported work suggest that diltiazem reduces insulin secretion from pancreatic B-cells in vitro possibly by the calcium-antagonistic property, while the compound exhibits practically no inhibitory action on the insulin secretion in vivo.In a preceding paper (1), it was shown that in isolated islets of Langerhans from rats, diltiazem produced a concentration-dependent inhibition of the release of insulin following stimulation with glucose. This inhibitory effect of diltiazem was antagonized with increasing concentrations of extracellular calcium ion. We suggested that diltiazem may suppress the glucose-induced insulin secretion by reducing free calcium ion concentration in B-cells.In the present study, the time course for change in insulin secretion from rat pancreas was followed using a perfusion method and the dynamic aspects of the inhibitory effect by diltiazem were studied. In vivo effects of diltiazem on the insulin secretion were also studied in dogs and rats with and without glucose loading. MATERIALS AND METHODS1. Perfusion of rat pancreas: The perfused rat pancreas was prepared according to the method described by Sussman et al. (2) with slight modification. Male Sprague-Dawley rats (about 450 g) were anesthetized with sodium pentobarbital (50 mg/kg i.p.) and the abdominal cavity was opened. All abdominal vessels except for the superior mesenteric artery and celiac axis were ligated and cut. A portion of the duodenum tightly adhering to the pancreas was left intact. The thoracic aorta was cannulated to a point just superior of the celiac axis and the perfusate was allowed to flow through the pancreas and a portion of the small intestine. The effluent was continuously collected through a cannulated portal vein at one to two min intervals. At the end of the experiments, the perfusion circuit was confirmed to be complete by perfusion with Evans blue. The perfusate was Krebs-bicarbonate

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“…In another series of supplemental experiments, in order to study the effects of calcium (Ca++) channel blocker on production of VT in ten dogs other than the above 15 dogs, LCX injection was carried out following intravenous infusion over a 4 min of diltiazem hydrochloride (Nakajima et al 1975), in a dose of 1 mg/kg body weight.…”

Section: Methodsmentioning

confidence: 99%

Observations with endocardial electrography on ventricular tachycardia by intracoronary saline in dogs.

Abe¹

1982

Tohoku J. Exp. Med.

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Selective injection of 1.5 ml of 10% saline into the left circumflex coronary artery (LCX) was carried out during sinus rhythm twice in each of 15 mongrel dogs anesthetized with sodium pentobarbital, and multiple endocardial recordings including His bundle electrogram (HBE) were made. Ventricular tachycardia (VT) was elicited in all of the 15 dogs both in the first and second injections. The cycle length of sinus rhythm before injection was 468+88 msec (mean+s.D.). The coupling interval between the last depolarization of the left ventricle (LV) of sinus origin and the first premature LV depolarization of the VT was 395+57 msec. Coupling interval between the first and the second LV depolarizations was 348+78 msec. Significant difference was noted between any pair of these values (p<0.01). No bundle branch re-entry in the beginning of VT was observed. The site of origin of the VT was referred to the LV in 13 dogs. Rapid pacing during paroxysm of VT applied at the apex of the LV made no marked influence upon VT after pacing. The calcium channel blocker, diltiazem failed to block the production of VT. The mechanism for genesis of this VT may not be re-entry but rather enhanced automaticity independent of the calcium inward current. --ventricular tachycardia; intracoronary injection; endocardial electrography The incidence of VT per se is not quite high, although many methods for experimental production of VT in animal study have been reported (Siebecker et al. 1961;Scherf and Bornemann 1967;Wallace et al. 1967;Bellet 1971;Lown et al. 1977) and ventricular tachyarrhythmias including VT can be induced by these methods. In the previous reports (Abe 1979(Abe , 1980) the author demonstrated with surface electrocardiography (ECG) that VT could be successfully elicited by intracoronary injections of hyperosmotic solutions in canine hearts with 100% incidence. In the present experiments VT produced by intracoronary hyperosmotic saline was studied with endocardial electrography. METHODSFifteen mongrel dogs weighing between 20 and 29 kg (average, 24.6 kg) were anesthetized with intramuscular sodium pentobarbital (35 mg/kg), incubated with a cuffed

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Effect of Diltiazem on Electrical and Mechanical Activity of Isolated Cardiac Ventricular Muscle of Guinea Pig

Cited by 174 publications

References 32 publications

Electrical and Mechanical Responses to Diltiazem in Potassium Depolarized Myocardium of the Guinea Pig

Electrical and Mechanical Responses to Diltiazem in Potassium Depolarized Myocardium of the Guinea Pig

Effect of diltiazem on insulin secretion

Observations with endocardial electrography on ventricular tachycardia by intracoronary saline in dogs.

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