Inhibition of sympathetic neuroeffector transmission in human corpus cavernosum

Abstract

Study Type – Aetiology (case control) Level of Evidence 2b What's known on the subject? and What does the study add? In the present study the mechanisms regulating EFS‐evoked neurogenic contraction in the human corpus cavernosum (HCC) were investigated. Overall, our data adds to current knowledge that the NO‐independent heme dependent activation of sGC and the RhoA/Rho‐kinase signaling pathways play an important role in the regulation of neurogenic contractile activity in HCC tissue. OBJECTIVE To investigate the mechanisms of adrenergically mediated smooth muscle contraction in the human corpus cavernosum (HCC) using an organ bath approach. METHODS Human corpus cavernosum specimens were obtained from patients (aged 59–72 years) with erectile dysfunction (ED), undergoing penile prosthesis implantation surgery. Isolated HCC strips (1 × 1 × 6 mm) were suspended in tissue bath chambers for isometric tension recording. The effects of various drugs on neurogenic contractions evoked by electrical field stimulation (EFS) were investigated. The drugs included nitric oxide (NO) donors, phosphodiesterase 5 (PDE5) inhibitor, Rho kinase (ROCK) inhibitor, NO‐independent stimulator, L‐type Ca2+ channel blocker and α‐receptor antagonist. RESULTS Pre‐incubation with the NO donor sodium nitroprusside (SNP; 104 M) significantly reduced the initial peak increase in tension evoked by EFS (by 71%, P < 0.05). The PDE5 inhibitor sildenafil (10−4 M) reduced the increase in tension by 69%, while a combination of sildenafil and ROCK inhibitor, fasudil, inhibited tension by 81%. The EFS‐induced contractile response at 80 Hz was decreased by 65% with fasudil and by 70% with isradipine (P < 0.001), while a combination of these drugs decreased the response by 88%. An NO‐independent stimulator soluble guanylate cyclase (sGC), BAY 41‐8543, significantly reduced the response (by 82%, P < 0.001) Phentolamine, an α‐receptor antagonist, nearly eliminated the contractile response (98%, P < 0.001). CONCLUSIONS These data suggest that neurogenic contractions are mediated by an increase in Ca(2+) influx via L‐type voltage‐gated Ca(2+) channels and that an increase in Ca(2+) sensitivity is mediated by the ROCK pathway and the PDE5 enzyme system as well as by the inhibitory NO/sGC/cGMP pathway. The neurogenic contractile response in HCC is mediated by several intracellular pathways, including adrenergic receptors, Ca(2+) entry, Ca(2+) sensitization and activation of the PDE5 enzyme. The Rho‐kinase (ROCK) inhibitor fasudil, L‐type Ca(2+) channel antagonist isradipine, and PDE5 inhibitor sildenafil, as well as a NO‐independent stimulator of sGC, had similar inhibitory effects, suggesting parallel mechanisms in the HCC.

Effects of silodosin, a selective alpha‐1A adrenoceptor antagonist, on erectile function in a rat model of partial bladder outlet obstruction

“…In an attempt to study, the contractile response elicited only by the adrenergic nerve component of EFS, the tissues were treated with a non‐selective NO synthase inhibitor, L‐N(G)‐nitroarginine methyl ester (L‐NAME, 100 µM), and the muscarinic receptor antagonist atropine (1 µM) for 30 min to eliminate nitrergic and cholinergic influences . The increases in the tension of the muscle in contractile response to EFS and Phe were measured in gram/gram tissue …”

“…14 The increases in the tension of the muscle in contractile response to EFS and Phe were measured in gram/ gram tissue. 15…”

Pathogenic mechanisms linking benign prostatic hyperplasia, lower urinary tract symptoms and erectile dysfunction

“…It is worthwhile mentioning that even the alphaadrenergic blockers, one of the main drugs to treat LUTS/BPH, facilitate relaxation of isolated fibers of smooth cavernous muscles [Gur et al 2008[Gur et al , 2012; in addition these agents can revert functional and molecular alterations triggered by partial vesical obstruction [Gur et al 2008].…”

“…The authors verified that functional (diminished contractions in cavernous body muscle fibers, induced by acetylcholine and electrical stimulus) and molecular changes (alteration in expression and bioavailability of nitric oxide) were partially reverted by treating with an alpha-adrenergic blocker. More recently, the same group [Gur et al 2012] demonstrated alpha-adrenergic blockage produces relaxation of the muscle fibers of human cavernous body that is comparable to PDE-5i. Furthermore, in the past it was shown that the intracavernous and oral use of phentolamine and phenoxybenzamine caused erection in men with erectile dysfunction [Padma-Nathan et al 2002;Glina et al 2008].…”

Ionic Channels as Potential Therapeutic Targets for Erectile Dysfunction: A Review

“…Penile flaccidity process primarily have been stimulated by the sympathetic nervous system, where the release of norepinephrine (NA) by adrenergic neurons stimulates its α 1 and α 2 receptors in the smooth muscle of the penile vessels and corpus cavernosum, inducing its contraction and reduction of the blood flow ( Goldstein, 2000 ; Gur et al., 2012 ; Traish et al., 2015 ).…”