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1 We have characterized the prostanoid receptors involved in the regulation of human penile arterial and trabecular smooth muscle tone. 2 Arachidonic acid induced relaxation of human corpus cavernosum strips (HCCS) that was blocked by the cyclo-oxygenase inhibitor, indomethacin, and augmented by the thromboxane receptor (TP) antagonist, SQ29548, suggesting that endogenous production of prostanoids regulates penile smooth muscle tone. 3 TP-receptors mediate contraction of HCCS and penile resistance arteries (HPRA), since the agonist of these receptors, U46619, potently contracted HCCS (EC 50 8.3+2.8 nM) and HPRA (EC 50 6.2+2.2 nM), and the contractions produced by prostaglandin F 2a at high concentrations (EC 50 6460+3220 nM in HCCS and 8900+6700 nM in HPRA) were inhibited by the selective TP-receptor antagonist, SQ29548 (0.02 mM). 4 EP-receptors are responsible for prostanoid-induced relaxant e ects in HCCS because only prostaglandin E 1 (PGE 1 ), prostaglandin E 2 and the EP 2 /EP 4 -receptor agonist, butaprost, produced consistent relaxation of this tissue (EC 50 93.8+31.5, 16.3+3.8 and 1820+1284 nM, respectively). In HPRA, both prostacyclin and PGE 1 (EC 50 60.1+18.4 and 109.0+30.9 nM, respectively) as well as the selective IP receptor agonist, cicaprost, and butaprost (EC 50 25.2+15.2 and 7050+6020 nM, respectively) caused relaxation, suggesting co-existence of IP-and EP-receptors (EP 2 and/or EP 4 ).

Increased incidence of impotence is associated with some selective serotonin‐reuptake‐inhibitors (SSRIs), but the pathophysiological mechanism is unknown. Paroxetine and citalopram are extensively used SSRIs, but only paroxetine has been shown to inhibit nitric oxide synthase (NOS) activity. NO is a key mediator of penile erection. Thus, the aim of this study was to determine the effects of paroxetine and citalopram on erectile function and NO production, in a rat model. Application of cavernosal nerve electrical stimulation produced frequency‐related intracavernosal pressure (ICP) increases, which were inhibited by the NOS inhibitor, NG‐nitro‐L‐arginine (0.3 mg kg−1). Acute or chronic (2 weeks) paroxetine‐treatment (10 mg kg−1) reduced ICP‐responses, while citalopram did not. Paroxetine, but not citalopram, significantly reduced nitrite+nitrate plasma levels by 61.4% and inhibited penile neuronal NOS (nNOS) protein expression by 31.2% after chronic treatment. The results show that paroxetine inhibits erectile responses in rats. We propose that this effect is due to reduced NO production and nNOS expression. British Journal of Pharmacology (2001) 134, 1190–1194; doi:

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 þ (35 mm) or by blocking Ca 2 þ -activated K þ 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 mm) 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 þ or a combination of APA and CTX. 4 In vivo, DOBE (10 mg kg À1 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.

Introduction Diabetes is associated with a high incidence of erectile dysfunction (ED) and poor response to standard treatments. Oxidative stress could be relevant in the pathophysiology of diabetic ED. Aim To evaluate the effects of the antioxidant, AC3056 (2,6-di-t-butyl-4-((dimethyl-4-methoxyphenylsilyl)methyloxy)phenol), on diabetic ED. Methods Erectile responses to cavernosal nerve electrical stimulation were determined in streptozotocin-induced diabetic rats. Relaxation of human corpus cavernosal (HCC) tissue and penile resistance arteries (HPRA) from human cavernosal specimens was evaluated in organ chambers and myographs, respectively. Main Outcome Measures The influence of AC3056 on erectile responses, lipid peroxidation, and nitrite plus nitrate serum content, and nuclear factor-κB (NF-κB) expression in penile tissue, in diabetic rats, and on endothelium-dependent and neurogenic relaxation of HCC and HPRA from diabetic patients was determined. Results Eight weeks of diabetes caused ED in rats that was prevented by oral AC3056 (0.3% w/w in rat chow) when given from the induction of diabetes. AC3056 also prevented the diabetes-induced elevation of serum thiobarbituric acid-reactive substances (TBARS), the reduction of serum nitric oxide (NO) derivatives, and the increase of NF-κB expression. Acute oral administration of AC3056 (450 mg/kg) partially reversed ED in 8-week diabetic rats. Complete reversion of ED was achieved after 3 days of treatment with 0.3% AC3056. This effect remained after 5 weeks of treatment, but it disappeared after withdrawing for 1 week. Erectile function in diabetic rats was inversely related to serum TBARS. AC3056- (30 µM) reversed endothelial dysfunction in diabetic HCC and enhanced endothelium-dependent relaxation in diabetic HPRA and significantly potentiated neurogenic relaxation of both tissues. The reduced cGMP content in HCC from diabetic patients after exposure to acetylcholine (10 µM) was corrected by AC3056 (30 µM). Conclusions These results suggest that oxidative stress has a relevant role in pathophysiology of diabetic ED and provide a rationale for the use of antioxidant therapy in the treatment of ED in diabetes.