Calcium dobesilate potentiates endothelium-derived hyperpolarizing factor-mediated relaxation of human penile resistance arteries.
1 We have evaluated the participation of endothelium-derived hyperpolarizing factor (EDHF) in the endothelium-dependent relaxation of isolated human penile resistance arteries (HPRA) and human corpus cavernosum (HCC) strips. In addition, the effect of the angioprotective agent, calcium dobesilate (DOBE), on the endothelium-dependent relaxation of these tissues was investigated. 2 Combined inhibition of nitric oxide synthase (NOS) and cyclooxygenase (COX) nearly abolished the endothelium-dependent relaxation to acetylcholine (ACh) in HCC, while 60% relaxation of HPRA was observed under these conditions. Endothelium-dependent relaxation of HPRA resistant to NOS and COX inhibition was prevented by raising the extracellular concentration of K(+) (35 mM) or by blocking Ca(2)(+)-activated K(+) channels, with apamin (APA; 100 nM) and charybdotoxin (CTX; 100 nM), suggesting the involvement of EDHF in these responses. 3 Endothelium-dependent relaxation to ACh was markedly enhanced by DOBE (10 micro M) in HPRA but not in HCC. The potentiating effects of DOBE on ACh-induced responses in HPRA, remained after NOS and COX inhibition, were reduced by inhibition of cytochrome P450 oxygenase with miconazole (0.3 mM) and were abolished by high K(+) or a combination of APA and CTX. 4 In vivo, DOBE (10 mg kg(-1) i.v.) significantly potentiated the erectile responses to cavernosal nerve stimulation in male rats. 5 EDHF plays an important role in the endothelium-dependent relaxation of HPRA but not in HCC. DOBE significantly improves endothelium-dependent relaxation of HPRA mediated by EDHF and potentiates erectile responses in vivo. Thus, EDHF becomes a new therapeutic target for the treatment of erectile dysfunction (ED) and DOBE could be considered a candidate for oral therapy for ED.
Angulo
Javier
J
Fundación para la Investigación y el Desarrollo en Andrología, Spain.
Cuevas
Pedro
P
Fernández
Argentina
A
Gabancho
Sonia
S
Videla
Sebastián
S
Sáenz de Tejada
Iñigo
I
D000818:Animals; D001685:Biological Factors / Q000502:physiology*; D002123:Calcium Dobesilate / Q000008:administration & dosage / Q000493:pharmacokinetics*; D004357:Drug Synergism; D004558:Electric Stimulation; D004727:Endothelium / Q000187:drug effects / Q000503:physiopathology; D006801:Humans; D007275:Injections, Intravenous; D008297:Male; D009126:Muscle Relaxation / Q000187:drug effects* / Q000502:physiology; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D019001:Nitric Oxide Synthase / Q000502:physiology; D010410:Penile Erection / Q000187:drug effects* / Q000502:physiology; D010413:Penis / Q000098:blood supply* / Q000187:drug effects* / Q000503:physiopathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D014655:Vascular Resistance / Q000187:drug effects / Q000502:physiology; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology
D001685:Biological Factors; C067410:endothelium-dependent hyperpolarization factor; D002123:Calcium Dobesilate; D019001:Nitric Oxide Synthase