PDE1a Linked to Heart Failure


Sildenafil also significantly prolongs the time before cut flowers wilt
Sildenafil also significantly prolongs the time before cut flowers wilt.

Photo: Flickr: AbiznessDigital

Although sildenafil (Viagra®) is best known for the treatment of erectile dysfunction, it also reduces pulmonary hypertension and its use in the treatment of heart failure and cardiac hypertrophy is being investigated.

Sildenafil is a selective inhibitor of phosphodiesterase type 5 (PDE5) which enhances nitric oxide-mediated vasodilation by preventing breakdown of the intracellular second messenger, cyclic guanosine monophosphate (cGMP). Phosphodiesterases regulate cGMP-dependent signalling pathways including control of Ca2+ concentrations which, as well as modulating the strength of contractions, are believed to regulate myocyte growth and hypertrophy. At least five PDE families (PDE1-5) are expressed in the human heart and a study led by researchers at the University of Rochester Medical Center has now shown that the Ca2+/calmodulin-activated phosphodiesterase type 1 (PDE1) enzymes play a major role in cardiac disease.

Either down-regulation of PDE1 using siRNA or treatment with the selective inhibitor, IC86340, prevented phenylephrine-induced pathological myocyte hypertrophy and hypertrophic marker expression in neonatal rat ventricular myocytes and adult rat ventricular myocytes. Studies in mice showed that IC86340 also reduced the cardiac hypertrophy caused by chronic infusion of isoproterenol. Although both PDE1a and PDE1c mRNA and protein were detected in human hearts, only PDE1a was found in rodent hearts. PDE1a is also up-regulated in heart tissue from various animals that model pathological hypertrophy, suggesting that PDE1a plays a key role in mediating pathological cardiomyocyte hypertrophy. Studies in isolated myocytes showed that a combination of sildenafil and IC86340 reduced hypertrophy more than either compound alone and the team now plan to explore the effects of combination treatment in animal studies.

The study is published in the journal Circulation Research.

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