Inhibition of renal dipeptidyl peptidase IV enhances peptide YY1-36-induced potentiation of angiotensin II-mediated renal vasoconstriction in spontaneously hypertensive rats.
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 Y(1) receptors, but not Y(2) 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 Y(1)-receptor agonist, whereas peptide YY(3-36) is a selective Y(2)-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.
Jackson
Edwin K
EK
Department of Pharmacology and Center for Clinical Pharmacology, 100 Technology Dr., Suite 450, University of Pittsburgh School of Medicine, Pittsburgh, PA 15219, USA. edj+@pitt.edu
Zhang
Mingdi
M
Liu
Weili
W
Mi
Zaichuan
Z
D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D018819:Dipeptidyl Peptidase 4 / Q000502:physiology; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D006973:Hypertension / Q000503:physiopathology*; D007668:Kidney / Q000098:blood supply / Q000201:enzymology*; D008297:Male; D019894:Peptide YY / Q000494:pharmacology*; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D014661:Vasoconstriction / Q000187:drug effects*
D054873:Dipeptidyl-Peptidase IV Inhibitors; D019894:Peptide YY; D000804:Angiotensin II; D018819:Dipeptidyl Peptidase 4; C514549:peptide YY (1-36)