Involvement of α-receptors and potassium channels in the mechanism of action of sildenafil citrate

El-Metwally, M A; Sharabi, Fouad M.; Daabees, Tahia T.; Senbel, Amira; Mostafa, Taymour

doi:10.1038/sj.ijir.3901590

Cited by 13 publications

(15 citation statements)

References 31 publications

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“…Phase III was intensified by the choline esterase inhibitor, eserine, and abolished by atropine, indicating that the relaxation of phase III was mediated by the cholinergic neuro‐effector system (Figure 6). Other factors may also affect the corporal tracing elicited by EFS, such as the self‐recovery property of the cavernosum smooth muscle and ion channels in smooth muscle membranes [25–30]; however, the neuronal systems play the most important role. The triphasic response to EFS can help us understand the potential mechanism involved in EFS‐induced signal transductions.…”

Section: Discussionmentioning

confidence: 99%

Three Phases of Corporal Tracing Elicited by Electrical Field Stimulation on Rabbit Corpus Cavernosum Smooth Muscle in Penile Perfusion Model

Zhao

Cho

Park

2011

The Journal of Sexual Medicine

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Introduction Nitric oxide (NO) has been shown to mediate electrical field stimulation (EFS)-caused smooth muscle relaxation. It is known that the neural control of penile erection involves adrenergic, cholinergic, and non-adrenergic-non-cholinergic (NANC) neuro-effector systems; however, the effects of EFS on adrenergic and cholinergic nerves are not clear. Aims To elucidate EFS-induced signal transductions involved in adrenergic, cholinergic, and NANC neuro-effector systems by using an in vitro penile perfusion model. Methods EFS was performed on penile corpus cavernosum smooth muscle from male New Zealand White rabbits, which was pre-contracted with L-phenylephrine (10 µM). We investigated the penile tracing elicited by EFS on tissues pre-incubated with guanethidine (Guan, 50 µM), tetrodotoxin (TTX, 10 µM), Nω nitro-L-arginine-methyl ester (L-NAME, 1 mM), atropine (50 µM), or eserine (10 µM). Main Outcome Measures The time-to-peak of each phase, the percentage of relaxation, and the area under the curve (AUC). Results We discovered an extraordinary phenomenon: three distinct phases elicited by EFS. Phase I was abolished by L-NAME. Phase II was decreased by eserine and Guan, but increased by L-NAME. Phase III was abolished by atropine, but enhanced by eserine and Guan. TTX diminished all three phases. The time to reach the top of phase I was delayed by TTX. The time to attain the peak of phase II was shortened by L-NAME, but delayed by TTX and atropine. The time to reach the top of phase III was shortened by L-NAME, eserine, and Guan. AUC was significantly decreased by L-NAME and TTX. Conclusions EFS stimulated adrenergic, cholinergic, and NANC neuro-effector systems simultaneously. Phase I was related to the NO pathway. Phase II was multiply affected by self-recovery properties, and adrenergic and cholinergic nerves. Phase III was related to cholinergic nerves. The corporal tracing elicited by EFS was the balanced result of multiple factors.

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Section: Discussionmentioning

confidence: 99%

Three Phases of Corporal Tracing Elicited by Electrical Field Stimulation on Rabbit Corpus Cavernosum Smooth Muscle in Penile Perfusion Model

Zhao

Cho

Park

2011

The Journal of Sexual Medicine

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“…Sildenafil (phosphodiesterase type 5 inhibitor) also relaxes the human corpus cavernosum by K ATP channels. 23 It would therefore seem that, by acting through K ATP channels, yohimbine hyperpolarizes the muscle cell membrane, and thereby reduces Ca þ þ flow into the cell promoting relaxation in the human corpus cavernosum smooth muscle. This mechanism may be similar to phentolamine, an a 1 -adrenoceptor blocker, as reported before.…”

Section: Discussionmentioning

confidence: 99%

Yohimbine relaxes the human corpus cavernosum through a non-adrenergic mechanism involving the activation of K+ATP-dependent channels

et al. 2009

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The mechanism by which yohimbine relaxes the human corpus cavernosum remains unclear. Using the human corpus cavernosum strips immersed in isometric baths containing Krebs-Henseleit solution, this study investigates the effect of yohimbine on the relaxation of the human corpus cavernosum through nitrergic pathways involving the activation of ATP-dependent potassium channels (K ATP ). The maximal relaxation induced by yohimbine in the human corpus cavernosum strips pre-contracted with phenylephrine was 100±0% and only 30.5±5.0% when they were precontracted with 60-mM potassium (K þ ) solution. The maximal relaxation induced by yohimbine in phenylephrine pre-contracted tissues was significantly inhibited by tetrodotoxin, 1H-[1,2,4] oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) or 7-nitroindazole (43.6, 36.1 and 42.6%, respectively). Neither the combination charybdotoxin-apamin nor tetraethylammonium altered the response of the human corpora cavernosa strips to yohimbine. Nevertheless, glibenclamide decreased the maximum relaxant response to yohimbine by 29.8% (Po0.05; n ¼ 12). The results suggest that yohimbine relaxes the human corpus cavernosum by a non-adrenergic, non-cholinergic mechanism, probably activating the nitrergic-soluble guanylate cyclase (NO-sGc) pathway and K ATP .

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“…We investigated the role of K þ channel opening with respect to the synergistic effects of mirodenafil and alpha-adrenergic blockers because the K þ channel-opening effect has been described for alpha-adrenergic blockers 32 and PDE5 inhibitors. 33 As shown in Figure 4, the nonspecific K þ channel blocker tetraethylammonium (1 mM, n ¼ 6, Po0.05) significantly inhibited the enhancement effect of tamsulosin and doxazosin on mirodenafilinduced relaxation. We suggest that K þ channel activation with alpha-adrenergic blockers and mirodenafil is one of the action mechanisms in this enhancing effect.…”

Section: Angiotensin Receptor Blockermentioning

confidence: 95%

“…It has been reported that sildenafil citrate is capable of producing cavernosal smooth-muscle relaxation by an additional mechanism that may involve a-receptors and K þ channel openings. 33 In addition, the K þ channel opening effect of phentolamine in the corpus cavernosum has been previously described. 32 In our study, TEA significantly inhibited the enhancement effect of tamsulosin and doxazosin on mirodenafilinduced relaxation.…”

Section: à6mentioning

confidence: 99%

The effects of the combined use of a PDE5 inhibitor and medications for hypertension, lower urinary tract symptoms and dyslipidemia on corporal tissue tone

et al. 2012

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ED is closely associated with its comorbidities (hypertension, dyslipidemia and lower urinary tract symptoms (LUTS)). Therefore, several drugs have been prescribed simultaneously with PDE5 inhibitors. If a specific medication for ED comorbidities has enhancing effects on PDE5 inhibitors, it offers alternative combination therapy in nonresponders to monotherapy with PDE5 inhibitors and allows clinicians to treat ED and its comorbidities simultaneously. To establish theoretical basis of choosing an appropriate medication for ED and concomitant disease, we examined the effects combining a PDE5 inhibitor with representative drugs for hypertension, dyslipidemia and LUTS on relaxing the corpus cavernosum of rabbits using the organbath technique. The effect of mirodenafil on relaxing phenylephrine-induced cavernosal contractions was significantly enhanced by the presence of 10 À4 M losartan, 10 À6 M nifedipine, 10 À6 M amlodipine, 10 À7 M doxazosin and 10 À9 M tamsulosin (Po0.05). The maximum relaxation effects were 47.2 ± 3.8%, 57.6 ± 2.6%, 64.0 ± 3.7%, 76.1 ± 5.7% and 71.7 ± 5.4%, respectively. Enalapril and simvastatin had no enhancing effects. The relaxation induced by sodium nitroprusside alone (39.0±4.0%) was significantly enhanced in the presence of the 10 À4 M losartan (66.0 ± 6.0%, Po0.05). Tetraethylammonium (1 mM) significantly inhibited the enhancement effects of tamsulosin and doxazosin on mirodenafil-induced relaxation (doxazosin: 76.1 ± 5.7% vs 45.3 ± 2.3%; tamsulosin: 71.7±5.4% vs 48.1±3.5%). On the basis of these findings, losartan seemed to induce synergistic effects through an interaction with nitric oxide. In addition, K þ channel activation could be one of the mechanisms for the synergistic effect of combining mirodenafil with doxazosin or tamsulosin. We believe that the combination of a PDE5 inhibitor with losartan, nifedipine, amlodipine, doxazosin or tamsulosin could be a pharmacologic strategy for simultaneously treating ED and its comorbidities and increasing response rates to PDE5 inhibitors.International Journal of Impotence Research (2012) 24, 221--227; doi:10.1038/ijir.2012; published online 5 July 2012Keywords: comorbidity; ED; PDE5 inhibitor INTRODUCTION ED is a common condition, with a reported prevalence of 52% in men aged 40--70 years in the United States 1 and 49% in men aged 50--80 years in Europe.2 It can affect patients' lives in different ways, including disrupting interpersonal relationships, interfering with sexual life, causing problems with partners and increasing stress, all of which make ED a major quality of life issue.

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Involvement of α-receptors and potassium channels in the mechanism of action of sildenafil citrate

Cited by 13 publications

References 31 publications

Three Phases of Corporal Tracing Elicited by Electrical Field Stimulation on Rabbit Corpus Cavernosum Smooth Muscle in Penile Perfusion Model

Three Phases of Corporal Tracing Elicited by Electrical Field Stimulation on Rabbit Corpus Cavernosum Smooth Muscle in Penile Perfusion Model

Yohimbine relaxes the human corpus cavernosum through a non-adrenergic mechanism involving the activation of K+ATP-dependent channels

The effects of the combined use of a PDE5 inhibitor and medications for hypertension, lower urinary tract symptoms and dyslipidemia on corporal tissue tone

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