title: Dipeptidyl peptidase-4 inhibition with saxagliptin enhanced nitric oxide release and reduced blood pressure and sICAM-1 levels in hypertensive rats.
abstract: Most patients with diabetes also have hypertension, a risk factor associated with atherothrombotic disease and characterized by endothelial cell (EC) dysfunction and loss of nitric oxide (NO) bioavailability. Recent studies suggest a possible antihypertensive effect with dipeptidyl peptidase-4 (DPP4) inhibition; however, the underlying mechanism is not understood. In this study, we tested the effects of the DPP4 inhibitor, saxagliptin, on EC function, blood pressure, and soluble intercellular adhesion molecule 1 (sICAM-1) levels in hypertensive rats. Spontaneously hypertensive rats were treated with vehicle or saxagliptin (10 mg·kg(-1)·day(-1)) for 8 weeks. NO and peroxynitrite (ONOO(-)) release from aortic and glomerular ECs was stimulated with calcium ionophore and measured using electrochemical nanosensor technology. Changes in EC function were correlated with fasting glucose levels. Saxagliptin treatment was observed to increase aortic and glomerular NO release by 22% (P < 0.001) and 23% (P < 0.001), respectively, with comparable reductions in ONOO(-) levels; the NO/ONOO(-) ratio increased by >50% in both EC types (P < 0.001) as compared with vehicle. Saxagliptin also reduced mean arterial pressure from 170 ± 10 to 158 ± 10 mm Hg (P < 0.001) and decreased sICAM-1 levels by 37% (P < 0.01). The results of this study suggest that DPP4 inhibition reduces blood pressure and inflammation in hypertensive rats while increasing NO bioavailability.
authors.affiliation: Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA. rpmason@elucidaresearch.com
authors.forename: R Preston
authors.initials: RP
authors.lastname: Mason
authors.forename: Robert F
authors.initials: RF
authors.lastname: Jacob
authors.forename: Ruslan
authors.initials: R
authors.lastname: Kubant
authors.forename: Aleksander
authors.initials: A
authors.lastname: Ciszewski
authors.forename: J Jose
authors.initials: JJ
authors.lastname: Corbalan
authors.forename: Tadeusz
authors.initials: T
authors.lastname: Malinski
mesh_terms: D000218:Adamantane / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects*; D004151:Dipeptides / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism; D005951:Glucose Tolerance Test; D006973:Hypertension / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism / Q000503:physiopathology; D007328:Insulin / Q000097:blood; D018799:Intercellular Adhesion Molecule-1 / Q000097:blood*; D007678:Kidney Glomerulus / Q000187:drug effects / Q000378:metabolism; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism*; D030421:Peroxynitrous Acid / Q000378:metabolism; D051381:Rats; D011924:Rats, Zucker
chemical_list: D004151:Dipeptides; D054873:Dipeptidyl-Peptidase IV Inhibitors; D007328:Insulin; D018799:Intercellular Adhesion Molecule-1; D030421:Peroxynitrous Acid; D009569:Nitric Oxide; C502994:saxagliptin; D000218:Adamantane