Abstract
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 F2α (U46619), 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 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.
Footnotes
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These studies were supported by Project Grant ID 208969 from the National Health and Medical Research Council of Australia (NHMRC). C.G.S. is a Senior Research Fellow and P.D.M. is a Principal Research Fellow of the NHMRC. K.B. is supported by a Melbourne University Research Scholarship.
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
doi:10.1124/jpet.105.100040.
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ABBREVIATIONS: VSM, vascular smooth muscle; MLC, myosin light chain; MLCK, myosin light chain kinase; MLCP, myosin light chain phosphatase; PKC, protein kinase C; SMA, superior mesenteric artery; BMA, second order branches of superior mesenteric artery; KPSS, high K+-containing physiological saline solution; U46619, 9,11-dideoxy-9,11-methanoepoxy prostaglandin F2α; Y-27632, R-[+]-trans-N-[4-pyridyl]-4-[1-aminoethyl]-cycloheaxanecarboxamide; Ro 31-8220, 3-[1-[3-(amidinothio)propyl-1H-indol-3-yl]-3-(1-methyl-1H-indol-3-yl) maleimide; PdB, phorbol 12,13-dibutyrate; EDHF, endothelium-derived hyperpolarizing factor.
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↵1 Current affiliation: Department of Pharmacology, Monash University, Clayton, VIC, Australia.
- Received December 15, 2005.
- Accepted January 30, 2006.
- The American Society for Pharmacology and Experimental Therapeutics
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