Effect of cGMP on pharmacomechanical coupling in the uterine artery of near-term pregnant sheep.
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.
Zhang
Lubo
L
Center for Perinatal Biology, Department of Physiology and Pharmacology, Loma Linda University School of Medicine, Loma Linda, CA 92350, USA. lzhang@llu.edu
Xiao
Daliao
D
Hu
Xiangqun
X
D000818:Animals; D001158:Arteries / Q000502:physiology; D002118:Calcium / Q000378:metabolism; D006152:Cyclic GMP / Q000031:analogs & derivatives / Q000494:pharmacology / Q000502:physiology*; D005260:Female; D015544:Inositol 1,4,5-Trisphosphate / Q000096:biosynthesis; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000032:analysis; D009638:Norepinephrine / Q000494:pharmacology; D011247:Pregnancy; D011270:Pregnancy, Animal / Q000502:physiology*; D018340:Receptors, Adrenergic, alpha-1 / Q000502:physiology; D012756:Sheep; D014599:Uterus / Q000098:blood supply*; D014661:Vasoconstriction / Q000187:drug effects*
D053496:Inositol 1,4,5-Trisphosphate Receptors; D018340:Receptors, Adrenergic, alpha-1; C016276:8-bromocyclic GMP; D015544:Inositol 1,4,5-Trisphosphate; D006152:Cyclic GMP; D002118:Calcium; D009638:Norepinephrine