Theoretical bases for vascular selectivity of Ca2+ antagonists.

The purpose of these studies was to characterize mechanisms of activation of vascular tissues in order to clarify possible theoretical bases for Ca2+-antagonist (CAt) selectivity. Activation of rabbit aorta, mesenteric artery, and mesenteric resistance vessels by agonists and depolarizing potassium (K+) solution, and inhibition by CAts were studied by measurement of contractions, 45Ca fluxes, and membrane potentials (via intracellular electrodes). We found that the CAts studied (D-600, diltiazem, and nisoldipine) inhibited K+-induced Ca2+ influx and contractions in a closely correlated manner, suggesting inhibition of Ca2+ entry as their primary, if not sole, mechanism of action. Diltiazem and nisoldipine had no effect on intracellular Ca2+ release or on the contractile protein system. The following evidence was obtained to support the tenet that norepinephrine (NE) and 80 mM K+ open two distinct Ca2+ channels, one receptor-operated (ROC) and the other potential-operated (POC): (a) NE activated the rabbit aorta without eliciting a change in membrane potential; (b) NE activation of the rabbit mesenteric resistance vessels was accompanied by membrane depolarization, but this depolarization was blocked by 10(-5) M diltiazem, whereas that induced by 80 mM K+ was not; (c) 45Ca influx stimulated by 80 mM K+ and that stimulated by a maximal [NE] were additive when the two agents were administered together in the aorta and the resistance vessels; (d) the Ca2+-channel agonist Bay K8644 opens the POC but not the ROC in rabbit aorta, as it is capable of stimulating Ca2+ influx in addition to 10(-5) M NE, but not to 80 mM K+; (e) the CAts show selective inhibition of the POC over the ROC in the aorta, whereas diltiazem preferentially inhibits the ROC in the resistance vessels; and (f) alpha adrenoreceptor occupation, phosphodiesterase inhibition, or dibutyryl cyclic AMP selectively inhibits the POC over the ROC in the aorta.(ABSTRACT TRUNCATED AT 250 WORDS)