Experimental models have shown that chronic PDE5 inhibition with sildenafil treatment and subsequent PKG activation inhibits cardiac hypertrophy development and stops progressive remodeling in well-established cardiac hypertrophy. The mechanism of the former may be RGS2 activation by PKG, leading to Gαq signal inhibition, including Cn/NFAT. Ongoing studies are testing other Gαq-coupled cascades, including the role of transient receptor potential canonical channels, that have been linked to Cn/NFAT activation. Discovery of additional novel targets within the sarcomere and coupled to other central signaling cascades is anticipated. It is likely that the mitochondrial changes revealed in ischemia studies will also play a role in the antihypertrophic signaling process. The issue of RV versus LV disparities is very intriguing, but this needs to be addressed at the molecular level. The ongoing NIH-funded trial will help to test the relevance of the cardiac PDE5 modulation data to a very relevant human disease (nearly 50% of all heart failure). The role of PDE5 inhibition in systolic dysfunction remains unclear, but in settings where PKG-targetable cascades play a pathophysiologic role, one would anticipate some benefits as well.
ASJC Scopus subject areas
- Pharmacology, Toxicology and Pharmaceutics(all)
- Pharmacology (medical)