Role of 4-Hydroxylated Estradiol in Reducing Ca2+ Uptake of Uterine Arterial Smooth Muscle Cells through Potential-Sensitive Channels1

Abstract

Entry of ionic Ca2+ into the vascular smooth muscle cell for contraction is thought to be mediated by two major membrane channels. The first are designated as potential-sensitive channels (PSCs), which are opened by membrane depolarization, and the second, as receptor-operated channels (ROCs), which are activated by alpha 1-receptor-ligand interactions. This study was designed to determine the presence of these 2 distinct populations of Ca2+ entry channels in smooth muscle cells of the uterine arteries in pigs. This was studied by measuring the baseline tone and contractile properties of uterine arteries in in vitro perfusion studies, as well as their specific Ca2+ uptakes. These parameters showed markedly different sensitivities towards two smooth muscle inhibitors used in this study: D-600 and amrinone. D-600 specifically inhibits uptake of extracellular Ca2+ through PSCs, while amrinone specifically inhibits Ca2+ uptake through ROCs. By choosing an appropriate concentration of D-600 or amrinone, Ca2+ uptake and contractions of uterine arterial segments induced by high-K+ (PSC activator) and phenylephrine (ROC activator) could be selectively inhibited. Furthermore, it was demonstrated that the blockade of Ca2+ uptake by D-600 and amrinone was additive, excluding the interpretation of a common Ca2+ pathway with two separate mechanisms for opening it. It was also determined that 4-hydroxylated estradiol (4OH-E2), a compound known to increase uterine blood flow in pigs, decreased Ca2+ uptake through the PSCs and exhibited no effect on ROCs. The presence of separate Ca2+ pathways that can be activated independently by agonists may indicate a refined system for controlling uterine blood flow.