title: Pancreatic polypeptide-fold peptide receptors and angiotensin II-induced renal vasoconstriction.
abstract: The Gi pathway augments renal vasoconstriction induced by angiotensin II in spontaneously hypertensive but not normotensive Wistar-Kyoto rats. Because the Gi-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 micromol/L, highly selective Y1-receptor antagonist) and BIIE0246 (1 micromol/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 microg/kg IV, blocks Gi 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 Gi. Although Y2 receptors can also potentiate angiotensin II-mediated renal vasoconstriction via Gi, the effect is modest compared with Y1 receptors. These findings may have important implications for the etiology of genetic hypertension.
authors.affiliation: Center for Clinical Pharmacology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15219, USA.
authors.forename: John H
authors.initials: JH
authors.lastname: Dubinion
authors.forename: Zaichuan
authors.initials: Z
authors.lastname: Mi
authors.forename: Chongxue
authors.initials: C
authors.lastname: Zhu
authors.forename: Liping
authors.initials: L
authors.lastname: Gao
authors.forename: Edwin K
authors.initials: EK
authors.lastname: Jackson
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D001808:Blood Vessels / Q000187:drug effects; D015153:Blotting, Western; D006973:Hypertension / Q000235:genetics / Q000503:physiopathology*; D066298:In Vitro Techniques; D007668:Kidney / Q000098:blood supply*; D008297:Male; D009478:Neuropeptide Y / Q000031:analogs & derivatives / Q000494:pharmacology; D010446:Peptide Fragments; D019894:Peptide YY / Q000494:pharmacology; D010477:Perfusion; D011312:Pressure; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism*; D011964:Receptors, Gastrointestinal Hormone / Q000378:metabolism*; D018013:Receptors, Neuropeptide / Q000235:genetics / Q000378:metabolism*; D017476:Receptors, Neuropeptide Y / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014661:Vasoconstriction / Q000187:drug effects
chemical_list: D009478:Neuropeptide Y; C066211:Npy1r protein, rat; D010446:Peptide Fragments; D012333:RNA, Messenger; D043562:Receptors, G-Protein-Coupled; D011964:Receptors, Gastrointestinal Hormone; D018013:Receptors, Neuropeptide; D017476:Receptors, Neuropeptide Y; C095889:neuropeptide Y2 receptor; C029438:receptors, pancreatic polypeptide-specific; D019894:Peptide YY; D000804:Angiotensin II; C061785:peptide YY (3-36); C062259:neuropeptide Y, Leu(31)-Pro(34)-