Effect of cyproterone acetate on alpha1-adrenoceptor subtypes in rat vas deferens

Abstract

Gonadal hormones regulate the expression of α 1 -adrenoceptor subtypes in several tissues. The present study was carried out to determine whether or not cyproterone acetate, an anti-androgenic agent, regulates the α 1 -adrenoceptor subtypes that mediate contractions of the rat vas deferens in response to noradrenaline. The actions of subtype selective α 1 -antagonists were investigated in vas deferens from control and cyproterone acetate-treated rats (10 mg/day, sc, for 7 days). Prazosin (pA 2 ≈9.5), phentolamine (pA 2 ≈8.3) and yohimbine (pA 2 ≈6.7) presented competitive antagonism consistent with activation of α 1 -adrenoceptors in vas deferens from both control and treated rats. The pA 2 values estimated for WB 4101 (≈9.5), benoxathian (≈9.7), 5-methylurapidil (≈8.5), indoramin (≈8.7) and BMY 7378 (≈6.8) indicate that α 1A -adrenoceptors are involved in the contractions of the vas deferens from control and cyproterone acetate-treated rats. Treatment of the vas deferens from control rats with the α 1B /α 1D -adrenoceptor alkylating agent chloroethylclonidine had no effect on noradrenaline contractions, supporting the involvement of the α 1A -subtype. However, this agent partially inhibited the contractions of vas deferens from cyproterone acetate-treated rats, suggesting involvement of multiple receptor subtypes. To further investigate this, the actions of WB 4101 and chloroethylclonidine were reevaluated in the vas deferens from rats treated with cyproterone acetate for 14 days. In these organs WB 4101 presented complex antagonism characterized by a Schild plot with a slope different from unity (0.65 ± 0.05). After treatment with chloroethylclonidine, the complex antagonism presented by WB 4101 was converted into classical competitive antagonism, consistent with participation of α 1A -adrenoceptors as well as α 1B -adrenoceptors. These results suggest that cyproterone acetate induces plasticity in the α 1 -adrenoceptor subtypes involved in the contractions of the vas deferens.

Factors influencing biased agonism in recombinant cells expressing the human α1A‐adrenoceptor

“…α 1A ‐adrenoceptors are the main adrenoceptor subtype involved in the contractile responses to endogenous or exogenous agonists in the smooth muscle of the genitourinary system (Civantos Calzada and Aleixandre de Artinano, ) including the vas deferens (Campos et al, ), seminal vesicle (Silva et al, ), cauda epididymis (Queiroz et al, ) and prostate gland (Gray et al, ). This uroselectivity has driven the development of selective drugs for the treatment of benign prostatic hypertrophy (Ventura et al, ), and this receptor is also a target for male contraception (White et al, ).…”

Could α1-adrenoceptors and androgen receptors be modified by sexual maturation and testosterone in the rat testicular capsule?

“…Furthermore, it was observed that the remnant noradrenaline-induced contractions resistant to chloroethylclonidine treatment (40%) were readily blocked by an α 1A -antagonist 5-methyl-urapidil with high affinity (pA 2 of 8.8 to 8.9), in all conditions studied. It is well established that 5-methylurapidil interacts with higher affinity with α 1A -subtype (pA 2 of 9.0) than α 1B (pA 2 of 6.8) or α 1D (pA 2 of 7.3) subtypes (Ford et al 1997;Pupo et al 1997;Queiróz et al 2002;Campos et al 2003;Jurkiewicz et al 2006). Thus, these results indicate that noradrenaline-induced contractions of the testicular capsule are mediated by functional postsynaptic α 1A and α 1B -adrenoceptors, but pharmacological properties of these receptors were not influenced by sexual maturation or testosterone treatment.…”

“…hormones are able to modulate the expression and/or function of α 1 -adrenoceptor subtypes in reproductive tissues (Queiroz et al 1999;Campos et al 2003). Campos et al (2003) showed that noradrenaline-induced contractions in the rat vas deferens are mediated by α 1 -adrenoceptor subtypes and this response is affected by in vivo treatment with cyproterone acetate, an anti-androgenic agent.…”

“…Campos et al (2003) showed that noradrenaline-induced contractions in the rat vas deferens are mediated by α 1 -adrenoceptor subtypes and this response is affected by in vivo treatment with cyproterone acetate, an anti-androgenic agent. In fact, high affinity (pA 2 values) for prazosin (9.5), WB 4101 (9.5), benoxathian (9.7), indoramin (8.7), 5 -methyl-urapidil (8.5) and phentolamine (8.3), and low affinity for BMY 7378 (6.8) and yohimbine (6.7) were found in control and cyproterone acetate-treated vas deferens which is consistent with the main involvement of α 1A -, but not α 1B -or α 1D -adrenoceptor subtypes in these responses (Campos et al 2003).…”

“…Campos et al (2003) showed that noradrenaline-induced contractions in the rat vas deferens are mediated by α 1 -adrenoceptor subtypes and this response is affected by in vivo treatment with cyproterone acetate, an anti-androgenic agent. In fact, high affinity (pA 2 values) for prazosin (9.5), WB 4101 (9.5), benoxathian (9.7), indoramin (8.7), 5 -methyl-urapidil (8.5) and phentolamine (8.3), and low affinity for BMY 7378 (6.8) and yohimbine (6.7) were found in control and cyproterone acetate-treated vas deferens which is consistent with the main involvement of α 1A -, but not α 1B -or α 1D -adrenoceptor subtypes in these responses (Campos et al 2003). Treatment with chloroethylclonidine had no effect in control vas deferens, but reduced noradrenalineinduced contractions in tissues from cyproterone acetate-treated rats, indicating that noradrenaline-induced contractions are related to the activation of single (α 1A -adrenoceptors) and multiple (α 1A -and α 1B -adrenoceptor) populations of α 1 -adrenoceptors in control and cyproterone acetate-treated vas deferens, respectively (Campos et al 2003).…”