Combination of phentolamine and l-arginine or sildenafil synergistically improves neurogenic relaxation of rabbit corpus cavernosum smooth muscle

Angulo, Javier; Cuevas, Pedro; Fernández, Argentina; Gabancho, Sonia; Tejada, Iñigo Sáenz de

doi:10.1016/s0090-4295(00)01032-3

Cited by 22 publications

(18 citation statements)

References 20 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…19--21 Although the effects of the aforementioned drugs on the corpus cavernosum have been addressed, only a few studies have focused on the possible enhancement interaction with PDE5 inhibitors. 34,35 However, considering that approximately 30--40% of all ED patients do not respond to PDE5 inhibitors 36 and that many ED patients may take several drugs 37 for their comorbidities, this issue is important. The enhancing interaction with PDE5 inhibitors offers alternative combination therapy in nonresponders to monotherapy with PDE5 inhibitors and allows clinicians to treat ED and its comorbidities simultaneously.…”

Section: Discussionmentioning

confidence: 99%

“…And other investigational studies have demonstrated the enhancing effect of phentolamine with sildenafil. 34,35 We analyzed the influence of the receptor selectivity of each alpha-adrenergic blocker on the enhancing effect with a PDE5 inhibitor. The predominant a1-adrenoceptor subtype is a1A in the human corpus cavernosum, 53 and the predominant a1-adrenoceptor subtype is a1B in the rabbit corpus cavernosum.…”

Section: à6mentioning

confidence: 99%

See 1 more Smart Citation

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

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionmentioning

confidence: 99%

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

View full text Add to dashboard Cite

show abstract

“…Nitrergic nerves are regulated through pre-junctional, a-2 adrenergic receptors. 4,5 An a-2 agonist inhibits release of NO and, conversely, an a-2 antagonist such as yohimbine enhances release of NO. Furthermore, it has been demonstrated that the combination of yohimbine (an a-2 receptor antagonist) or phentolamine (an a-1 and a-2 receptor antagonist) with a PDE5 inhibitor synergistically potentiates nitrergic nervemediated relaxation of corpus cavernosum tissue.…”

Section: Populations Resistant To Pde5 Inhibitor Therapymentioning

confidence: 99%

Therapeutic strategies for optimizing PDE-5 inhibitor therapy in patients with erectile dysfunction considered difficult or challenging to treat

Tejada¹

2004

Int J Impot Res

View full text Add to dashboard Cite

Fundacion para la Investigacion y el Desarrollo en Andrologia (FI þ DA) Madrid, SpainPhosphodiesterase 5 (PDE5) inhibitors prevent the normal hydrolysis of cGMP. As the resulting cGMP accumulation facilitates penile smooth muscle relaxation, PDE5 inhibitors can partially reverse deficiencies in the nitric oxide (NO)/cGMP pathway to treat erectile dysfunction (ED). However, approximately 30-40% of men with ED do not respond to drug therapy. Patients with severe neurologic damage, diabetes mellitus, or severe vascular disease may be resistant to PDE5 inhibitors. Decreased expression or activity of neuronal or endothelial NO synthase (NOS), impaired NO release, or NO destruction will preclude sufficient cGMP formation to permit PDE5 inhibitor efficacy. This article discusses the possible reasons for unresponsiveness and strategies to overcome it. Therapeutic approaches proposed to increase available NO in penile tissue include facilitating NO release by using a-2 antagonists, enhancing NO synthesis by providing more substrate for the reaction, and using antioxidants to inhibit NO breakdown by reactive oxygen species. Populations resistant to PDE5 inhibitor therapyNitric oxide (NO), a key mediator in the initiation and maintenance of penile erection, is synthesized and released by the endothelium and the autonomic nerves of penile arteries and corpus cavernosum tissue. 1 Upon its release, NO enters the smooth muscle cell and activates soluble guanylyl cyclase, which promotes the formation of cGMP. Cellular concentrations of cGMP are regulated by phosphodiesterase (PDE) enzymes, of which PDE5, a cGMP specific hydrolyzing enzyme, is the most functionally important in human penile tissue. 2,3 Certain conditions, which include aging, vascular and metabolic diseases, and traumatic or degenerative alterations of nerves, can result in the impaired synthesis, release, or availability of NO from the endothelium, the autonomic nerves, or both. The specific patient populations considered challenging-to-treat with respect to PDE5 inhibitor therapy include patients with severe neurologic damage (eg, due to radical prostatectomy), diabetes mellitus, and severe vascular disease. The result is erectile dysfunction (ED) due to insufficient dilation of penile arteries and relaxation of trabecular smooth muscle.PDE5 inhibitors prevent the normal hydrolysis of cGMP by PDE5 and thereby promote its accumulation, which facilitates penile smooth muscle relaxation. For this reason, PDE5 inhibitors can reverse, to a certain degree, deficiencies in the NO/cGMP pathway and are effective in the treatment of ED. The limitation in the efficacy of these agents is that a minimum or 'critical amount' of NO is necessary for these drugs to work. Nerves that are severely damaged will not be able to synthesize NO. Also, conditions in which there is a decrease in the expression or activity of neuronal or endothelial NO synthase (NOS), impairment of NO release, or destruction of NO will preclude sufficient guanylyl cyclase activation and formation of suf...

show abstract

“…Venlafaxine, although having relatively low affinity for the 5-HT and NE transporters (Table 1), has been shown to inhibit the reuptake of 5-HT and NE in humans (Harvey et al, 2000). In addition, prejunctional ␣ 2 -adrenergic receptors inhibit ni- jpet.aspetjournals.org trergic neurotransmission in various organs (Angulo et al, 2001a) and may represent an additional mechanism for the inhibition of GVRs by venlafaxine. A direct effect of venlafaxine on ␣-adrenoceptors is not likely, since this compound shows low affinity for these receptors (Table 1).…”

Section: Antidepressant-induced Female Sexual Dysfunction 145mentioning

confidence: 99%

Mechanisms for the Inhibition of Genital Vascular Responses by Antidepressants in a Female Rabbit Model

Angulo¹,

Cuevas²,

Cuevas³

et al. 2004

J Pharmacol Exp Ther

Self Cite

View full text Add to dashboard Cite

Vaginal and clitoral vasodilator responses (genital vascular responses; GVRs) to pelvic nerve electrical stimulation in female rabbits were measured by laser Doppler flow needle probes. The intravenous administration of various treatments was evaluated. GVRs were attenuated by a nitric-oxide synthase inhibitor (48.5 and 51.8% of control at 8 Hz in the vagina and clitoris, respectively) and norepinephrine (NE) (78.5 and 61.5%), whereas serotonin (5-HT) had no inhibitory effect. The selective 5-HT reuptake inhibitor (SSRI) escitalopram did not modify GVRs, whereas the SSRI paroxetine dose-dependently inhibited GVRs in female rabbits (43.3 and 53.1% at 5 mg/kg). GVRs were also significantly inhibited by the 5-HT and NE reuptake inhibitors venlafaxine (53.4 and 52.6% at 5 mg/kg) and duloxetine (40.9 and 37.4% at 1 mg/kg). L-arginine prevented the inhibitory effects of paroxetine (105.5 and 115.3%) and partially prevented duloxetine-induced reduction of GVRs but had no effect on the inhibition of GVRs induced by venlafaxine. Conversely, the ␣-adrenergic receptor blocker phentolamine had no effect on paroxetine-induced reduction of GVRs, partially prevented the inhibitory effects of duloxetine, and fully prevented the effects of venlafaxine (93.0 and 96.7%). Duloxetineinduced inhibition of GVRs was completely prevented by combined administration of L-arginine and phentolamine (123.5 and 103.6%). Although 5-HT or the highly selective SRI escitalopram did not inhibit GVRs, NE or inhibition of nitric oxide (NO) synthesis did. Inhibition of the NO pathway by paroxetine and duloxetine or activation of ␣-adrenergic mechanisms by venlafaxine and duloxetine lead to antidepressant-induced inhibition of GVRs in female rabbits.

show abstract

Combination of phentolamine and l-arginine or sildenafil synergistically improves neurogenic relaxation of rabbit corpus cavernosum smooth muscle

Cited by 22 publications

References 20 publications

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

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

Therapeutic strategies for optimizing PDE-5 inhibitor therapy in patients with erectile dysfunction considered difficult or challenging to treat

Mechanisms for the Inhibition of Genital Vascular Responses by Antidepressants in a Female Rabbit Model

Contact Info

Product

Resources

About