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(Hypertension. 2006;47:545.)
© 2006 American Heart Association, Inc.

Part 2 Original Articles

Pancreatic Polypeptide-Fold Peptide Receptors and Angiotensin II–Induced Renal Vasoconstriction

John H. Dubinion; Zaichuan Mi; Chongxue Zhu; Liping Gao; Edwin K. Jackson

From the Center for Clinical Pharmacology, Departments of Medicine (Z.M., C.Z., L.G., E.K.J.) and Pharmacology (J.H.D., E.K.J.), University of Pittsburgh School of Medicine, Pittsburgh, Pa.

Correspondence to Edwin K. Jackson, Center for Clinical Pharmacology, University of Pittsburgh School of Medicine, 100 Technology Dr, Suite 450, Pittsburgh, PA 15219. E-mail edj{at}pitt.edu

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.

Key Words: receptors • neuropeptides • peptides • hypertension

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