Department of Pharmacology and Toxicology, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt.
Eur J Pharmacol. 2013 Jun 15;710(1-3):1-9. doi: 10.1016/j.ejphar.2013.04.011. Epub 2013 Apr 23.
We tested the hypothesis that nitric oxide synthase (NOS) and/or heme oxygenase (HO) modulate the hormonally-dependent nicotine interaction with adenosine receptor-mediated renal vasodilations. Vasodilations caused by 5'-N-ethylcarboxamidoadenosine (NECA) in phenylephrine-preconstricted perfused kidneys were reduced in ovariectomized (OVX) rats and restored to sham levels after treatment with estrogen (E2), medroxyprogesterone acetate (MPA) or their combination. The facilitatory action of E2 or MPA was abolished after blockade of their respective receptors by ICI-182780 and mifepristone, or inhibition of NOS (N(ω)-nitro-L-arginine-methyl ester, L-NAME) but not HO (zinc protoporphyrin, ZnPP). NECA vasodilations were (i) decreased and increased by nicotine (1 mg/kg/day, 2 weeks) in OVX/MPA and OVX/E2 kidneys, respectively, and (ii) resistant to nicotine in females with deficient (OVX) or balanced (sham or E2/MPA-replaced OVX) hormonal milieu. The attenuation of NECA responses by nicotine in OVX/MPA kidneys disappeared after treatment with hemin (HO inducer) but not L-arginine (NOS substrate). Alternatively, nicotine enhancement of NECA responses in OVX/E2 kidneys was abolished following treatment with ICI 182780 or L-NAME. Overall, the NOS-coupled E2/progesterone receptor contributes to the enhancement of NECA vasodilations by ovarian hormones. Further, HO inhibition and NOS facilitation mediate the directionally opposite effects of nicotine on NECA responses in MPA- or E2-replaced OVX rats, respectively.
我们检验了这样一个假设，即一氧化氮合酶（NOS）和/或血红素加氧酶（HO）调节了尼古丁与腺苷受体介导的肾血管舒张之间的激素依赖性相互作用。在去卵巢（OVX）大鼠的苯肾上腺素预收缩的灌注肾脏中，5'-N-乙基羧酰胺腺苷（NECA）引起的血管舒张减少，并且在用雌激素（E2）、醋酸甲羟孕酮（MPA）或它们的组合处理后恢复到假手术水平。E2 或 MPA 的促进作用在其各自的受体被 ICI-182780 和米非司酮阻断后或在 NOS（N（ω）-硝基-L-精氨酸甲酯，L-NAME）被抑制但 HO（锌原卟啉，ZnPP）不被抑制后被消除。NECA 血管舒张在以下情况下分别减少和增加：（i）在 OVX/MPA 和 OVX/E2 肾脏中，尼古丁（1mg/kg/天，2 周）减少和增加，以及（ii）在缺乏（OVX）或平衡（假手术或 E2/MPA 替代 OVX）激素环境的雌性中对尼古丁有抗性。在 OVX/MPA 肾脏中，尼古丁对 NECA 反应的衰减在给予血红素（HO 诱导剂）后消失，但在给予 L-精氨酸（NOS 底物）后不消失。相反，在 OVX/E2 肾脏中，尼古丁增强 NECA 反应的作用在给予 ICI 182780 或 L-NAME 后被消除。总体而言，NOS 偶联的 E2/孕激素受体有助于卵巢激素增强 NECA 血管舒张。此外，HO 抑制和 NOS 促进分别介导了尼古丁对 MPA 或 E2 替代 OVX 大鼠中 NECA 反应的方向相反的作用。
