Research in our laboratory corroborates that hypertension in the spontaneously hypertensive rat (SHR) is mediated in part by an enhanced renovascular response to angiotensin II (Ang II). Recently, we discovered that the enhanced renovascular response to Ang II in SHR is caused by potentiation of Ang II-induced renal vasoconstriction by the Gi signal transduction pathway. The finding of an enhanced coincidence signaling between the Ang II signal transduction pathway and the Gi signal transduction pathway in the renal microcirculation of SHR has important implications regarding the pathophysiology of genetic hypertension. Renal sympathetic nerves release two major neurotransmitters, norepinephrine (NE) and neuropeptide Y (NPY). NE and NYP activate postjunctional alpha 2-adrenoceptors and Y1 receptors, respectively, and both receptors are coupled nearly exclusively to the Gi signal transduction pathway. Our research suggests that an important contributing cause to genetic hypertension is release of NE and NPY from renal sympathetic nerves with subsequent activation of postjunctional alpha 2-adrenoceptors and Y1 receptors leading to significant stimulation of the Gi signal transduction pathway and, therefore, potentiation of renovascular responses to Ang II. To test this hypothesis we will determine in normotensive and hypertensive rats: 1) whether a Y1 receptor agonist potentiates renovascular responses to Ang II (studies with an alpha 2- adrenoceptor agonist were completed in preliminary studies); 2) whether near threshold activation of alpha 2-adrenoceptors combined with near threshold activation of Y1 receptors enhances renovascular responses to Ang II; 3) whether renal sympathetic activation potentiates Ang II-induced renal vasoconstriction by a mechanism involving co-activation of alpha 2-adrenoceptors and Y1 receptors; 4) whether blockade of the Gi signal transduction pathway prevents enhancement of Ang II-induced renal vasoconstriction by activation of alpha 2-adrenoceptors, by activation of Y1 receptors, by co-activation of alpha 2-adrenoceptors and Y1 receptors and by renal nerve stimulation; and 5) the expression of Y1 receptors in the renal microcirculation. We also will address the mechanism of coincidence signaling between the Ang II signal transduction pathway and the Gi signal transduction pathway in the renal microcirculation by testing the hypothesis that coincidence signaling between Ang II and Gi is mediated by RhoA/Rho kinase/PLD. [unreadable] [unreadable]