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Role of Protein Kinase C Isozymes in the Regulation of alpha₁-Adrenergic Receptor-Mediated Contractions in Ovine Uterine Arteries¹

Center for Perinatal Biology, Department of Physiology & Pharmacology, Loma Linda University School of Medicine, Loma Linda, California 92350

ABSTRACT

Previously, we demonstrated that activation of protein kinase C (PRKC) enhanced alpha₁-adrenergic receptor-induced contractions in nonpregnant ovine uterine arteries but inhibited the contractions in pregnant ovine uterine arteries. The present study tested the hypothesis that differential regulation of PRKC isozyme activities contributes to the different effects of phorbol 12, 13-dibutyrate (PDBu) on alpha₁-adrenergic receptor-mediated contractions between the pregnant and nonpregnant ovine uterine arteries. Phenylephrine-induced contractions of ovine nonpregnant and pregnant uterine arteries were determined in the absence or presence of the PRKC activator PDBu and/or in combination with conventional and novel PRKC isozyme inhibitor GF109203X, PRKC isozyme-selective inhibitory peptides for conventional PRKC, PRKCB1, PRKCB2, and PRKCE. GF109203X produced a concentration-dependent inhibition of phenylephrine-induced contractions in both nonpregnant and pregnant uterine arteries, and it reversed the PDBu-mediated potentiation and inhibition of phenylephrine-induced contractions in nonpregnant and pregnant uterine artieries, respectively. In addition, PRKCB1, PRKCB2, and PRKCE inhibitory peptides blocked the PDBu-mediated responses in both nonpregnant and pregnant uterine arteries. Western blot analysis showed that PDBu induced a membrane translocation of PRKCA, PRKCB1, PRKCB2, and PRKCE in pregnant uterine arteries, and PRKCB1, PRKCB2, and PRKCE in nonpregnant uterine arteries. The results disprove the hypothesis that the dichotomy of PRKC mechanisms in the regulation of alpha₁-adrenergic receptor-induced contractions in nonpregnant and pregnant uterine arteries is caused by the activation of different PRKC isozymes, and suggest downstream mechanisms of differential subcellular distributions for the distinct functional effects of PRKC isozymes in the adaptation of uterine arteries to pregnancy.

GF109203X, phenylephrine, phorbol 12, 13-dibutyrate, pregnancy, protein kinase C, protein kinase C inhibitor peptides

¹Supported in part by National Institutes of Health grants HL57787 and HD31226 and by the Loma Linda University School of Medicine.

Correspondence: ²Lubo Zhang, Center for Perinatal Biology, Department of Physiology & Pharmacology, Loma Linda University School of Medicine, Loma Linda, CA 92350. FAX: 909 558 4029; e-mail: lzhang{at}llu.edu