Coronary arteriolar flow-induced vasodilation signals through tyrosine kinase. Muller, Judy M., Michael J. Davis, and William M. Chilian. Department of Medical Physiology, Texas A&M University Health Sciences Center, College Station, Texas
APStracts 2:0513H, 1995.
Coronary arterioles demonstrate flow-dependent vasodilation that is mediated by endothelial release of nitric oxide. The signaling mechanisms for this response remain unknown. Because tyrosine kinases are an enzyme family linked to many signalling pathways, including some for mechanosensitive transduction, we hypothesized that tyrosine kinase activation is a critical step in flow-induced vasodilation. To test this, coronary arterioles were isolated, cannulated with micropipettes, and perfused by two independent reservoir systems. Intraluminal pressure was set at 60 cm H2O and flow was generated by changing the heights of the reservoirs in equal and opposite directions, thus establishing a pressure difference across the arteriole without altering intraluminal pressure. Vasodilatory responses to intraluminal flow and substance P (1x10-12 to 1x10-7M) were evaluated before and after intraluminal application of the tyrosine kinase inhibitors genistein (5 [mu]M) and piceatannol (10 [mu]M). Exposure to these inhibitors did not alter spontaneous tone. Substance P caused dose-dependent vasodilation that was not affected by genistein or piceatannol. Increases in intraluminal flow (generated by pressure differences ranging from 4 to 60 cm H2O) elicited graded increases in diameter. Both genistein and piceatannol inhibited the vasodilatory responses to flow. Treatment with daidzein, an inactive analog of genistein, had no effect on either the flow-induced responses or substance P-induced vasodilation. To further confirm that tyrosine kinase activation is involved in flow -induced vasodilation, vessels were exposed to flow in the absence or presence of genistein and subsequently stained with a FITC-labeled phosphotyrosine antibody. Exposure to flow significantly increased fluorescence of endothelial cells. Genistein treatment reversed the flow-induced increase in tyrosine phosphorylation. These results indicate that endothelium-dependent, flow-induced vasodilation in isolated porcine coronary arterioles is accompanied by an increase in tyrosine kinase activity. We conclude that endothelium-dependent, nitroxidergic, flow-induced vasodilation is mediated, at least in part, by a signaling pathway involving a tyrosine kinase. 

Received 8 May 1995; accepted in final form 7 November 1995.
APS Manuscript Number H438-5.
Article publication pending Am. J. Physiol. (Heart Circ. Physiology).
ISSN 1080-4757 Copyright 1995 The American Physiological Society.
Published in APStracts on 30 November 95