Phentolamine relaxes human corpus cavernosum by a nonadrenergic mechanism activating ATP-sensitive K+ channel

Abstract

To investigate the pharmacodynamics of phentolamine in human corpus cavernosum (HCC) with special attention to the role of the K þ channels. Strips of HCC precontracted with nonadrenergic stimuli and kept in isometric organ bath immersed in a modified Krebs-Henseleit solution enriched with guanethidine and indomethacine were used in order to study the mechanism of the phentolamine-induced relaxation. Phentolamine caused relaxation (E50%) in HCC strips precontracted with K þ 40 mM. This effect was not blocked by tetrodotoxin (1 lM) (54.674.6 vs 48.976.4%) or (atropine (10 lM) (52.776.5 vs 58.675.6%). However, this relaxation was significantly attenuated by L-NAME (100 lM) (59.775.8 vs 27.877.1%; Po0.05; n ¼ 8) and ODQ (100 lM) (62.775.1 vs 26.873.9%; Po0.05; n ¼ 8). Charybdotoxin and apamin (K Ca -channel blockers) did not affect the phentolamine relaxations (54.674.6 vs 59.375.2%). Glibenclamide (100 lM), an inhibitor of K ATP -channel, caused a significant inhibition (56.776.3 vs 11.372.3%; Po0.05; n ¼ 8) of the phentolamine-induced relaxation. In addition, the association of glibenclamide and L-NAME almost abolished the phentolamine-mediated relaxation (54.675.6 vs 5.771.4%; Po0.05; n ¼ 8). The results suggest that phentolamine relaxes HCC by a nonadrenergicnoncholinergic mechanism dependent on nitric oxide synthase activity and activation of K ATPchannel.

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

“…With the sudden change in the extracellular K þ concentration, the balance of the transmembrane potential is lost and the ionic current is inverted resulting in the opening of voltage-dependent calcium channels and, subsequently, muscle contracture. 11 Matching findings reported by Filippi 4 in our study 10 À4 -M yohimbine was found to induce an adequate level of relaxation in the human corpus cavernosum pre-contracted with phenylephrine. When samples were pre-contracted with a K þ solution in combination with guanetidine and phentolamine, thus abolishing the adrenergic pathway, yohimbine induced a lesser degree of relaxation but was still effective, indicating the involvement of another pathway in addition to the known adrenergic pathway, as demonstrated by Silva et al 11 in a study using phentolamine.…”

“…22 In the present study, when glibenclamide was added, yohimbine-induced relaxation decreased (Figure 3), indicating that yohimbine also acts through K ATP pathways. Recently, Silva et al 11 reported similar findings using phentolamine a a 1 -adrenoceptor blocker. Sildenafil (phosphodiesterase type 5 inhibitor) also relaxes the human corpus cavernosum by K ATP channels.…”

“…4 Another a 2 -adrenergic antagonist, the phentolamine, relaxes both the rabbit and the human corpus cavernosum by blocking off a 1 and a 2 -adrenergic receptors, using the nitrergic and K þ channel pathways as well. 10,11 As mentioned before, the yohimbine appears to affect the central erectogenic mechanism, as well, as a 2 -adrenergic receptors are abundant in the central nervous system. 7 Another medication, bremelanotide, a melanocortin agonist of central action, seems to improve the quality of erection in male patients with erectile dysfunction.…”

“…This mechanism may be similar to phentolamine, an a 1 -adrenoceptor blocker, as reported before. 11 This can be achieved directly or through a cGMP-dependent pathway.…”

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

“…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. Thus, it may be hypothesized that the K þ channel-opening effect of mirodenafil and alpha-adrenergic blockers is one of the possible action mechanisms for enhancing the relaxation effect along with alpha-receptor blockage by mirodenafil and alpha-adrenergic blockers.…”