title: Effect of dipeptidyl peptidase 4 inhibition on arterial blood pressure is context dependent.
abstract: Because the effects of dipeptidyl peptidase 4 (DPP4) inhibitors on blood pressure are controversial, we examined the long-term effects of sitagliptin (80 mg/kg per day) on blood pressure (radiotelemetry) in spontaneously hypertensive rats (SHR), Wistar-Kyoto rats, and Zucker Diabetic-Sprague Dawley rats (metabolic syndrome model). In SHR, chronic (3 weeks) sitagliptin significantly increased systolic, mean, and diastolic blood pressures by 10.3, 9.2, and 7.9 mm Hg, respectively, a response abolished by coadministration of BIBP3226 (2 mg/kg per day; selective Y1-receptor antagonist). Sitagliptin also significantly increased blood pressure in SHR treated with hydralazine (vasodilator; 25 mg/kg per day) or enalapril (angiotensin-converting enzyme inhibitor; 10 mg/kg per day). In Wistar-Kyoto rats, chronic sitagliptin slightly decreased systolic, mean, and diastolic blood pressures (-1.8, -1.1, and -0.4 mm Hg, respectively). In Zucker Diabetic-Sprague Dawley rats, chronic sitagliptin decreased systolic, mean, and diastolic blood pressures by -7.7, -5.8, and -4.3 mm Hg, respectively, and did not alter the antihypertensive effects of chronic enalapril. Because DPP4 inhibitors impair the metabolism of neuropeptide Y1-36 (NPY1-36; Y1-receptor agonist) and glucagon-like peptide (GLP)-1(7-36)NH2 (GLP-1 receptor agonist), we examined renovascular responses to NPY1-36 and GLP-1(7-36)NH2 in isolated perfused SHR and Zucker Diabetic-Sprague Dawley kidneys pretreated with norepinephrine (to induce basal tone). In Zucker Diabetic-Sprague Dawley kidneys, NPY1-36 and GLP-1(7-36)NH2 exerted little, if any, effect on renovascular tone. In contrast, in SHR kidneys, both NPY1-36 and GLP-1(7-36)NH2 elicited potent and efficacious vasoconstriction.
  
  
  CONCLUSIONS
  (1) The effects of DPP4 inhibitors on blood pressure are context dependent; (2) The context-dependent effects of DPP4 inhibitors are due in part to differential renovascular responses to DPP4’s most important substrates (NPY1–36 and GLP-1(7–36)NH2) [corrected]; (3) Y1 receptor antagonists may prevent the prohypertensive and possibly augment the antihypertensive effects of DPP4 inhibitors.
authors.affiliation: From the Department of Pharmacology and Chemical Biology, University of Pittsburgh, School of Medicine, PA. edj@pitt.edu.
authors.forename: Edwin K
authors.initials: EK
authors.lastname: Jackson
authors.affiliation: From the Department of Pharmacology and Chemical Biology, University of Pittsburgh, School of Medicine, PA.
authors.forename: Zaichuan
authors.initials: Z
authors.lastname: Mi
authors.affiliation: From the Department of Pharmacology and Chemical Biology, University of Pittsburgh, School of Medicine, PA.
authors.forename: Stevan P
authors.initials: SP
authors.lastname: Tofovic
authors.affiliation: From the Department of Pharmacology and Chemical Biology, University of Pittsburgh, School of Medicine, PA.
authors.forename: Delbert G
authors.initials: DG
authors.lastname: Gillespie
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000187:drug effects*; D001795:Blood Pressure Determination; D018819:Dipeptidyl Peptidase 4 / Q000187:drug effects / Q000378:metabolism*; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000494:pharmacology*; D004195:Disease Models, Animal; D052216:Glucagon-Like Peptide 1; D006973:Hypertension / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D011719:Pyrazines / Q000494:pharmacology*; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D000068900:Sitagliptin Phosphate; D016896:Treatment Outcome; D014230:Triazoles / Q000494:pharmacology*
chemical_list: D054873:Dipeptidyl-Peptidase IV Inhibitors; D011719:Pyrazines; D014230:Triazoles; D052216:Glucagon-Like Peptide 1; D018819:Dipeptidyl Peptidase 4; D000068900:Sitagliptin Phosphate
keywords: Wistar-Kyoto rat; Y1 receptor; dipeptidyl peptidase 4; sitagliptin; spontaneously hypertensive rat