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FC1 Dipeptidyl peptidase IV inhibitors limit myocardial infarct size in a glucose-sensitive manner.
MedLine Citation:
PMID:  20801789     Owner:  NLM     Status:  In-Data-Review    
Abstract/OtherAbstract:
Rationale The novel anti-diabetic agents, vildagliptin and sitagliptin, reduce blood glucose by augmenting endogenous levels of glucagon-like peptide (GLP-1), a substance which confers cardioprotection. They do this by inhibiting dipeptidyl peptidase (DPP) IV, the enzyme responsible for breaking down GLP-1. We hypothesised that DPPIV inhibitors might have cardioprotective effects. Methodology Sprague-Dawley rats were given vildagliptin (oral gavage, 20 mg/kg/day), sitagliptin (oral gavage, 100 mg/kg/day), or control for 2 weeks. Excised hearts were then mounted on a Langendorff apparatus and perfused with buffer containing either 5 mmol/l or 11 mmol/l glucose and subjected to 35 min ischaemia/120 min reperfusion. Results Vildagliptin pretreatment reduced myocardial infarct size in hearts perfused with buffer containing 11 mmol/l of glucose (34.4%+/-4.1% with vildagliptin vs 52.9%+/-5.2% with control: p<0.05:N>5/group) but not 5 mmol/l glucose (53.2%+/-4.8% with vildagliptin vs 52.6%+/-7.2% with control: p>0.05:N>5/group). The infarct-limiting effects were abolished in the presence of exendin9-39 (a GLP-1 receptor antagonist) and H-89 (a PKA antagonist) (61.5%+/-3.3% with vildagliptin+exendin9-39 and 59.4%+/-2.1% with vildagliptin+H-89 vs 35.0%+/-5.0% with vildagliptin+vehicle: p<0.05:N>5/group). Similarly, sitagliptin pretreatment reduced myocardial infarct size in hearts perfused with buffer containing 11 mmol/l of glucose (29.5%+/-5.1% with sitagliptin vs 52.9%+/-5.2% with control: p<0.05:N>5/group) but not 5 mmol/l glucose (44.4%+/-8.8% with sitagliptin vs 52.6%+/-7.2% with control: p>0.05:N>5/group). Again, the infarct-limiting effects were abolished in the presence of exendin9-39 (63.6%+/-5.5% with sitagliptin+exendin9-39 vs 30.1%+/-3.4% with sitagliptin+vehicle: p<0.05:N>5/group). Conclusions Chronic treatment with the DPP-IV inhibitors reduced myocardial infarction via the GLP-1 receptor pathway and may also involve the PKA signalling pathway. Interestingly, this effect appears to be dependent on the blood glucose levels.
Authors:
D J Hausenloy; A M Wynne; L Theodorou; M M Mocanu; D M Yellon
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Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  Heart (British Cardiac Society)     Volume:  96     ISSN:  1468-201X     ISO Abbreviation:  Heart     Publication Date:  2010 Sep 
Date Detail:
Created Date:  2010-08-30     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9602087     Medline TA:  Heart     Country:  England    
Other Details:
Languages:  eng     Pagination:  e11     Citation Subset:  AIM; IM    
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