Dual role of PKC in modulating pharmacomechanical coupling in fetal and adult cerebral arteries

This study tested the hypothesis that protein kinase C (PKC) has dual regul ation on norepinephrine (NE)-mediated inositol 1,4,5-trisphosphate [Ins (1, 4,5)P-3] pathway and vasoconstriction in cerebral arteries from near-term f etal (similar to 140 gestational days) and adult sheep. Basal PKC activity values (% membrane bound) in fetal and adult cerebral arteries were 38 +/- 4% and 32 +/- 4%, respectively. In vessels of both age groups, the PKC isof orms alpha, beta(I), beta(II), and delta were relatively abundant. In contr ast, compared with the adult, cerebral arteries of the fetus had low levels of PKC-epsilon. In response to 10(-4) M phorbol 12,13-dibutyrate (PDBu; PK C agonist), PKC activity in both fetal and adult cerebral arteries increase d 40-50%. After NE stimulation, PKC activation with PDBu exerted negative f eedback on Ins(1,4,5)P-3 and intracellular Ca2+ concentration ([ Ca2+](i)) in arteries of both age groups. In turn, PKC inhibition with staurosporine resulted in augmented NE-induced Ins(1,4,5)P-3 and [Ca2+](i) responses in a dult, but not fetal, cerebral arteries. In adult tissues, PKC stimulation b y PDBu increased vascular tone, but not [Ca2+](i). In contrast, in the feta l artery, PKC stimulation was associated with an increase in both tone and [Ca2+](i). In the presence of zero extracellular [Ca2+], these PDBu-induced responses were absent in the fetal vessel, whereas they remained unchanged in the adult. We conclude that, although basal PKC activity was similar in fetal and adult cerebral arteries, PKC's role in NE-mediated pharmacomecha nical coupling differed significantly in the two age groups. In both fetal and adult cerebral arteries, PKC modulation of NE-induced signal transducti on responses would appear to play a significant role in the regulation of v ascular tone. The mechanisms differ in the two age groups, however, and thi s probably relates, in part, to the relative lack of PKC-epsilon in fetal v essels.