Effects of phosphodiesterase-5 A (PDE5A) inhibition on the hypertrophied myocardium of spontaneously hypertensive rats (SHR).

DIAZ RG; PÉREZ NG; ESCUDERO DS; PORTIANSKY EL; BREA MS

Buenos Aires

Congreso; World Congress of the International Society for Heart Research; 2016

In a previous study we showed that an increased protein Kinase G (PKG) activity after PDE5A inhibition (sildenafil, ?SIL?) inhibits the myocardial Na+/H+ exchanger (NHE1). Since NHE1 hyperactivity is linked to the development of cardiac hypertrophy, our study was aimed to study the potential antihypertrophic effects of SIL on the hypertrophic myocardium of SHR. We initially tested the inhibitory capability of SIL (1M) on NHE1 in isolated cardiomyocytes of SHR by comparing H+ efflux (JH+) in the absence or presence of SIL at a common pHi of 6.8, during the pHi recovery from an acidic load (ammonium prepulse in the absence of bicarbonate where the NHE1 is the only active pHi regulatory mechanism). SIL significantly decreased JH+: (mmol /L/ min) 12.93±3.80, n= 5vs. 2.09±0.87, n=4 (P <0.05), confirming its inhibitory effect on the NHE1. Then 8 months old SHR were chronically treated (3 months) with SIL (100mg/kg/day, orally through drinking water, n=4) and compared to age-matched untreated controls (n=6). SIL treatment decreased left ventricular weight to body weight ratio (hypertrophy index) from 3.2±0.1 (control) to 2.7±0.1 mg/g (SHR +SIL). Accordingly, cardiomyocytes cross-sectional area (CSA) from treated rats was significantly reduced (688 ±39 vs. 496±23m2, P <0.05). SIL treatment also reduced myocardial interstitial fibrosis: (in percentage of total interstitial collagen) 7.01±0.018 vs. 1.36±0.003%, P <0.05), which was in accordance to the lower myocardial stiffness detected in treated hearts by comparing length-tension curves in isolated papillary muscles (P<0.05, 2-wayANOVA). Finally, we measured kinases upstream NHE1. Not significant changes in ERK1/2-p90RSK MAP kinases phosphorylation, or in NHE1 protein expression were detected between groups. In summary, the results show that PDE5A acute inhibition by SIL inhibits NHE1 activity in SHR, suggesting that this effect would be responsible for the decreased cardiac hypertrophy and the lower stiffness observed in hearts from SIL treated SHR.