The sympathetic nervous system (SNS) and the renin angiotensin system (RAS) are both thought to contribute to the development and maintenance of hypertension in experimental models such as the Spontaneously Hypertensive Rat (SHR). We demonstrated that periarterial nerve stimulation (NS) increased the perfusion pressure (PP) and NPY overflow from the perfused mesenteric arterial bed of SHR at 4-6, 10-12 , and 18-20 weeks of age; which correspond to a prehypertensive, developing hypertensive and maintained hypertensive stages respectively in the SHR. NS also increased PP and NPY overflow from the mesenteric beds of Wistar Kyoto (WKY) normotensive rats. The NS-induced increase in PP and NPY was greater in vessels obtained from SHR of all 3 ages compared to WKY. Angiotensin II (Ang II) produced a greater increase in PP in preparations taken from SHR than WKY. Ang II also resulted in a greater increase in basal NPY overflow from 10-12 and 18-20 week old SHR than age matched WKY. Ang II enhanced the NS induced overflow of NPY from SHR preparations more than WKY controls at all ages studied. The enhancement of NS induced NPY overflow by Ang II was blocked by the AT1 receptor antagonist EMD 66684 and AT2 receptor antagonist PD 123319. In contrast, Ang II greatly enhanced NE overflow in the presence of PD 123319. Both Captopril and EMD 66684 decreased neurotransmitter overflow from SHR mesenteric beds, therefore we conclude that an endogenous RAS is active in this preparation. It is concluded that the Ang II induced enhancement of sympathetic nerve stimulation may contribute to the development and maintenance of hypertension in the SHR.