Vanadate stimulation of adenylyl cyclase: an index of tyrosine kinase vascular effects.

BACKGROUND: Beyond their mitogenic effects, hormones such as insulin, which activate receptor tyrosine kinases, regulate vascular tone. Further, we have demonstrated that receptor tyrosine kinase activation enhances adenylyl cyclase activation, a prominent mechanism that mediates vasodilation. However, whether tyrosine kinase-mediated human vascular responses parallel tyrosine kinase-mediated cellular effects on adenylyl cyclase activity is unknown. METHODS AND RESULTS: To assess tyrosine kinase-mediated vascular responses, vascular sensitivity to insulin was assessed with the dorsal hand vein linear variable differential transformer technique. Insulin infusion resulted in a dose-dependent relaxation in all subjects. Cellular responses were assessed by means of the insulinomimetic vanadate-mediated sensitization of vascular adenylyl cyclase activity. Vanadate stimulated a tyrosine kinase-dependent enhancement of adenylyl cyclase function in human and rat aortic vascular smooth muscle cells, human lymphocytes, and human aortic endothelial cells. Further, maximal insulin-mediated vasodilation was significantly positively correlated with maximal vanadate-mediated enhancement of human lymphocyte adenylyl cyclase activity. CONCLUSION: Insulin-mediated vasodilation is positively correlated with vanadate-mediated enhancement of adenylyl cyclase activity. Vanadate-mediated enhancement of adenylyl cyclase activity in lymphocytes may represent an index of tyrosine kinase-mediated vascular effects.