Cardiac DPP-4 inhibition by saxagliptin ameliorates isoproterenol-induced myocardial remodeling and cardiac diastolic dysfunction in rats

• Published in: Journal of pharmacological sciences 2016-09, Vol.132 (1), p.65-70
• Main Authors: Ikeda, Junichi, Kimoto, Naoya, Kitayama, Tetsuya, Kunori, Shunji
• Format: Article
• Language: English
• Subjects: Adamantane - analogs & derivatives; Adamantane - pharmacology; Animals; Cardiac diastolic dysfunction; Cardiac dipeptidyl peptidase-4; Diastole; Dipeptides - pharmacology; Dipeptidyl Peptidase 4 - blood; Dipeptidyl peptidase-4 inhibitor; Dipeptidyl-Peptidase IV Inhibitors - pharmacology; Echocardiography; Heart - diagnostic imaging; Heart - drug effects; Heart - physiopathology; Isoproterenol; Male; Myocardial remodeling; Myocardium - metabolism; Myocardium - pathology; Rats, Sprague-Dawley; Saxagliptin; Ventricular Remodeling - drug effects
• ISSN: 1347-8613; 1347-8648
• DOI: 10.1016/j.jphs.2016.08.008

Saxagliptin, a potent and selective DPP-4 inhibitor, is characterized by its slow dissociation from DPP-4 and its long half-life and is expected to have a potent tissue membrane-bound DPP-4-inhibitory effect in various tissues. In the present study, we examined the effects of saxagliptin on in situ cardiac DPP-4 activity. We also examined the effects of saxagliptin on isoproterenol-induced the changes in the early stage such as, myocardial remodeling and cardiac diastolic dysfunction. Male SD rats treated with isoproterenol (1 mg/kg/day via osmotic pump) received vehicle or saxagliptin (17.5 mg/kg via drinking water) for 2 weeks. In situ cardiac DPP-4 activity was measured by a colorimetric assay. Cardiac gene expressions were examined and an echocardiographic analysis was performed. Saxagliptin treatment significantly inhibited in situ cardiac DPP-4 activity and suppressed isoproterenol-induced myocardial remodeling and the expression of related genes without altering the blood glucose levels. Saxagliptin also significantly ameliorated cardiac diastolic dysfunction in isoproterenol-treated rats. In conclusion, the inhibition of DPP-4 activity in cardiac tissue by saxagliptin was associated with suppression of myocardial remodeling and cardiac diastolic dysfunction independently of its glucose-lowering action in isoproterenol-treated rats. Cardiac DPP-4 activity may contribute to myocardial remodeling in the development of heart failure.