Segmental differences in the roles of rho-kinase and protein kinase C in mediating vasoconstriction

• Published in: The Journal of pharmacology and experimental therapeutics Vol. 317; no. 2; p. 791
• Main Authors: Budzyn, Klaudia, Paull, Michelle, Marley, Philip D, Sobey, Christopher G
• Format: Journal Article
• Language: English
• Published: United States 01-05-2006
• Subjects: Animals; Aorta, Thoracic - enzymology; Aorta, Thoracic - physiology; Dose-Response Relationship, Drug; Enzyme Inhibitors - pharmacology; In Vitro Techniques; Intracellular Signaling Peptides and Proteins; Male; Mesenteric Artery, Superior - enzymology; Mesenteric Artery, Superior - physiology; Protein Kinase C - antagonists & inhibitors; Protein Kinase C - physiology; Protein-Serine-Threonine Kinases - antagonists & inhibitors; Protein-Serine-Threonine Kinases - physiology; Rats; Rats, Sprague-Dawley; rho-Associated Kinases; Vasoconstriction - physiology; Vasoconstrictor Agents - pharmacology
• ISSN: 0022-3565
• DOI: 10.1124/jpet.105.100040

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 approximately 2 mm), superior mesenteric artery (SMA; approximately 1.5 mm), and second order branches of the superior mesenteric artery (BMA; approximately 300 mum). The roles of rho-kinase and PKC in mediating contractile responses to phenylephrine, 9,11-dideoxy-9,11-methanoepoxy prostaglandin F(2alpha) (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 muM) 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 muM). Contractile responses of aorta and SMA were reduced by either 1 or 10 muM Y-27632 (P < 0.05), whereas responses of BMA were reduced by 10 muM (P < 0.05) but not 1 muM 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.