Estrogen dependence of the renal vasodilatory effect of nicotine in rats: Role of α7 nicotinic cholinergic receptor/eNOS signaling

Abstract

Aims We recently reported that acute exposure to nicotine vasodilates the renal vasculature of male rats via facilitation of endothelial nitric oxide synthase (eNOS). In this study, we investigated whether this effect of nicotine is sexually dimorphic and the role of estrogen in modulating the nicotine effect. Main methods Nicotine-evoked vasodilation was evaluated in phenylephrine-preconstricted perfused kidneys obtained from male, proestrus female, ovariectomized (OVX) and estrogen-replaced OVX (OVXE2) rats. Key findings Nicotine infusion (5×10−5, 1×10−4, and 5×10−4 M) produced greater concentration-dependent reductions in the renal perfusion pressure (RPP) in isolated kidney from proestrus females than from males. Inhibition of NOS by NG-nitro-L-arginine abolished the nicotine-evoked reduction in RPP and abolished the gender difference in the nicotine effect. Nicotine vasodilation was also attenuated in kidneys isolated from OVX and diestrus rats, models characterized by reduced estrogen levels. Further, estrogen or L-arginine supplementation in OVX rats largely restored the renal vasodilatory response to nicotine. Estrogen receptor blockade by tamoxifen abrogated the enhanced nicotine-evoked vasodilation elicited by E2 in OVX rats. The nitrite/nitrate levels and protein expressions of eNOS and α7 nicotinic cholinergic receptor (α7 nAChRs) were significantly higher in renal tissues of OVXE2 compared with OVX rats, suggesting a facilitatory effect for E2 on α7 nAChRs/eNOS signaling. Significance Estrogen-dependent facilitation of NOS signaling mediates the enhanced vasodilator capacity of nicotine in the renal vasculature of female rats. Preliminary evidence also suggests a potential role for α7 nAChRs in this estrogen-dependent phenomenon.

Therapeutic Potential ofα7 Nicotinic Acetylcholine Receptors

“…In addition, studies need to be performed across species, age, and sex to ensure consistent results and to account for the sex differences noted in both preclinical (Kang et al, 2014) as well as clinical studies demonstrating that sex plays a role in the prediction of renal decline (Halbesma et al, 2008). From preclinical studies, the sex difference Therapeutic Potential of a7 nAChRs resulted in greater renovascular vasodilation in female rat kidney tissue with the suggestion that it could be facilitated by estrogen having a direct effect on a7 nAChR downstream signaling (El-Mas et al, 2011).…”

The Non-Neuronal Cholinergic System in Health and Disease

“…It is assumed that ACh acts directly on renal tubules, glomeruli and Bowman's capsule via binding to cholinergic receptors. Both, nAChR as well as mAChR were expressed in several renal regions [119,120,121,122,123,124,125,126]. Only few reports are available on the involvement of molecular components of the cholinergic system in renal pathologies.…”

Estrogen Provokes the Depressant Effect of Chronic Nicotine on Vagally Mediated Reflex Chronotropism in Female Rats

“…The last dose of 17␤-estradiol was administered 24 h before the experiment. This dose regimen of 17␤-estradiol has been shown in our previous studies to produce physiological estrogen levels , 2011b. Rats in the OVX group received the vehicle (sesame oil) instead of 17␤-estradiol.…”

“…Diestrus rats exhibit significantly lower estrogen levels compared with proestrus rats (El-Mas et al, 2011b). The phase of the cycle was identified through microscopic examination of vaginal smears.…”