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(Hypertension. 2008;51:1637.)
© 2008 American Heart Association, Inc.

Original Articles

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

From the Departments of Pharmacology and Medicine, Center for Clinical Pharmacology, University of Pittsburgh, School of Medicine, Pa.

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

Dipeptidyl peptidase IV converts neuropeptide Y_1-36 (Y₁-receptor agonist released from renal sympathetic nerves) to neuropeptide Y_3-36 (selective Y₂-receptor agonist). Previous studies suggest that Y₁, but not Y₂, 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 Y₁ 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 Y₁ 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 Y₁ 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.

Key Words: neuropeptide Y • CD26 • receptors • neuropeptide Y • rats • inbred SHR • sympathetic nervous system • kidney • renal circulation