EFFECTS OF SEMOTIADIL FUMARATE (SD-3211) AND ITS ENANTIOMER, SD-3212, ON THE CHANGES IN CYTOSOLIC CA2+ AND TENSION CAUSED BY KCL AND NOREPINEPHRINE IN ISOLATED RAT AORTAS

Semotiadil fumarate (SD-3211), a Ca2+ channel blocker of benzothiazine derivative and its (S)-(-)enantiomer (SD-3212), inhibited K+- and norepinephrine (NE)-induced contractions in isolated rat aortas. Inhibition of NE contraction induced by both drugs was greater than that induced by diltiazem or bepridil, whereas inhibition of K+-contraction was similar to that induced by diltiazem or bepridil. Semotiadil and SD-3212 (10 mu M) nhibited the increase in cytosolic Ca2+ ([Ca2+](i)) induced by 65.4 mM K+ in fura-2-loaded preparations as well as diltiazem and bepridil(10 mu M). On the other hand, semotiadil and SD-3212 (10 mu M) inhibited only the early phase of increase in [Ca2+](i) induced by 1 mu M NE. After 5 min, no significant effect on [Ca2+](i) was observed with these compounds despite the significant decrease in the contraction. In contrast to these compounds, diltiazem and bepridil 10 mu M affected neither the increase in [Ca2+](i) nor the contraction induced by NE, Semotiadil and SD-3212 inhibited the transient contraction induced by 1 mu M NE in the absence of external Ca2+. Both compounds partially but significantly inhibited the NE-induced contraction in nifedipine-treated muscles. These results suggest that semotiadil and SD-3212 inhibit contractions of vascular smooth muscle (VSM) not only through blockade of voltage-dependent Ca2+ channels but also through other mechanisms, such as inhibition of Ca2+ release from Ca2+ stores or decrease in sensitivity of the contractile elements to Ca2+.