The purpose of this study was to test the hypothesis that renal sympathetic nerves modulate angiotensin II-induced renal vasoconstriction in kidneys from genetically hypertensive rats via Y1 receptors activating the Gi pathway. In isolated, perfused kidneys from spontaneously hypertensive rats, the naturally occurring renal sympathetic cotransmitter neuropeptide Y at 6 nM enhanced angiotensin II (0.3 nM)-induced changes in perfusion pressure by 47 +/- 7 mm Hg, and this effect was inhibited by BIBP3226 [N2-(diphenylacetyl)-N-[(4-hydroxyphenyl)-methyl]-D-arginine amide)], a selective Y1 receptor antagonist (1 microM). We next examined whether periarterial nerve stimulation (5 Hz) enhances renal vascular responses to a physiological level of angiotensin II (100 pM). Kidneys were pretreated with prazosin (a selective alpha1-adrenoceptor antagonist) to block nerve stimulation-induced changes in perfusion pressure. In kidneys from spontaneously hypertensive rats, but not normotensive rats, periarterial nerve stimulation significantly augmented angiotensin II-induced changes in perfusion pressure (177 +/- 26% of response in absence of stimulation). BIBP3226, but not rauwolscine (a selective alpha2-adrenoceptor antagonist), abolished periarterial nerve stimulation-induced enhancement of angiotensin II-mediated renal vasoconstriction. Pretreatment of hypertensive animals with pertussis toxin 3 days prior to kidney perfusion significantly (p < 0.000001) decreased mean blood pressure (203 +/- 2 versus 145 +/- 6 mm Hg in nonpretreated versus pertussis toxin-pretreated spontaneously hypertensive rats) and abolished periarterial nerve stimulation-induced enhancement of angiotensin II-mediated renal vasoconstriction. We conclude that, in spontaneously hypertensive rats but not normotensive rats, sympathetic nerve stimulation enhances renal vascular responses to physiological levels of angiotensin II via a mechanism mainly involving Y1 receptors coupled to Gi proteins.