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J Appl Physiol 98: 1940-1948, 2005. First published December 30, 2004; doi:10.1152/japplphysiol.01104.2004
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HIGHLIGHTED TOPICS
Biomechanics and Mechanotransduction in Cells and Tissues

Effects of Rho kinase inhibition on cerebral artery myogenic tone and reactivity

Natalia I. Gokina, Kristen M. Park, Keara McElroy-Yaggy, and George Osol

Department of Obstetrics and Gynecology, University of Vermont, College of Medicine, Burlington, Vermont

Submitted 1 October 2004 ; accepted in final form 17 December 2004

Several recent studies have implicated the RhoA-Rho kinase pathway in arterial myogenic behavior. The goal of this study was to determine the effects of Rho kinase inhibition (Y-27632) on cerebral artery calcium and diameter responses as a function of transmural pressure. Excised segments of rat posterior cerebral arteries (100–200 µm) were cannulated and pressurized in an arteriograph at 37°C. Increasing pressure from 10 to 60 mmHg triggered an elevation of cytosolic calcium concentration ([Ca2+]i) from 113 ± 9 to 199 ± 12 nM and development of myogenic tone. Further elevation of pressure to 120 mmHg induced only a minor additional increase in [Ca2+]i and constriction. Y-27632 (0.3–10 µM) inhibited myogenic tone in a concentration-dependent manner at 60 and 120 mmHg with comparable efficacy; conversely, sensitivity was decreased at 120 vs. 60 mmHg (50% inhibitory concentration: 2.5 ± 0.3 vs. 1.4 ± 0.1 µM; P < 0.05). Dilation was accompanied by further increases in [Ca2+]i and an enhancement of Ca2+ oscillatory activity. Y-27632 also effectively dilated the vessels permeabilized with {alpha}-toxin in a concentration-dependent manner. However, dilator effects of Y-27632 at low concentrations were larger at 60 vs. 100 mmHg. In summary, the results support a significant role for RhoA-Rho kinase pathway in cerebral artery mechanotransduction of pressure into sustained vasoconstriction (myogenic tone and reactivity) via mechanisms that augment smooth muscle calcium sensitivity. Potential downstream events may involve inhibition of myosin phosphatase and/or stimulation of actin polymerization, both of which are associated with increased smooth muscle force production.

mechanotransduction; Y-27632; fura 2; {alpha}-toxin; actin polymerization


Address for reprint requests and other correspondence: N. I. Gokina, Dept. of Obstetrics and Gynecology, The Univ. of Vermont, College of Medicine, Burlington, VT 05405 (E-mail: Natalia.Gokina{at}uvm.edu)




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