ACE gene I/D and NOS3 G894T polymorphisms and response to sildenafil in men with erectile dysfunction.
OBJECTIVE
To examine a potential association between the response to the phosphodiesterase-5 inhibitor sildenafil and angiotensin-converting enzyme (ACE), as well as NOS3 G894T genotypes in patients with erectile dysfunction (ED). An insertion/deletion (I/D) polymorphism in the gene encoding the ACE and a single nucleotide exchange polymorphism (G894T) in the gene NOS3 encoding endothelial nitric oxide synthase have been associated with cardiovascular disorders.


METHODS
The response to sildenafil in 113 men with ED was monitored according to the patients' diaries. ACE and NOS3 genotypes were determined in patients with ED and in 108 healthy male blood donors.


RESULTS
Genotype distributions of ACE and NOS3 polymorphisms in the patient group were similar to those of the healthy control group. Analysis of the response to sildenafil revealed that 15 of 20 individuals homozygous for the ACE II genotype showed a positive erectile response after sildenafil use and only 46 of 93 D allele (combined DD and DI genotypes) carriers had a positive response (positive erectile response, odds ratio 3.07, 95% confidence interval 1.03 to 9.13, P = 0.04; chi-square test). Analysis of NOS3 genotypes revealed that 30 of 52 individuals homozygous for the G894 allele had a sufficient response to sildenafil and only 4 of 12 patients homozygous for the 894T allele had a sufficient erection.


CONCLUSIONS
It appears that patients with elevated ACE serum concentrations, as associated with the D allele of the ACE I/D polymorphism, are less likely to respond to sildenafil.
Eisenhardt
Andreas
A
Department of Pharmacology, University Hospital Essen, Essen, Germany.
Sperling
Herbert
H
Hauck
Ekkehard
E
Porst
Hartmut
H
Stief
Christian
C
Rübben
Herbert
H
Müller
Norbert
N
Siffert
Winfried
W
D015106:3',5'-Cyclic-GMP Phosphodiesterases; D000328:Adult; D000368:Aged; D000483:Alleles; D019943:Amino Acid Substitution; D003430:Cross-Sectional Studies; D006152:Cyclic GMP / Q000502:physiology; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; D004351:Drug Resistance / Q000235:genetics; D007172:Erectile Dysfunction / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000503:physiopathology; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D009569:Nitric Oxide / Q000502:physiology; D019001:Nitric Oxide Synthase / Q000235:genetics* / Q000502:physiology; D052250:Nitric Oxide Synthase Type III; D010413:Penis / Q000098:blood supply / Q000201:enzymology; D007703:Peptidyl-Dipeptidase A / Q000235:genetics* / Q000502:physiology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D010727:Phosphoric Diester Hydrolases / Q000187:drug effects; D010879:Piperazines / Q000494:pharmacology / Q000627:therapeutic use*; D011110:Polymorphism, Genetic; D011687:Purines; D012189:Retrospective Studies; D000068677:Sildenafil Citrate; D013450:Sulfones; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology
D010726:Phosphodiesterase Inhibitors; D010879:Piperazines; D011687:Purines; D013450:Sulfones; D009569:Nitric Oxide; D000068677:Sildenafil Citrate; C496314:NOS3 protein, human; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; D010727:Phosphoric Diester Hydrolases; D015106:3',5'-Cyclic-GMP Phosphodiesterases; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; C517381:PDE5A protein, human; D007703:Peptidyl-Dipeptidase A; D006152:Cyclic GMP