Cardiovascular effects of sildenafil in hypertensive men with erectile dysfunction and different alleles of the type 5 cGMP-specific phosphodiesterase (PDE5)

Abstract

Erectile dysfunction (ED) is frequent in patients with essential hypertension (EH); a likely common pathogenetic pathway could be a reduced ability of arteriolar vascular smooth muscle (VSM) to relax. Increasing intracellular levels of cGMP reduce the contractile status of VSM; on the contrary, type 5 cGMP-specific phosphodiesterase (PDE5, codified by PDE5A gene) regulates cGMP levels through its clearance. The PDE5A gene represents a good candidate for the intermediate phenotype EH/ED: genetic variants of the PDE5A may predispose to EH and ED and could affect the local and systemic response to sildenafil administration. Thus, a functionally relevant portion of PDE5 5 0 -flanking promoter region was analyzed by PCR and direct sequencing in patients with EH and idiopathic ED. The sequences obtained showed a T/G polymorphism at position -1142, near an AP1 regulatory element, that was not apparently associated with the intermediate phenotype. We also studied the relationship between this polymorphism and the effects of oral sildenafil on blood pressure (BP) and heart rate (HR) in men with ED. Sildenafil caused a significant decrease of BP, but had no effects on HR; statistical analysis showed no differences in BP and HR variations among PDE5A genotypes. In conclusion, our data showed no correlations of a novel polymorphism of the PDE5A promoter gene with the intermediate phenotype EH/ED and the BP and HR response to sildenafil administration. Further studies are necessary to define the role of this polymorphism and to study the genetic predisposition for EH with ED.

Identification of PDE5A:E90K: A Polymorphism in the Canine Phosphodiesterase 5A Gene Affecting Basal cGMP Concentrations of Healthy Dogs

“…[2][3][4] Examples of the importance of a pharmacogenetic relationship in human beings are polymorphisms in the phosphodiesterase 5A (PDE5A) gene that may predict response to therapy with sildenafil and nitric oxide, be linked to disease progression, and aid in risk assessment in childhood IgA nephropathy, pulmonary hypertension (PH), systemic hypertension, and erectile dysfunction. [5][6][7] The PDE5A gene encodes a cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase. It is a key physiologic regulator of cGMP and pharmacologic target of vasodilatory drugs (such as sildenafil citrate) used commonly to treat PH and erectile dysfunction.…”

Genetic variation in phosphodiesterase (PDE) 7B in chronic lymphocytic leukemia: overview of genetic variants of cyclic nucleotide PDEs in human disease

“…33–35 Polymorphisms in PDE5A appear unable to explain differences in cardiovascular effects in subjects who are administered sildenafil or other PDE5 inhibitors, implicating other mechanisms besides such genetic variation as contributing to variable responses. 33,34,36 …”

Pulmonary Hemodynamic Responses to Inhaled NO in Chronic Heart Failure Depend on PDE5 G(‐1142)T Polymorphism

“…[14] The only baseline feature that differed significantly across the three genotype groups (TT, GT, and GG) was plasma cGMP concentration, which was lower in the TT group (Fig. 1), suggesting a functional effect of the PDE5 polymorphism, with the TT genotype being associated with greater PDE5 activity and higher clearance of cGMP.…”