Substance P increases sympathetic activity during combined angiotensin-converting enzyme and dipeptidyl peptidase-4 inhibition

Abstract

Dipeptidyl peptidase-4 inhibitors prevent the degradation of incretin hormones and reduce postprandial hyperglycemia in patients with type 2 diabetes mellitus. Dipeptidyl peptidase-4 degrades other peptides with a penultimate proline or alanine, including bradykinin and substance P, which are also substrates of angiotensin-converting enzyme (ACE). During ACE inhibition, substance P is inactivated primarily by dipeptidyl peptidase-4, whereas bradykinin is first inactivated by aminopeptidase P. This study tested the hypothesis that dipeptidyl peptidase-4 inhibition potentiates vasodilator and fibrinolytic responses to substance P when ACE is inhibited. Twelve healthy subjects participated in this randomized, double-blinded, placebo-controlled crossover study. On each study day, subjects received sitagliptin 200 mg by mouth or placebo. Substance P and bradykinin were infused via brachial artery before and during intra-arterial enalaprilat. Sitagliptin and enalaprilat each reduced forearm vascular resistance and increased forearm blood flow without affecting mean arterial pressure, but there was no interactive effect of the inhibitors. Enalaprilat increased bradykinin-stimulated vasodilation and tissue plasminogen activator release; sitagliptin did not affect these responses to bradykinin. The vasodilator response to substance P was unaffected by sitagliptin and enalaprilat; however, substance P increased heart rate and vascular release of norepinephrine during combined ACE and dipeptidyl peptidase-4 inhibition. In women, sitagliptin diminished tissue plasminogen activator release in response to substance P both alone and during enalaprilat. Substance P increases sympathetic activity during combined ACE and dipeptidyl peptidase-4 inhibition.

Clinical trial registration: - URL: http://www.clinicaltrials.gov. Unique identifier: NCT01413542.

Keywords: diabetes mellitus; dipeptidyl peptidase-4; hypertension; norepinephrine; renin–angiotensin system; vasodilation.

Figures

Figure 1

Study Protocol. Each intra-arterial peptide was given in a randomized fashion as 3 graded doses, lasting 5 minutes each. A 30-minute wash-out separated infusions. Forearm blood flow measurement, followed by arterial and venous sampling, was performed at baseline and at completion of each dose of peptide. A minimum of one week separated each study day.

Figure 2

Effect of treatment on forearm blood flow (FBF) response to intra-arterial bradykinin, with and without intra-arterial enalaprilat, and to substance P, with and without intra-arterial enalaprilat (n=12). Data presented as mean ± standard error of the mean. Quadratic model-based p-values presented in the text. *p

Figure 3

Effect of the maximal dose of substance P and bradykinin on heart rate (A) and norepinephrine release (B, C) after treatment with placebo, angiotensin-converting enzyme inhibitor (ACEi) alone, dipeptidyl peptidase-4 inhibitor (DPP4i) alone, or the combination (n=12). Data presented as mean ± standard error of the mean. P values from Wilcoxon signed rank test and separate means models presented in the text. * p<0.05 versus placebo, †p<0.05 versus DPP4i alone, ‡p<0.05 versus ACEi alone

Figure 4

Effect of treatment on net tissue plasminogen activator (tPA) release in response to intra-arterial bradykinin, with and without intra-arterial enalaprilat, and substance P, with and without intra-arterial enalaprilat (n=7 females, n=5 males). Data presented as mean ± standard error of the mean. Linear model-based p-values presented in the text. * p