Cardiovascular effects of sildenafil in hypertensive men with erectile dysfunction and different alleles of the type 5 cGMP-specific phosphodiesterase (PDE5).
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'-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.
Salvi
F
F
Department of Internal Medicine, Polytechnical University of Marche, Ancona, Italy. fbidlv@libero.it
Sarzani
R
R
Giorgi
R
R
Donatelli
G
G
Pietrucci
F
F
Micheli
A
A
Baldoni
M
M
Minardi
D
D
Minaroli
D
D
Dessì-Fulgheri
P
P
Polito
M
M
Muzzonigro
G
G
Rappelli
A
A
D015106:3',5'-Cyclic-GMP Phosphodiesterases / Q000096:biosynthesis* / Q000235:genetics*; D024506:5' Flanking Region / Q000235:genetics; D000328:Adult; D000368:Aged; D000483:Alleles; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; D004247:DNA / Q000235:genetics; D007172:Erectile Dysfunction / Q000150:complications / Q000235:genetics* / Q000503:physiopathology*; D005838:Genotype; D006439:Hemodynamics / Q000187:drug effects*; D006801:Humans; D006973:Hypertension / Q000150:complications / Q000235:genetics* / Q000503:physiopathology*; D008297:Male; D008875:Middle Aged; D010879:Piperazines / Q000494:pharmacology*; D011687:Purines; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000068677:Sildenafil Citrate; D013450:Sulfones; D018808:Transcription Factor AP-1 / Q000235:genetics; D014665:Vasodilator Agents / Q000494:pharmacology*
D010879:Piperazines; D011687:Purines; D013450:Sulfones; D018808:Transcription Factor AP-1; D014665:Vasodilator Agents; D004247:DNA; D000068677:Sildenafil Citrate; D015106:3',5'-Cyclic-GMP Phosphodiesterases; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; C517381:PDE5A protein, human