title: 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.
  
  
  BACKGROUND
  - URL: http://www.clinicaltrials.gov. Unique identifier: NCT01413542.
authors: Division of Diabetes, Endocrinology and Metabolism, 7465 MRB4, 2213 Garland Ave, Nashville, TN 37232. Jessica.devin@vanderbilt.edu.
authors: Jessica K
authors: JK
authors: Devin
authors: Mias
authors: M
authors: Pretorius
authors: Hui
authors: H
authors: Nian
authors: Chang
authors: C
authors: Yu
authors: Frederic T
authors: FT
authors: Billings
authors: Nancy J
authors: NJ
authors: Brown
mesh_terms: D000328:Adult; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D001920:Bradykinin / Q000494:pharmacology; D018592:Cross-Over Studies; D018819:Dipeptidyl Peptidase 4 / Q000187:drug effects*; D004311:Double-Blind Method; D015773:Enalaprilat / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D008297:Male; D008875:Middle Aged; D018377:Neurotransmitter Agents / Q000494:pharmacology*; D009638:Norepinephrine / Q000378:metabolism; D007703:Peptidyl-Dipeptidase A / Q000187:drug effects*; D011719:Pyrazines / Q000494:pharmacology; D000068900:Sitagliptin Phosphate; D013373:Substance P / Q000494:pharmacology*; D013564:Sympathetic Nervous System / Q000187:drug effects*; D014230:Triazoles / Q000494:pharmacology; D014655:Vascular Resistance / Q000187:drug effects
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D004791:Enzyme Inhibitors; D018377:Neurotransmitter Agents; D011719:Pyrazines; D014230:Triazoles; D013373:Substance P; C042807:DPP4 protein, human; D018819:Dipeptidyl Peptidase 4; D007703:Peptidyl-Dipeptidase A; D015773:Enalaprilat; D001920:Bradykinin; D000068900:Sitagliptin Phosphate; D009638:Norepinephrine
keywords: diabetes mellitus; dipeptidyl peptidase-4; hypertension; norepinephrine; renin–angiotensin system; vasodilation