Sitagliptin Augments Sympathetic Enhancement of the Renovascular Effects of Angiotensin II in Genetic Hypertension

Abstract

Dipeptidyl peptidase IV converts neuropeptide Y 1-36 (Y 1 -receptor agonist released from renal sympathetic nerves) to neuropeptide Y 3-36 (selective Y 2 -receptor agonist). Previous studies suggest that Y 1 , but not Y 2 , receptors enhance renovascular responses to angiotensin II in kidneys from genetically-susceptible animals. Therefore, we hypothesized that inhibition of dipeptidyl peptidase IV with sitagliptin (antidiabetic drug) would augment the ability of exogenous and endogenous neuropeptide Y 1-36 to enhance renal vascular responses to angiotensin II in kidneys from spontaneously hypertensive rats. This hypothesis was tested using 3 protocols in isolated perfused kidneys. Results from Protocol 1: Exogenous neuropeptide Y 1-36 enhanced renovascular responses to angiotensin II. This effect of neuropeptide Y 1-36 was blocked by BIBP3226 (selective Y 1 receptor antagonist); Exogenous neuropeptide Y 3-36 did not enhance renovascular responses to angiotensin II. Results from Protocol 2: Sitagliptin augmented the ability of exogenous neuropeptide Y 1-36 to enhance renovascular responses to angiotensin II. This effect of sitagliptin was blocked by BIBP3226. Results from Protocol 3: Renal sympathetic nerve stimulation enhanced renovascular responses to angiotensin II; this enhancement was augmented by sitagliptin and abolished by BIBP3226. Neuropeptide Y 1-36 via Y 1 receptors enhances renovascular responses to angiotensin II in kidneys from genetically hypertensive animals. Sitagliptin, by blocking dipeptidyl peptidase IV, prevents metabolism of neuropeptide Y 1-36 and thereby increases the effects of neuropeptide Y 1-36 released from renal sympathetic nerves on Y 1 receptors leading to augmentation of neuropeptide Y 1-36 –induced enhancement of the renovascular effects of angiotensin II. The renal effects of dipeptidyl peptidase IV inhibitors in hypertensive diabetic patients merit a closer examination.