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

Abstract

This study examines the effect of male sex hormones on the release, metabolism and function of endothelial nitric oxide (eNO) in rat aorta. Aortic segments from orchidectomized and control male Sprague-Dawley rats were used to measure eNO synthase (eNOS) expression, nitric oxide (NO) release, acetylcholine (ACh)-and sodium nitroprusside (SNP)-induced relaxation and Cu/Zn-superoxide dismutase (SOD) expression and activity. eNOS expression as well as basal and ACh-induced NO release were similar in arteries from both groups of rats. Basal superoxide anion production was similar in arteries from both groups, while ACh-induced superoxide anion formation was greater in arteries from orchidectomized than control rats. Orchidectomy increased the vasodilator effect induced by ACh, but did not alter that induced by SNP. SOD, a superoxide anion scavenger, did not modify the SNP-induced relaxation in aortas from control or orchidectomized rats. The membrane-permeable mimetic of SOD, tempol, increased the SNP-induced relaxation more in aortas from orchidectomized than control rats. The effect of endogenous SOD inhibitor, diethyl-dithiocarbamate, reduced the relaxation induced by SNP in segments from both groups of rats. The expression and activity of Cu/Zn-SOD were greater in aortas from orchidectomized than control rats. These data show that endogenous male sex hormone deprivation altered neither eNOS expression nor eNO release, while it increased the expression and activity of Cu/Zn-SOD. However, the predominant vascular effect of orchidectomy is to increase NO metabolism.

Androgens and Vascular Function

“…As above commented, we have previously demonstrated that EFS induced similar contractile response (Fig.1) in mesenteric arteries from control and orchidectomized rats, responses that appear to be mediated by NA release from adrenergic nerve terminals and the subsequent activation of α-adrenoceptors (Martín et al, 2005); in addition, we found that the contractile response to exogenous NA was decreased by orchidectomy, suggesting the EFS could increase NA release in arteries from orchidectomized rats; however, we later demonstrated the EFSinduced NA release was not modified by orchidectomy (Blanco-Rivero et al, 2006) which indicated that other vasoconstrictor factors could be released when the artery was electrically stimulated. We observed that the EFS induced a greater TXA 2 formation in arteries from orchidectomized than control rats, which was in line with other reports showing increased TXA 2 release after activation of muscarinic or α 2 -adrenoceptors (Blanco-Rivero et al, 2006), and it confirmed the endothelial and smooth muscle cells as sources of TXA 2 production. The increased TXA 2 release could be the contractile factor that was released when the artery is electrically stimulated, and explains the non modification of the EFS-induced response in arteries from control and orchidectomized rats, in spite of the fact that the NA response was diminished in arteries from the latter animals.…”

“…Others researchers have demonstrated that androgens increased (Orshal & Khalil, 2004;Wynne & Khalil, 2003) and decreased (Ba et al, 2001;Gonzales et al, 2004) the vasodilator effect of endothelial NO. In our experimental rat model, we have found that the release of endothelial NO was not modified by orchidectomy, either in mesenteric artery or aorta (Blanco-Rivero et al, 2006). However, orchidectomy reduced the endothelium-dependent vasodilator response induced by Acetylcholine (Ach) in mesenteric artery while increased in rat aorta (Fig.…”

“…Thus, a decrease (Guan &Dluzen, 1991;Holmquist et al, 1994), an increase (Shan & Dluzen, 2002;Siddiqui & Shah, 1997) and no modification (Agostini et al, 1981;Chen et al, 1999) of NA release have been reported in orchidectomized male animals. In a later study we demonstrated that the NA release was not modified by orchidectomy (Blanco-Rivero et al, 2006). Since sex hormone modulation of the calcitonin gene related peptide (CGRP) system has been described (Sun et al, 2001), and that the CGRP, the essential neurotransmitter in sensory nerves (Kawasaki et al, 1988), had been proposed to play a role in vascular tone regulation, the participation of sensory innervation in the vasomotor response to EFS was assessed by the use of capsaicin, which selectively depletes the sensory nerves of the neurotransmitter (Li & Duckles, 1992).…”

“…However, little information is available on the effect of androgens on vascular effects of endogenous TXA 2. Thus, orchidectomy has been reported to either decrease (Gonzales et al, 2005) or not modify (Blanco-Rivero et al, 2006) TXA 2 synthase expression. Likewise, the contractile effect induced by the TXA 2 mimetic, U-46619, was not modified by orchidectomy in mesenteric (Blanco-Rivero et al, 2006) and cerebral (Gonzales et al, 2005) rat arteries.…”

“…Thus, orchidectomy has been reported to either decrease (Gonzales et al, 2005) or not modify (Blanco-Rivero et al, 2006) TXA 2 synthase expression. Likewise, the contractile effect induced by the TXA 2 mimetic, U-46619, was not modified by orchidectomy in mesenteric (Blanco-Rivero et al, 2006) and cerebral (Gonzales et al, 2005) rat arteries. On the other hand, the role of COX-derivates, other than TXA 2 , such as prostaglandin (PG) I 2 , PGF 2α and PGE 2 , which can act as vasoconstrictors under certain pathological conditions, is the objective of numerous studies (Félétou et al, 2010;Gluais et al, 2005;Rapoport & Williams, 1996).…”