Effect of cGMP on pharmacomechanical coupling in the uterine artery of near-term pregnant sheep

Abstract

The present study examined the role of cGMP in the regulation of α1-adrenoceptor-mediated pharmacomechanical coupling in the uterine artery of near-term pregnant sheep. The cell-permeable cGMP analog 8-bromo-cGMP produced a dose-dependent relaxation of the uterine artery and shifted norepinephrine (NE) dose-response curve to the right with a decreased maximal contraction. Accordingly, 8-bromo-cGMP significantly decreased the potency and the maximal response of NE-induced inositol 1,4,5-trisphosphate (IP3) synthesis in the uterine artery. In addition, 8-bromo-cGMP significantly reduced the binding affinity of IP3 to the IP3 receptor. The density of IP3 receptors was not affected. Simultaneous measurement of intracellular Ca2+ concentrations ([Ca 2+]i) and tensions in the same tissue indicated that 8-bromo-cGMP decreased NE-induced contractions by 92% but only blocked 44% [Ca2+]i. In accordance, 8-bromo-cGMP significantly decreased tension generation for a given [Ca2+]i (g/R f340/380, 24.87 ± 3.43 versus 3.10 ± 0.35). In the absence of extracellular Ca2+, NE produced a transient increase in [Ca2+]i and contraction, which were inhibited by 8-bromo-cGMP by 47 and 76%, respectively. In contrast to NE-induced responses, 8-bromo-cGMP had no significant effects on KCl-induced [Ca2+] i and contractions. The results indicate that cGMP suppresses α1-adrenoceptor-mediated pharmacomechanical coupling in the uterine artery by inhibiting IP3 synthesis and Ca2+ release from intracellular stores, as well as inhibiting the agonist-mediated Ca2+ sensitization of myofilaments, which is likely to play an important role in the adaptation of uterine artery contractility during pregnancy. Copyright © 2008 by The American Society for Pharmacology and Experimental Therapeutics.