title: 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.
authors.affiliation: Department of Pharmacology, Center for Clinical Pharmacology, University of Pittsburgh, School of Medicine, PA 15219, USA. edj@pitt.edu
authors.forename: Edwin K
authors.initials: EK
authors.lastname: Jackson
authors.forename: Zaichuan
authors.initials: Z
authors.lastname: Mi
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D003928:Diabetic Nephropathies / Q000188:drug therapy; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000494:pharmacology*; D004357:Drug Synergism; D006977:Hypertension, Renal / Q000188:drug therapy* / Q000235:genetics / Q000503:physiopathology; D007668:Kidney / Q000187:drug effects / Q000294:innervation / Q000502:physiology; D008297:Male; D009478:Neuropeptide Y / Q000378:metabolism; D010446:Peptide Fragments / Q000378:metabolism; D011719:Pyrazines / Q000494:pharmacology*; D051381:Rats; D011918:Rats, Inbred SHR; D012079:Renal Circulation / Q000187:drug effects / Q000502:physiology; D000068900:Sitagliptin Phosphate; D013564:Sympathetic Nervous System / Q000187:drug effects* / Q000502:physiology; D014230:Triazoles / Q000494:pharmacology*; D014662:Vasoconstrictor Agents / Q000494:pharmacology*
chemical_list: D054873:Dipeptidyl-Peptidase IV Inhibitors; D009478:Neuropeptide Y; D010446:Peptide Fragments; D011719:Pyrazines; D014230:Triazoles; D014662:Vasoconstrictor Agents; D000804:Angiotensin II; D000068900:Sitagliptin Phosphate