Interactive Hemodynamic Effects of Dipeptidyl Peptidase-IV Inhibition and Angiotensin-Converting Enzyme Inhibition in Humans

• Published in: Hypertension (Dallas, Tex. 1979) Vol. 56; no. 4; pp. 728 - 733
• Main Authors: Marney, Annis, Kunchakarra, Siri, Byrne, Loretta, Brown, Nancy J.
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD American Heart Association, Inc 01.10.2010; Lippincott Williams & Wilkins
• Subjects: Adult; Aldosterone - blood; Angiotensin-Converting Enzyme Inhibitors - therapeutic use; Antihypertensive agents; Arterial hypertension. Arterial hypotension; Biological and medical sciences; Blood and lymphatic vessels; Blood Glucose - metabolism; Blood Pressure - drug effects; Cardiology. Vascular system; Cardiovascular system; Diabetes Mellitus, Type 2 - drug therapy; Diabetes Mellitus, Type 2 - physiopathology; Dipeptidyl Peptidase 4 - metabolism; Dose-Response Relationship, Drug; Double-Blind Method; Drug Interactions; Drug Therapy, Combination; Enalapril - therapeutic use; Female; Heart Rate - drug effects; Hemodynamics - drug effects; Humans; Insulin - blood; Male; Medical sciences; Metabolic Syndrome - drug therapy; Metabolic Syndrome - physiopathology; Middle Aged; Peptidyl-Dipeptidase A - metabolism; Pharmacology. Drug treatments; Prospective Studies; Pyrazines - therapeutic use; Renal Circulation - drug effects; Sitagliptin Phosphate; Sodium - urine; Triazoles - therapeutic use; Human; Hypertension; Enzyme; Cardiovascular disease; Sympathetic nervous system; dipeptidyl peptidase-IV inhibitors; Peptidases; Angiotensin; Hydrolases; Arterial pressure; Blood pressure; Hemodynamics; ACE inhibitors; ACE inhibitor
• ISSN: 0194-911X; 1524-4563; 1524-4563
• DOI: 10.1161/HYPERTENSIONAHA.110.156554

ABSTRACT—Dipeptidyl peptidase-IV inhibitors improve glucose homeostasis in type 2 diabetics by inhibiting degradation of the incretin hormones. Dipeptidyl peptidase-IV inhibition also prevents the breakdown of the vasoconstrictor neuropeptide Y and, when angiotensin-converting enzyme (ACE) is inhibited, substance P. This study tested the hypothesis that dipeptidyl peptidase-IV inhibition would enhance the blood pressure response to acute ACE inhibition. Subjects with the metabolic syndrome were treated with 0 mg of enalapril (n=9), 5 mg of enalapril (n=8), or 10 mg enalapril (n=7) after treatment with sitagliptin (100 mg/day for 5 days and matching placebo for 5 days) in a randomized, cross-over fashion. Sitagliptin decreased serum dipeptidyl peptidase-IV activity (13.08±1.45 versus 30.28±1.76 nmol/mL/min during placebo; P≤0.001) and fasting blood glucose. Enalapril decreased ACE activity in a dose-dependent manner (P<0.001). Sitagliptin lowered blood pressure during enalapril (0 mg; P=0.02) and augmented the hypotensive response to 5 mg of enalapril (P=0.05). In contrast, sitagliptin attenuated the hypotensive response to 10 mg of enalapril (P=0.02). During sitagliptin, but not during placebo, 10 mg of enalapril significantly increased heart rate and plasma norepinephrine concentrations. There was no effect of 0 or 5 mg of enalapril on heart rate or norepinephrine after treatment with either sitagliptin or placebo. Sitagliptin enhanced the dose-dependent effect of enalapril on renal blood flow. In summary, sitagliptin lowers blood pressure during placebo or submaximal ACE inhibition; sitagliptin activates the sympathetic nervous system to diminish hypotension when ACE is maximally inhibited. This study provides the first evidence for an interactive hemodynamic effect of dipeptidyl peptidase-IV and ACE inhibition in humans.