Abstract
The mechanism of diltiazem-induced inhibition of smooth muscle contractility was investigated by studying its effects on tension development and Ca++ fluxes in the rabbit aorta. Diltiazem caused a dose-dependent inhibiton of contractions as well as Ca++ influx stimulated by alpha adrenoceptor activation and high-K+ depolarization. Diltiazem was roughly equally potent in inhibiting contractions induced by high-K+ and a low concentration of norepinephrine (NE; 10(-8) M). The contractions induced by high concentrations (10(-6)-10(-5) M) of NE were more resistant to diltiazem inhibition. It was also observed that there was a close relationship between diltiazem inhibition of Ca++ influx and inhibition of contraction when either 40 mM K+ or 10(-8) M NE was applied, but not when 10(-6) M NE was used. Also, diltiazem produced a noncompetitive inhibition of Ca++-induced contractions of depolarized rabbit aorta. Furthermore, there was a lack of parallelism between the smooth muscle effects of removal of [Ca++]ex and of addition of diltiazem. It is suggested that diltiazem causes inhibition of stimulated Ca++ influx by interacting with the Ca++ pathway involved in excitation rather than competing with Ca++ for the entry.
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