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CARDIOVASCULAR

Regulation of ₁-Adrenoceptor-Mediated Contractions of the Uterine Artery by Protein Kinase C: Role of the Thick- and Thin-Filament Regulatory Pathways

Department of Pharmacology and Physiology, Center for Perinatal Biology, Loma Linda University School of Medicine, Loma Linda, California

Previously we demonstrated that activation of protein kinase C (PKC) enhanced ₁-adrenoceptor-induced contractions in nonpregnant uterine arteries (NPUA) by increasing the Ca²⁺ sensitivity but that it inhibited the contractions in pregnant uterine arteries (PUA) by decreasing intracellular Ca²⁺ mobilization. The present study tested the hypothesis that PKC activation differentially regulated the thick- and thin-filament regulatory pathways in ₁-adrenoceptor-induced contractions of NPUA and PUA in sheep. Simultaneous measurements of contractions and phosphorylation levels of 20-kDa regulatory myosin light chain (LC₂₀) in the same tissue revealed that the PKC activator phorbol-12,13-dibutyrate (PDBu) inhibited phenylephrine-induced phosphorylation of LC₂₀ and contractions in PUA. In NPUA, PDBu significantly potentiated phenylephrine-induced contractions without significantly changing phosphorylation levels of LC₂₀. Further studies in NPUA demonstrated that PDBu-mediated potentiation of phenylephrine-induced contractions was associated with a significant increase in phosphorylation levels of extracellular signal-regulated kinase (ERK_42/44) and caldesmon-Ser⁷⁸⁹, measured simultaneously with the tension in the same tissue. In addition, the ERK_42/44 inhibitor PD98059 [2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one] and the actin polymerization inhibitor cytochalasin B produced a concentration-dependent inhibition of PDBu-mediated potentiation of phenylephrine-induced contractions in NPUA. The results suggest that activation of PKC inhibits ₁-adrenoceptor-mediated contractions in PUA through down-regulation of the thick-filament pathway and decreased myosin light chain phosphorylation, but that it enhances the contractions in NPUA through its effect on the thin-filament regulatory pathway and activation of ERK/caldesmon and actin polymerization.

Address correspondence to: Dr. Lubo Zhang, Department of Pharmacology and Physiology, Center for Perinatal Biology, Loma Linda University School of Medicine, Loma Linda, CA 92350. E-mail: lzhang{at}llu.edu

This article has been cited by other articles:

				H. Zhang and L. Zhang Role of Protein Kinase C Isozymes in the Regulation of alpha1-Adrenergic Receptor-Mediated Contractions in Ovine Uterine Arteries Biol Reprod, January 1, 2008; 78(1): 35 - 42. [Abstract] [Full Text] [PDF]