Shigeru Motomura

Differentiation by cholinergic stimulation of positive inotropic actions mediated via α- and β-adrenoceptors in the rabbit heart

Abstract In the isolated rabbit papillary muscle, experiments were carried out in order to elucidate whether or not cholinergic stimulation produces a differential antagonistic action on the positive inotropic effects mediated via β- and α-adrenoceptor stimulation. Carbachol (0.1–30 μM) alone scarcely affected the basal tension developed. The postive inotropic effects of phenylephrine (30 μM) in the presence of phentolamine and of isoprenaline, which were mediated via β-adrenoceptors, were markedly inhibited by carbachol. Carbachol (3 μM) shifted the dose-response curve for isoprenaline in a parallel manner, and that for phenylephrine with phentolamine to the right and downwards. Carbachol administered during induction of the positive inotropic effects via α-adrenoceptors by phenylephrine (30 μM) with pindolol or by methoxamine failed to inhibit these effects and increased further the tension developed. The dose-response curve for phenylephrine determined in the presence of pindolol was not affected by carbachol. The present results indicate that the cholinergic antagonism of the adrenergic action on the contractility of the mammalian ventricular myocardium is exerted specifically to the β-adrenoceptor-mediated action, but not to the α-adrenoceptor-mediated one.

Experimental Pharmacological Investigations of Effects of Nifedipine on Atrioventricular Conduction in Comparison with Those of Other Coronary Vasodilators

Pharmacological investigations carried out so far on the cardiovascular actions of nifedipine (Adalat) (Vater et al. [10]; Hashimoto et al. [6]) have revealed that nifedipine is the most potent coronary vasodilator ever synthesized. The mechanism of its vasodilator action has been ascribed to the calcium antagonistic action: inhibition of the transmembrane calcium influx of the vascular smooth muscle to reduce the tone (Fleckenstein et al. [3]; Grun and Fleckenstein [4]). On the other hand, it has been suggested that the ionic channel operative in excitation of cells in the atrioventricular (A-V) junctional area concerned in the major delay of A-V conduction is a slow channel which allows the transmembrane inflow of calcium, sodium ions or both (Zipes and Mendez [12]). A coronary vasodilator, verapamil, the mechanism of action of which has also been described as that of calcium antagonism (Grun and Fleckenstein [4]), is able to block this slow channel and cause impairment of A-V conduction (Zipes and Fischer [11]). From a therapeutic point of view, however, the impairment of A-V conduction by coronary vasodilators is one of their untoward effects. Thus, it is worthy to examine whether nifedipine as a potent calcium antagonist might impair A-V conduction. The present study was carried out in an attempt to elucidate this point. To characterize the effect of nifedipine on A-V conduction, comparison was made with those of other coronary vasodilators—verapamil, diltiazem (Sato et al. [9]), dipyridamole and dilazep.

Differential effects of organic slow inward current inhibitors, verapamil and nifedipine, on rate of atrioventricular rhythm and supraventricular tachycardia in the canine isolated, blood-perfused AV node preparation

SummaryThe present experiments were performed to elucidate whether the organic slow inward current inhibitors, verapamil and nifedipine, would affect the automaticity of the atrioventricular (AV) junctional area.1.In the canine isolated, blood-perfused AV node preparation, there appeared AV rhythm at a rate of 54±3 beats/min (n=12) after elimination of the sinoatrial node activity. The AV rhythm originated from the distal portion of the AV junctional area supplied by the anterior septal artery (ASA) and was attended by retrograde conduction with ventriculo-atrial (VA) conduction time of 94±6 ms (n=12).2.During AV rhythm, verapamil and nifedipine in a dose range of 1–10 nmol injected into the ASA affected neither rate of AV rhythm nor VA conduction time.3.When injected into the posterior septal artery (PSA) which supplies the proximal portion of the AV junctional area, the two substances in a similar dose range to that given into the ASA produced dose-related prolongation of VA conduction time and VA conduction block at 10 nmol. However, the rate of AV rhythm remained unchanged in all the dose range of the two drugs examined.4.Verapamil and nifedipine (10 nmol) given into the ASA failed to modify the increase in rate of AV rhythm induced by noradrenaline (NA) injected into the same artery.5.When NA in a dose range of 100 pmol to 3 nmol was injected into the PSA, AV rhythm was transiently replaced by supraventricular tachycardia, a rapid increase in a rate of the automaticity of the PSA area which is usually extremely low and masked by AV rhythm. Under this circumstance VA conduction time was first shortened and then VA conduction was replaced by antegrade conduction.6.Verapamil and nifedipine (10 nmol) given into the PSA, which caused retrograde VA conduction block, reduced the rate of NA-induced supraventricular tachycardia.7.These results indicate that two pacemakers within the AV junctional area have different pacemaking mechanisms; NA-induced automaticity of the proximal portion depends on the slow inward Ca/Na current whereas the inherent automaticity and that enhanced by NA of the distal portion do not.

COMPARISON OF EFFECTS OF GLUCAGON AND ISOPRENALINE ON ATRIO‐VENTRICULAR CONDUCTION AND SINO‐ATRIAL RATE IN THE DOG HEART

SUMMARY 1. The effects of glucagon and l‐isoprenaline on atrio‐ventricular (A‐V) conduction and sino‐atrial (S‐A) rate were studied in the isolated and cross‐circulated canine A‐V and S‐A node preparations. Drugs were injected intravenously into the donor dog.

Nuclear factor-κB activation during anesthesia and surgery

Abstract Transcription of the genes for proinflammatory cytokines is regulated by nuclear factor kappa B (NF-κB) activation. Cardiopulmonary bypass (CPB) is characterized by a systemic endotoxemia demonstrated immediately following CPB institution followed by the systemic release of proinflammatory cytokines, including tumor necrosis factor-α (TNF-α) and the interleukins (IL) 1, 6 and 8. However, the mechanism of the release of these proinflammatory cytokines remains to be determined. NF-κB is an inducible transcription factor implicated in activating various genes including those genes which encode for cytokines such as TNF, IL-1 and IL-6. The NF-κB protein is found in several cell types including inflammatory cells, for example peripheral blood monocytes, one of the cell types responsible for LPS-induced proinflammatory cytokine production. Therefore, we examined whether NF-κB is activated during CPB in order to define a mechanism of CPB-induced proinflammatory cytokine production and release.