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 YY1-36 ( circulating hormone) to peptide YY3-36, and peptide YY1-36 is a Y-1- receptor agonist, whereas peptide YY3-36 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 YY1-36 to potentiate angiotensin II- induced renal vasoconstriction. Here we demonstrate that in kidneys from spontaneously hypertensive rats 1) peptide YY1-36 potentiates renovascular responses to angiotensin II, whereas peptide YY3-36 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 YY1-36 to enhance renovascular responses to angiotensin II, 3) dipeptidyl peptidase IV is expressed in preglomerular microvessels and glomeruli, 4) kidneys metabolize arterial PYY1-36 to PYY3-36 via a mechanism blocked by P32/ 98, and 5) preglomerular microvessels and glomeruli convert peptide YY1-36 to peptide YY3-36, 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 PYY1-36 to more effectively enhance angiotensin II- induced renal vasoconstriction in genetically susceptible kidneys.