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Interactive hemodynamic effects of dipeptidyl peptidase-IV inhibition and angiotensin-converting enzyme inhibition in humans.

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.

SUBMITTER: Marney A

PROVIDER: S-EPMC3305047 | biostudies-literature | 2010 Oct

REPOSITORIES: biostudies-literature

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Interactive hemodynamic effects of dipeptidyl peptidase-IV inhibition and angiotensin-converting enzyme inhibition in humans.

Marney Annis A Kunchakarra Siri S Byrne Loretta L Brown Nancy J NJ

Hypertension (Dallas, Tex. : 1979) 20100802 4

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 w ...[more]

PMID: 20679179

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Project description:Angioedema is a potentially life-threatening adverse effect of angiotensin-converting enzyme inhibitors. Bradykinin and substance P, substrates of angiotensin-converting enzyme, increase vascular permeability and cause tissue edema in animals. Studies indicate that amino-terminal degradation of these peptides, by aminopeptidase P and dipeptidyl peptidase IV, may be impaired in individuals with angiotensin-converting enzyme inhibitor-associated angioedema. This case-control study tested the hypothesis that dipeptidyl peptidase IV activity and antigen are decreased in sera of patients with a history of angiotensin-converting enzyme inhibitor-associated angioedema. Fifty subjects with a history of angiotensin-converting enzyme inhibitor-associated angioedema and 176 angiotensin-converting enzyme inhibitor-exposed control subjects were ascertained. Sera were assayed for angiotensin-converting enzyme activity, aminopeptidase P activity, aminopeptidase N activity, dipeptidyl peptidase IV activity, and antigen and the ex vivo degradation half-lives of bradykinin, des-Arg(9)-bradykinin, and substance P in a subset. The prevalence of smoking was increased and of diabetes decreased in case versus control subjects. Overall, dipeptidyl peptidase IV activity (26.6+/-7.8 versus 29.6+/-7.3 nmol/mL per minute; P=0.026) and antigen (465.8+/-260.8 versus 563.1+/-208.6 ng/mL; P=0.017) were decreased in sera from individuals with angiotensin-converting enzyme inhibitor-associated angioedema compared with angiotensin-converting enzyme inhibitor-exposed control subjects without angioedema. Dipeptidyl peptidase IV activity (21.5+/-4.9 versus 29.8+/-6.7 nmol/mL per minute; P=0.001) and antigen (354.4+/-124.7 versus 559.8+/-163.2 ng/mL; P=0.003) were decreased in sera from cases collected during angiotensin-converting enzyme inhibition but not in the absence of angiotensin-converting enzyme inhibition. The degradation half-life of substance P correlated inversely with dipeptidyl peptidase IV antigen during angiotensin-converting enzyme inhibition. Environmental or genetic factors that reduce dipeptidyl peptidase IV activity may predispose individuals to angioedema.

Project description:Paramyosins, muscle proteins occurring exclusively in invertebrates, are abundant in seafoods. The potential of seafood paramyosins (SP) as sources of anti-angiotensin-converting-enzyme (ACE) and anti-dipeptidyl-peptidase (DPP-IV) peptides is underexplored. This in silico study investigated the release of anti-ACE and anti-DPP-IV peptides from SP after gastrointestinal (GI) digestion. We focused on SP of the common octopus, Humboldt squid, Japanese abalone, Japanese scallop, Mediterranean mussel, Pacific oyster, sea cucumber, and Whiteleg shrimp. SP protein sequences were digested on BIOPEP-UWM, followed by identification of known anti-ACE and anti-DPP-IV peptides liberated. Upon screening for high-GI-absorption, non-allergenicity, and non-toxicity, shortlisted peptides were analyzed via molecular docking and dynamic to elucidate mechanisms of interactions with ACE and DPP-IV. Potential novel anti-ACE and anti-DPP-IV peptides were predicted by SwissTargetPrediction. Physicochemical and pharmacokinetics of peptides were predicted with SwissADME. GI digestion liberated 2853 fragments from SP. This comprised 26 known anti-ACE and 53 anti-DPP-IV peptides exhibiting high-GI-absorption, non-allergenicity, and non-toxicity. SwissTargetPrediction predicted three putative anti-ACE (GIL, DL, AK) and one putative anti-DPP-IV (IAL) peptides. Molecular docking found most of the anti-ACE peptides may be non-competitive inhibitors, whereas all anti-DPP-IV peptides likely competitive inhibitors. Twenty-five nanoseconds molecular dynamics simulation suggests the stability of these screened peptides, including the three predicted anti-ACE and one predicted anti-DPP-IV peptides. Seven dipeptides resembling approved oral-bioavailable peptide drugs in physicochemical and pharmacokinetic properties were revealed: AY, CF, EF, TF, TY, VF, and VY. In conclusion, our study presented in silico evidence for SP being a promising source of bioavailable and safe anti-ACE and anti-DPP-IV peptides following GI digestions.

Dataset Information

Interactive hemodynamic effects of dipeptidyl peptidase-IV inhibition and angiotensin-converting enzyme inhibition in humans.

Publications

Interactive hemodynamic effects of dipeptidyl peptidase-IV inhibition and angiotensin-converting enzyme inhibition in humans.

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