Dual effects of a new coronary vasodilator, diltiazem, on the contractile force of the blood-perfused papillary muscle of the dog.

Nifedipine, prenylamine and verapamil are coronary vasodilators the mechanism of action of which is attributed mainly to calcium antagonism (1, 2). Pronounced negative inotropic effects of these drugs were reported for prenylamine by Linder (3), for verapamil by Haas et al. (4), and for nifedipine by Vater et al. (5), Hashimoto et al. (6), and Flecken stein et al. (1, 2). A coronary vasodilator, d-cis-isomer of 3-acetoxy-2,3-dihydro-5-[2 (dimethylamino) ethyl]-2 (p-methoxyphenyl)-1, 5-benzothiazepin-4 (5H)-one hydrochloride (Diltiazem), developed recently by Sato et al. (7) and Nagao et al. (8), appears to belong to the calcium antagonistic coronary vasodilators, because it was found to exert a negative inotropic effect on the guinea-pig ventricular muscle and this was overcome by an increase in calcium ion concentration in the bathing media (Nakajima, personal communication). The present experiments were performed in an attempt to examine how diltiazem affects the contractile force of the heart and coronary blood flow. The isolated blood perfused papillary muscle was utilized. Experiments were carried out on 10 anterior papillary muscles of the right ventricle of the dog heart. The procedures were essentially the same as those of Endoh and Hashimoto (9). The preparations were placed in a water-jacket at about 38°C and were cross-circulated through the anterior septal artery with arterial blood of the supporting dog. The support ing animals were anesthetized with sodium pentobarbital (30 mg/kg, i.v.) and heparinized (500 U/kg, i.v.). Constant pressure perfusion was performed at about 100 mm Hg by use of a peristaltic pump and a Starling pneumatic resistance. The preparations were driven with rectangular pulses of 0.6-1.5 V (about twice threshold) and 5-cosec duration at a frequency of 120,/min delivered through bipolar silver electrodes sutured at the base of the papillary muscle. The isometric tension of the papillary muscle with a load of 1.5 g was picked up with a strain gauge transducer. The blood flow rate was measured by an electromagnetic flowmeter. Diltiazem hydrochloride (Tanabe Pharmaceutical Co.), l-norepinephrine bitartrate (Merck) and dl-propranolol hydrochloride (Sumitomo Chemicals) were dissolved in 0.9'),/' saline. Drug solutions were injected using a microsyringe in a constant volume of 30 Id for 4 sec into the blood-conducting rubber tubing close to the preparation. Doses are expressed in terms of their bases.