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GASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

Inhibition of Renal Dipeptidyl Peptidase IV Enhances Peptide YY_1–36-Induced Potentiation of Angiotensin II-Mediated Renal Vasoconstriction in Spontaneously Hypertensive Rats

Departments of Pharmacology (E.K.J.) and Medicine (E.K.J., W.L., Z.M.) and Center for Clinical Pharmacology (E.K.J., M.Z., W.L., Z.M.), University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania

Dipeptidyl peptidase IV inhibitors are a new class of antidiabetic drugs. It is urgent, therefore, to fully understand the pharmacology of these inhibitors. Although dipeptidyl peptidase IV metabolizes at least 24 endogenous substrates, the pharmacological consequences of inhibiting the metabolism of most of these substrates is unknown. Our previous results show that Y₁ receptors, but not Y₂ receptors, enhance renovascular responses to angiotensin II in kidneys from genetically susceptible animals (spontaneously hypertensive rats). Dipeptidyl peptidase IV converts peptide YY_1–36 (circulating hormone) to peptide YY_3–36, and peptide YY_1–36 is a Y₁-receptor agonist, whereas peptide YY_3–36 is a selective Y₂-receptor agonist. Therefore, it is conceivable that inhibition of dipeptidyl peptidase IV in genetically susceptible kidneys may increase the ability of peptide YY_1–36 to potentiate angiotensin II-induced renal vasoconstriction. Here we demonstrate that in kidneys from spontaneously hypertensive rats 1) peptide YY_1–36 potentiates renovascular responses to angiotensin II, whereas peptide YY_3–36 has little effect, 2) 3-N-[(2S,3S)-2-amino-3-methylpentanoyl]-1,3-thiazolidine (P32/98) (dipeptidyl peptidase IV inhibitor) augments the ability of peptide YY_1–36 to enhance renovascular responses to angiotensin II, 3) dipeptidyl peptidase IV is expressed in preglomerular microvessels and glomeruli, 4) kidneys metabolize arterial PYY_1–36 to PYY_3–36 via a mechanism blocked by P32/98, and 5) preglomerular microvessels and glomeruli convert peptide YY_1–36 to peptide YY_3–36, and this conversion is inhibited by P32/98. We conclude that dipeptidyl peptidase IV is expressed in the renal microcirculation and inhibition of this ecto-enzyme causes arterial PYY_1–36 to more effectively enhance angiotensin II-induced renal vasoconstriction in genetically susceptible kidneys.

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

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				E. K. Jackson and Z. Mi Sitagliptin Augments Sympathetic Enhancement of the Renovascular Effects of Angiotensin II in Genetic Hypertension Hypertension, June 1, 2008; 51(6): 1637 - 1642. [Abstract] [Full Text] [PDF]