Phosphodiesterase‐5 inhibitors “Sildenafil and Ordonafil” suppress/reverse L‐NAME induced cardiac hypertrophy in isolated rabbit heart and in phenylephrine induced hypertrophy in isolated neonatal rat myocytes
Authors: Khatib Said Y. , Zeidan Asad , Siam Ayad 
Published: June 2021

Phosphodiesterase 5 inhibitors (PDE5Is) have been shown to suppress and reverse myocardial hypertrophy induced by pressure overload. Calcineurin, a protein phosphatase, has been suggested to function as an important hypertrophic factor in cardiac myocytes and its signaling regulates the cardiac hypertrophic response in coordination with mitogen‐activated protein kinases (MAPKs). The present study investigated the effects of two PDE5Is i.e. Sildenafil (SILD) ‘ Viagra’ and Ordonafil (ORD) on N‐nitro‐L‐arginine methyl ester (L‐NAME) induced cardiac hypertrophy and assessed their ability to attenuate the activity of calcineurin, p38 and protein synthesis to exert their effect on hypertrophied cardiac myocytes.MethodsL‐NAME (10 mg/kg/day) was used to induce cardiac hypertrophy in rabbits' hearts and left ventricular thicknesses (LVTs) were measured in L‐NAME and PDE5Is treated hearts. Then, in cultured neonatal rat ventricular myocytes, Western Blot technique was used to assess the ability of these PDE5Is (different doses) to attenuate the activation of calcineurin, p38 and protein synthesis in phenylphrine‐induced ventricular hypertrophy as indicated by the cell surface area of cultured neonatal rat cardiomyocytes.ResultsL‐NAME significantly increased LVT to 6.1± 0.18 mm vs. 4.6±0.13 mm in control rabbit hearts, (p<0.05). SILD and ORD significantly regressed LVT to 4.8 ± 0.2 mm and 5.1 ± 0.1 mm, respectively (p<0.05). Phenylphrine significantly increased neonatal rat ventricular myocyte cell surface area to 131% of control values (p<0.05). This hypertrophic effect of phenylphrine was associated with significant increment in protein synthesis to 143+5% of control values, (p<0.05). Both drugs (in a dose dependent, 0.001–1 mg/L) decreased cell surface area to 95% and 90% of control value respectively, and both decreased protein synthesis to 88% of control values. Phosphatase activity of calcineurin significantly decreased from 1.93±0.09 IU to 1.15±0.05 IU after one hour and to 1.2±0.06 IU after 24 hours incubation with ORD (0.1 mg/l) incubation, (p<0.05). Whereas this activity significantly decreased after 24 hours (1.22±0.04 IU, (p<0.05)), but not after one hour (1.84±0.05 IU) of SILD (0.1 mg/l) incubation. Protein synthesis and p38 activation were significantly attenuated by both drugs (0.1 mg/L).ConclusionsThese results suggest that both SILD and ORD have the ability to reverse L‐NAME induced cardiac hypertrophy in rabbits and suppress phenylphrine induce hypertrophic myocytes. The results indicate these effects are mediated through inhibiting protein synthesis and the attenuation of calcineurin and p38 activity signaling pathways in neonatal rat ventricular myocytes which is reported in this study for the first time.Support or Funding InformationDeanship of Scientific research ‐ Jordan University of Science & TechnologyThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.