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Chronic inhibition of phosphodiesterase 5 with tadalafil affords cardioprotection in a mouse model of metabolic syndrome: role of nitric oxide

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Abstract

Patients with metabolic syndrome (MetS) often exhibit generalized endothelial and cardiac dysfunction with decreased nitric oxide (NO) production and/or bioavailability. Since phosphodiesterase 5 (PDE5) inhibitors restore NO signaling, we hypothesized that chronic treatment with long-acting PDE5 inhibitor tadalafil may enhance plasma NO levels and reduce cardiac dysfunction following ischemia/reperfusion (I/R) injury in C57BL/6NCrl-Leprdb−lb/Crl mice with MetS phenotypes. Adult male MetS mice were randomized to receive vehicle solvent or tadalafil (1 mg/kg,i.p.) daily for 28 days and C57BL/6NCrl mice served as healthy wild-type controls. After 28 days, cardiac function was assessed by echocardiography and hearts from a subset of mice were isolated and subjected to 30 min of global ischemia followed by 60 min of reperfusion (I/R) in ex vivo Langendorff mode. Body weight, blood lipids, and glucose levels were elevated in MetS mice as compared with wild-type controls. The dyslipidemia in MetS was ameliorated following tadalafil treatment. Although left ventricular (LV) systolic function was minimally altered in the MetS mice, there was a significant diastolic dysfunction as indicated by reduction in the ratio of peak velocity of early to late filling of the mitral inflow, which was significantly improved by tadalafil treatment. Post-ischemic cardiac function, heart rate, and coronary flow decreased significantly in MetS mice compared to wild-type controls, but preserved by tadalafil treatment. Myocardial infarct size was significantly smaller following I/R, which was associated with higher plasma levels of nitrate and nitrite in the tadalafil-treated MetS mice. In conclusion, tadalafil induces significant cardioprotective effects as shown by improvement of LV diastolic function, lipid profile, and reduced infarct size following I/R. Tadalafil treatment enhanced NO production, which may have contributed to the cardioprotective effects.

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Acknowledgements

This work was supported by grants from the National Institutes of Health (Grant Nos. CA221813, DK120866, HL118808, HL134366) to R.C.K. S.K. is supported by American Heart Association Institutional Research Enhancement Award (Grant No. 19AIREA34380223) and National Institutes of Health (Grant No. R56HL143809). L.X. is a recipient of Pauley Pilot Research Grant by Virginia Commonwealth University Pauley Heart Center.

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  1. Pauley Heart Center, Division of Cardiology, Department of Internal Medicine, Virginia Commonwealth University Medical Center, Richmond, VA, 23298-0204, USA

    Saisudha Koka, Lei Xi & Rakesh C. Kukreja

  2. Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, Houston, TX, 77204, USA

    Saisudha Koka

  3. Division of Cardiology, Virginia Commonwealth University, 1101 East Marshall Street, Room 7-020D, Box 980204, Richmond, VA, 23298-0204, USA

    Rakesh C. Kukreja

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SK and LX performed the experiments and data analysis. SK wrote the manuscript; RCK and LX critically edited the manuscript. All authors reviewed and approved the final version of the manuscript.

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Correspondence to Rakesh C. Kukreja.

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Koka, S., Xi, L. & Kukreja, R.C. Chronic inhibition of phosphodiesterase 5 with tadalafil affords cardioprotection in a mouse model of metabolic syndrome: role of nitric oxide. Mol Cell Biochem 468, 47–58 (2020). https://doi.org/10.1007/s11010-020-03710-0

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