Androgen deprivation facilitates acetylcholine-induced relaxation by superoxide anion generation

Abstract

The aim of the present study was to assess the role of superoxide anions in the relaxation induced by acetylcholine (ACh) in aortic segments from male rats, and to investigate if their production is altered by sex hormone deprivation. In segments precontracted with 10 nmol/l noradrenaline, ACh (0.1 nmol/l-10 micromol/l) induced concentration-dependent relaxation, which was greater in segments from castrated compared with control animals. ACh-induced relaxation was abolished in segments from control rats, and reduced in those from castrated rats, by 0.1 mmol/l N(G)-nitro-L-arginine methyl ester (L-NAME; a nitric oxide synthase inhibitor). Indomethacin (1 micromol/l; a cyclo-oxygenase blocker) decreased the ACh-induced relaxation in arteries from control males only. Incubation of segments with superoxide dismutase (SOD; 100 units/ml; a superoxide anion scavenger) enhanced and reduced relaxation in segments from control and castrated animals respectively. For arteries from castrated animals, the presence of SOD plus L-NAME abolished such responses. In these arteries, incubation with L-NAME abolished the relaxation caused by ACh when the segments were precontracted with 30 mmol/l KCl. In segments obtained from castrated rats and pretreated with L-NAME, 1 mmol/l tetraethylammonium or 0.4 micromol/l charybdotoxin [blockers of Ca(2+)-sensitive and large-conductance Ca(2+)-sensitive (BK(Ca)) K(+) channels respectively] abolished the relaxation induced by ACh. These results suggest that ACh generates endothelial NO and superoxide anions from the arterial wall in both control and castrated animals; these agents negatively modulate ACh-induced relaxation in control rats by destruction of NO, and positively modulate ACh-induced relaxation in castrated rats by activation of BK(Ca) channels.

Orchidectomy increases expression and activity of Cu/Zn-superoxide dismutase, while decreasing endothelial nitric oxide bioavailability

“…In a previous work, we found a dual behaviour of superoxide anion depending on the presence/absence of endogenous male sex hormones, in such a way that in aortas from control rats superoxide anions were involved in metabolising the ACh-induced NO, while in arteries from orchidectomized rats superoxide anion-induced vasorelaxation through K Ca channels activation (Ferrer et al 1999). These findings would explain why the sensitivity of smooth muscle cells to eNO was similar in aortas from control and orchidectomized rats; despite the ACh-induced vasodilator response was greater in aortas from orchidectomized rats (Ferrer et al 1999). We now analysed the superoxide anion formation in aortas from control and orchidectomized rats.…”

“…In a previous study, we described how ACh-induced relaxation was greater in aortas from orchidectomized than control male rats, and showed the involvement of superoxide anion vasodilatory action through BK Ca channel activation (Ferrer et al 1999). Since there is a lack of studies analysing the effect of endogenous male sex hormones on the whole NO pathway in the same experimental conditions, we have now analysed the possible regulation by endogenous male sex hormones of: (1) eNOS expression, (2) eNO release induced by ACh and (3) NO metabolism, taking into account both the production and the removal of superoxide anion.…”

“…The next step was to compare the possible functional role of superoxide anion and endogenous SOD in vessels from orchidectomized and control rats. Since the modulation of eNO release by K channels activation has been reported (Qiu & Quilley 2001, Gendron et al 2004, and taking into account that we have previously demonstrated the BK Ca channel activation by superoxide anion (Ferrer et al 1999), to avoid misinterpretation the vascular function of these anions was analysed in endothelium-denuded aorta.…”

Oxidant stress-induced increase in myogenic activation of skeletal muscle resistance arteries in obese Zucker rats

“…However, the majority of existing studies suggest that superoxide anion can activate K Ca channels in numerous tissues, thus increasing the K ϩ current leading to membrane hyperpolarization (6,9,29,30). These previous observations can be difficult to reconcile with the present data, where elevated oxidant tone is associated with increased myogenic activation.…”

The influence of testosterone upon vascular reactivity

“…The lower level of endogenous testosterone in these two patient groups may result in upregulation of the AR, through which a beneficial action upon the vascular endothelium may be exerted. In agreement with this hypothesis, castrated male rats exhibit increased endothelial-dependent dilatory responses to acetylcholine (as in castrated/ hypogonadal men) (36), while testosterone deficiency combined with a mutated, non-functional AR in the testicular feminised mouse is associated with reduced endothelial-dependent vasodilatation (42).…”