Received for publication May 20, 2008.
Revised August 4, 2008.
Accepted for publication August 4, 2008.

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 ₁-adrenoceptor-mediated pharmacomechanical coupling in the uterine artery of near-term pregnant sheep. The cell permeable cGMP analogue 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 ([Ca²⁺]_i) and tensions in the same tissue indicated that 8-bromo-cGMP decreased NE-induced contractions by 92%, but only blocked 44% of [Ca²⁺]_i. In accordance, 8-bromo-cGMP significantly decreased tension generation for a given [Ca²⁺]_i (g/Rf_340/380: 24.87 ± 3.43 vs. 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 ₁-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.

Key words: cGMP, calcium, norepinephrine, pregnancy, sheep, uterine artery