Abstract 613: Interactive Effect of Ace Inhibition and DPP4 Inhibition on Substance P-Stimulated T-PA Release

Dipeptidyl peptidase 4 (DPP4) inhibitors improve glycemic control in patients with T2DM by preventing the degradation of the incretin hormones. DPP4 inhibition prevents the degradation of other peptides with a penultimate proline or alanine, including the vasodilator substance P and the metabolite of bradykinin formed by its cleavage by aminopeptidase P. Substance P and bradykinin are normally inactivated by ACE. This study tested the hypothesis that during ACE inhibition, DPP4 inhibition would potentiate the effects of substance P. Ten healthy, lean (BMI<30 kg/m 2 ) subjects, age 24-60 years of old (2 Black, 8 White, 6 Female) participated in this randomized, double-blinded, placebo-controlled crossover study. On separate study days separated by at least one week, Subjects received sitagliptin 200 mg po or matching placebo. Substance P (2, 4, 8 pmol/min) and bradykinin (25, 50, 100 ng/min) were given via the brachial artery before and after administration of intra-arterial enalaprilat (0.33 mcg/min/100mL forearm volume). Enalaprilat potentiated the FBF and tissue plasminogen activator (t-PA) responses to bradykinin and there was no effect of sitagliptin (Figure). Neither ACE inhibition nor DPP4 inhibition altered the FBF flow response to substance P. In contrast, there was an interactive effect of ACE inhibition and DPP4 inhibition on t-PA release in response to substance P (p=0.026).