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CARDIOVASCULAR

Segmental Differences in the Roles of Rho-Kinase and Protein Kinase C in Mediating Vasoconstriction

Department of Pharmacology, University of Melbourne, Parkville, Victoria, Australia

Rho-kinase and protein kinase C (PKC) have each been reported to mediate vasoconstriction via calcium sensitization. However, the relative contributions of these two kinases to vascular contraction, and whether their roles vary between large and small arteries, are largely unknown. We therefore assessed the relative roles of rho-kinase and PKC in mediating vasoconstriction in arteries from three segments of the aortic and mesenteric vasculature. We studied contractile responses of rat isolated thoracic aorta (diameter 2 mm), superior mesenteric artery (SMA; 1.5 mm), and second order branches of the superior mesenteric artery (BMA; 300 µm). The roles of rho-kinase and PKC in mediating contractile responses to phenylephrine, 9,11-dideoxy-9,11-methanoepoxy prostaglandin F₂ (U46619 [GenBank] ), and KCl were assessed by using the rho-kinase inhibitor R-[+]-trans-N-[4-pyridyl]-4-[1-aminoethyl]-cycloheaxanecarboxamide (Y-27632) (1 and 10 µM) and the PKC inhibitor 3-[1-[3-(amidinothio)propyl-1H-indol-3-yl]-3-(1-methyl-1H-indol-3-yl) maleimide (Ro 31-8220) (5 µM). Contractile responses of aorta and SMA were reduced by either 1 or 10 µM Y-27632 (P < 0.05), whereas responses of BMA were reduced by 10 µM (P < 0.05) but not 1 µM Y-27632. In contrast, Ro 31-8220 partly reduced contractile responses in aorta and SMA (P < 0.05), but it abolished responses of BMA (P < 0.05). Cotreatment with Y-27632 and Ro 31-8220 markedly attenuated contractile responses to phenylephrine and KCl in all vessels, but it had only a moderate inhibitory effect on responses to U46619 [GenBank] in aorta and SMA. Thus, contractile responses of the larger arteries can involve both rho-kinase and PKC to varying degrees. Conversely, contractile responses of small mesenteric resistance arteries seem to be mediated exclusively by PKC, with no apparent role for rho-kinase.

Address correspondence to: Dr. Christopher G. Sobey, Department of Pharmacology, Monash University, Clayton, Victoria 3800, Australia. E-mail: chris.sobey{at}med.monash.edu.au

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