Abstract 555: The Effect Of Dipeptidyl Peptidase 4 Inhibition On Arterial Blood Pressure Is Context Dependent

Abstract

Dipeptidyl peptidase 4 (DPP4) inhibitors decrease the metabolism of endogenous glucagon-like peptide-1 (GLP-1) receptor (GLP-1R) agonists, such as GLP-1(7-36)NH 2 , and GLP-1R agonists are antihypertensive. However, DPP4 inhibitors also impair the metabolism of endogenous Y 1 receptor (Y 1 R) agonists, such as neuropeptide Y 1-36 (NPY 1-36 ), and Y 1 R agonists are pro-hypertensive. Consequently, the long-term effect of DPP4 inhibition on blood pressure may be context dependent. To test this, we conducted radiotelemetry studies under highly controlled conditions to quantify the effects of chronic sitagliptin (80 mg/kg/day; DPP4 inhibitor) on blood pressure in spontaneously hypertensive rats (SHR), Wistar-Kyoto rats (WKY) and Zucker Diabetic-Sprague Dawley rats (ZDSD; model of the metabolic syndrome developed by PreClinOmics). In SHR, chronic (3 weeks) administration of sitagliptin significantly increased systolic, mean and diastolic blood pressures by 10.3, 9.2 and 7.9 mmHg, respectively (p<0.01). Sitagliptin also significantly (p<0.01) increased blood pressure in SHR treated with hydralazine (vasodilator; 25 mg/kg/day) or enalapril (ACE inhibitor; 10 mg/kg/day). Co-administration of BIBP3226 (2 mg/kg/day; Y 1 R antagonist) abolished the pro-hypertensive effects of sitagliptin in SHR. In WKY, chronic sitagliptin slightly decreased (p<0.01) systolic, mean and diastolic blood pressures (-1.8, -1.1 and -0.4 mmHg, respectively). In ZDSD, chronic sitagliptin markedly decreased systolic, mean and diastolic blood pressures (-7.7, -5.8, -4.3 mmHg, respectively). In isolated, perfused ZDSD kidneys pretreated with norepinephrine to induce basal tone, NPY 1-36 and GLP-1(7-36)NH 2 exerted little effect on renovascular tone. In contrast, in isolated SHR kidneys, both NPY 1-36 and GLP-1(7-36)NH 2 elicited potent and efficacious vasoconstriction (increased perfusion pressure by 171 and 132 mmHg, respectively). 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 its most important substrates (NPY 1-36 and GLP-1(7-36)NH 2 ); 3) Y 1 R antagonists may augment the beneficial effects of DPP4 inhibitors.