Phosphodiesterase-9 inhibitors for the treatment of heart failure?

Phosphodiesterase-9 inhibitors for the treatment of heart failure? Phosphodiesterase-9 (PDE9) has the highest binding affinity among phosphodiesterases with cyclic guanosine monophosphate [1]. Cardioprotective effects of natriuretic peptides released in response to ventricular stretch in heart failure are mediated by the second messenger cyclic guanosine monophosphate (cGMP) [2]. Intracellular levels of cGMP and cAMP are governed by the activity of cyclic nucleotide phosphodiesterases. 11 phosphodiesterases with varying tissue selectivity and substrate affinity for cGMP and cAMP have been identified (PDE1 to PDE11) so far. Increased mortality with high doses of PDE3 inhibitors milrinone, vesnarinone, and enoximone in chronic heart failure with reduced ejection fraction (HFrEF) is thought to be secondary to the preferential affinity of PDE3 for cAMP relative to cGMP. This can lead to increase in the risk of ventricular arrhythmias as a result of increased intracellular levels of cAMP [2]. A metanalysis of PDE5 inhibitor sildenafil in the treatment of heart failure reported on 9 randomized controlled trials enrolling 612 heart failure patients. A pacifying finding was there was no significant differences in adverse events between sildenafil group and placebo group. Sildenafil improved hemodynamic parameters, particularly in HFrEF. Treatment was well tolerated and had no impact on quality of life [3]. PDE9 with greatest affinity for cGMP has specific affinity for the natriuretic...
Source: Cardiophile MD - Category: Cardiology Authors: Tags: General Cardiology Source Type: blogs