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The present study examined the role of cGMP in the regulation of alpha(1)-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 (IP(3)) synthesis in the uterine artery. In addition, 8-bromo-cGMP significantly reduced the binding affinity of IP(3) to the IP(3) receptor. The density of IP(3) 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% [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 alpha(1)-adrenoceptor-mediated pharmacomechanical coupling in the uterine artery by inhibiting IP(3) 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.

Effect of cGMP on Pharmacomechanical Coupling in the Uterine Artery of Near-Term Pregnant Sheep