Pharmacological Studies on a New Antihypertensive Agent, S-2150, a Benzothiazepine Derivative: 1. Antinecrotic and Antiarrhythmic Effects in Reperfused Rat Hearts

Abstract

S-2150 is a new 1,5-benzothiazepine derivative that inhibits [3H]diltiazem and [3H]WB4101 bindings to the membrane of rat tissue. The effects of S-2150 on ischemia/ reperfusion injury were studied in anesthetized rats. S-2150 reduced the myocardial infarct size (IS) induced by 20-min coronary artery occlusion followed by reperfusion. To evaluate reperfusion-induced ventricular tachycardia and fibrillation (VT, VF), we occluded the coronary artery for 4 min and then reperfused it. The incidence of arrhythmia was blocked by S-2150, and this effect offered protection against cardiac death. Prazosin did not modify the IS or incidence of reperfusion arrhythmias, but combined treatment with a noneffective dose of diltiazem showed significant cardioprotective effects. We also compared the direct effects of S-2150 and diltiazem on cardiac function and coronary perfusion flow using isolated rat hearts. Both drugs decreased mechanical function and increased coronary flow, with S-2150 being less cardiodepressive and more vasodilatory. S-2150 is cardioprotective at doses comparable to hypotensive doses even though its cardiodepressant effect is much weaker than that of diltiazem. This effectiveness may be partly explained by its dual characteristics: blocking the Ca channel and the alpha 1-adrenoceptor.

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“…But the cardio-depressant effect is much weaker than diltiazem [53]. Hypotensive effect of the S-2150 is 4e7 times more than diltiazem [54] due to simultaneous blockage of both, the Ca þ2 channels and a 1 -adrenoreceptors.…”

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“…Moreover, S-2150 also decreased cardiac mechanical function and increased CF [68]. Compared to diltiazem, S-2150 was less cardiodepressive but exerted stronger vasodilatation [68]. Similarly, in anesthetized open-chest dogs, S-2150 decreased myocardial work to a greater extent compared to diltiazem while caused a comparable hypotensive effect.…”

“…The incidence of VT and fibrillation, induced by 4 min occlusion followed by reperfusion of the coronary artery, was reduced almost to zero by 60 mg/kg S-2150. Moreover, S-2150 also decreased cardiac mechanical function and increased CF [68]. Compared to diltiazem, S-2150 was less cardiodepressive but exerted stronger vasodilatation [68].…”

“…3. ) applied to anesthetized rats (30-60 mg/kg per os or 5 mg/kg intravenous pretreatment) reduced the myocardial infarct size just as diltiazem (5 mg/kg) and verapamil (3 mg/kg) [68]. The incidence of VT and fibrillation, induced by 4 min occlusion followed by reperfusion of the coronary artery, was reduced almost to zero by 60 mg/kg S-2150.…”

“…The additional methoxy group probably plays a role in calcium chelating just like in the phenylalkylamines [67]. This molecule found to be less cardio-depressive than diltiazem [68] but its hypotensive effect is 4-7 times more potent than that of diltiazem [31]. This different vascular over cardiac selectivity may come from the wide spectra of the effects of benzothiazepine and derivatives, which are not just restricted to the L-type Ca 2+ channel inhibition [69].…”