Abstract--The G_i pathway augments renal vasoconstriction induced by angiotensin II in spontaneously hypertensive but not normotensive Wistar-Kyoto rats. Because the G_i-coupled pancreatic polypeptide (PP)-fold peptide receptors Y₁ and Y₂ are expressed in kidneys and are activated by endogenous PP-fold peptides, we tested the hypothesis that these receptors regulate angiotensin II-induced renal vasoconstriction in kidneys from hypertensive but not normotensive rats. A selective Y₁-receptor agonist [(Leu31,Pro34)-neuropeptide Y; 6 to 10 nmol/L] greatly potentiated angiotensin II-induced changes in perfusion pressure in isolated, perfused kidneys from hypertensive but not normotensive rats. A selective Y₂-receptor agonist (peptide YY_3-36; 6 nM) only slightly potentiated angiotensin II-induced renal vasoconstriction and only in kidneys from hypertensive rats. Neither the Y₁-receptor nor the Y₂-receptor agonist increased basal perfusion pressure. BIBP3226 (1 µmol/L, highly selective Y₁-receptor antagonist) and BIIE0246 (1 µmol/L, highly selective Y₂-receptor antagonist) completely abolished potentiation by (Leu31,Pro34)-neuropeptide Y and peptide YY_3-36, respectively. Y₁-receptor and Y₂-receptor mRNA and protein levels were expressed in renal microvessels and whole kidneys, but the abundance was similar in kidneys from hypertensive and normotensive rats. Both Y₁-receptor-induced and Y₂-receptor-induced potentiation of angiotensin II-mediated renal vasoconstriction was completely abolished by pretreatment with pertussis toxin (30 µg/kg IV, blocks G_i proteins). These data indicate that, in kidneys from genetically hypertensive but not normotensive rats, Y₁-receptor activation markedly enhances angiotensin II-mediated renal vasoconstriction by a mechanism involving G_i. Although Y₂ receptors can also potentiate angiotensin II-mediated renal vasoconstriction via G_i, the effect is modest compared with Y₁ receptors. These findings may have important implications for the etiology of genetic hypertension.