Amiloride Relaxes Rat Corpus Cavernosum Relaxation In Vitro and Increases Intracavernous Pressure In Vivo

Abstract

Introduction: The antihypertensive effects of thiazide diuretics such as hydrochlorothiazide are commonly associated with erectile dysfunction. The association of hydrochlorothiazide/amiloride is not associated with erectile dysfunction. The hypothesis is that amiloride has beneficial effect in penile erection and, therefore, counterbalances the hydrochlorothiazide-induced disruptive effect.

Aim: To investigate the effects of amiloride and its analogues hexamethylamiloride and benzamil on rat isolated corpus cavernosa (CC) and intracavernous pressure (ICP) in anaesthetized rats.

Methods: Rat isolated CC were incubated with amiloride, hexamethylamiloride, and benzamil (10 and 100 μmol/L each), followed by phenylephrine, potassium chloride, and electrical field stimulation (EFS). Their effect on the relaxant responses to EFS and sodium nitroprusside were also determined. Oral (30 mg/kg) and intraperitoneal (3 mg/kg) treatments with amiloride were also investigated on nerve-evoked ICP.

Main outcome measures: In vitro functional studies and in vivo ICP measurement on rat CC were performed. Additionally, phosphodiesterase type V isoform A1 activity and the mRNA expressions of Na⁺/H⁺ pump, epithelial sodium channel exchangers (ENaC) channels (α-, β- and γ subunits) and Na⁺/Ca²⁺ exchangers were evaluated in CC tissues.

Results: Amiloride and its analogues significantly reduced the phenylephrine-, potassium chloride-, and EFS-induced CC contractions, which were not changed by nitro-L-arginine methyl ester (100 μmol/L) or indomethacin (6 μmol/L). In phenylephrine-precontracted CC tissues, amiloride itself caused concentration-dependent relaxation and significantly increased the EFS-induced relaxation. Oral and intraperitoneal treatment with amiloride significantly increased the ICP. Phosphodiesterase type V isoform A1 activity was not affected by amiloride. Na⁺/H⁺ pump, ENaC, and Na⁺/Ca²⁺ exchanger mRNA expressions were all detected in rat CC tissues.

Clinical implication: Amiloride analogues may have therapeutic potential for erectile dysfunction.

Strength & limitations: The interesting effect of amiloride in penile erection was observed in both in vitro and in vivo methods. The evidence at the moment is restricted to rat CC.

Conclusion: Amiloride reduces in vitro CC contractility and enhances erectile function after oral and intraperitoneal administration, possibly via inhibition of ENaC. Campos R, Claudino MA, de Oliveira MG, et al. Amiloride Relaxes Rat Corpus Cavernosum Relaxation In Vitro and Increases Intracavernous Pressure In Vivo. J Sex Med 2019;16:500-511.

Keywords: Amiloride; Corpus Cavernosum; Penile Erection.