NEW 1,4-BENZOTHIAZEPINE DERIVATIVE, K201, DEMONSTRATES CARDIOPROTECTIVE EFFECTS AGAINST SUDDEN CARDIAC CELL-DEATH AND INTRACELLULAR CALCIUM BLOCKING ACTION

In order to find drugs with suppressive effects against sudden cardiac cell death due to myofibrillar overcontraction, the cardioprotective effects of a new 1,4-benzothiazepine derivative, 4-[3-{1-(4-benzyl)piperidinyl}propionyl]-7-methoxy-2,3,4,5-tetrahydro-1,4-benzothiazepine, K201, in comparison with five other compounds, including a representative alpha-antagonist, beta-antagonist, and Ca2+ channel antagonists, were investigated in an experimental myofibrillar overcontraction model of isolated rat heart. In addition, the effects of K201 on the contraction of isolated vascular smooth muscle of rat aorta and on the binding of cardiac annexin V with actin were compared with those of diltiazem and KT362. The degree of myofibrillar overcontraction was histologically scored on a four-grade scale (0, 1, 2, and 3) as myocardial injury score (MIS). Suppressive effects of myofibrillar overcontraction could not be observed with nicorandil and prazosin at 10(-5) M. Propranolol at 10(-5) M, verapamil at 10(-6) M, and diltiazem at 10(-6) M demonstrated a significant suppressive effect with MIS of 1.0 +/- 0.4 (P < 0.01), 1.5 +/- 0.3 (P < 0.01), and 1.5 +/- 0.3 (P < 0.01), respectively. K201, even at 10(-7) M, displayed significant suppression with MIS of 1.8 +/- 0.2 (P < 0.01). K201 inhibited contraction of isolated vascular muscle induced by K+ (40 mM) and NE (1 mu M) at almost the same concentration. The IC50 ratio (NE/K+) of K201 was 2.3. The inhibition by K201 of the response to K+ was less marked than that by diltiazem. Its inhibition of the response to NE was greater than that by diltiazem or KT362. K201 demonstrated an inhibitory effect on binding of cardiac annexin V with actin dependent on calcium concentration, but diltiazem and KT362 did not demonstrate any action to inhibit this reaction. These results indicate that K201 was a more effective cardioprotectant than propranolol, verapamil, and diltiazem in the experimental myofibrillar overcontraction model. K201 has intracellular Ca2+ blocking action in addition to weak alpha-1 adrenergic blocking activity and Ca2+ blocking activity. (C) 1994 Wiley-Liss, Inc.