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1 Pharmacology & Therapeutics, University of Florida, Gainesville, FL, USA; Regenerative Medicine, Wake-Forest University, Winston-Salem, NC, USA
2 Pharmacology & Therapeutics, University of Florida, Gainesville, FL, USA; Regenerative Medicine, Wake-Forest University, Winston-Salem, NC, USA; Medical Physiology, UMCG University of Groningen, Groningen, The Netherlands
* To whom correspondence should be addressed. E-mail: h.j.knot{at}med.umcg.nl.
Arterial smooth muscle constriction in response to pressure, myogenic tone, may involve calcium-dependent and calcium-sensitization mechanisms. Calcium-sensitization in vascular smooth muscle is regulated by kinases such as protein kinase C and Rho-kinase and activity of these kinases is known to be altered in cardiovascular disorders. In the present study we evaluated the relative contribution of PKC and Rho-kinase to myogenic tone in cerebral arteries in hypertension. Myogenic tone and arterial wall calcium in WKY and SHR arteries were measured simultaneously and the effect of PKC and Rho-kinase inhibitors on myogenic tone was evaluated. SHR arteries showed significantly greater myogenic tone than that of WKY arteries. Pressure/wall tension-arterial wall calcium curves showed a hyperbolic relationship in WKY arteries whereas in SHR arteries it was parabolic. Myogenic tone was decreased by Rho-kinase inhibitors, Y-27632 and HA1077, with this effect being significantly greater in SHR arteries compared to those from WKY. The extent of reduction in myogenic tone produced by PKC inhibitor, bisindolylmaleimide I, in both WKY and SHR arteries was significantly less than that produced by Rho-kinase inhibition. Pressure-dependent increase in myogenic tone was significantly decreased by Y-27632 and the extent of decrease was markedly higher than that observed with bisindolylmaleimide I in SHR arteries. In WKY arteries, pressure-dependent increase in myogenic tone was decreased to a similar extent by both Y-27632 and bisindolylmaleimide I. These results suggest that SHR arteries exhibit greater myogenic tone with increased calcium-sensitization, largely due to the activation of Rho-kinase with a minor contribution of PKC activation.
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