Department of Pharmacology and Toxicology, Faculty of Pharmacy, Alexandria University, Egypt.
Department of Pharmacology and Toxicology, Faculty of Pharmacy, Alexandria University, Egypt.
Pharmacol Rep. 2018 Jun;70(3):455-462. doi: 10.1016/j.pharep.2017.09.008. Epub 2017 Oct 3.
Chronic nicotine administration impairs reflex chronotropic responses that follow arterial baroreceptor unloading in female rats with repleted, but not depleted (ovariectomized, OVX), estrogen (E). This study investigated whether products of nitric oxide synthase (NOS) and/or heme oxygenase (HO) and related soluble guanylate cyclase (sGC)/phosphatidylinositol 3-kinase (PI3K)/mitogen-activated protein kinases (MAPKs) signaling mediate the E-sensitive depressant effect of nicotine on reflex tachycardia.
Baroreflex curves relating reflex tachycardic responses to falls in blood pressure (BP) generated by sodium nitroprusside (SNP) were established in conscious female rats and slopes of the curves were taken as measures of baroreflex sensitivity (BRS).
Nicotine (2 mg/kg/day ip, 14 days) reduced BRS in OVX rats treated with E but not vehicle. Baroreceptor dysfunction in nicotine-treated OVXE rats was abolished after iv treatment with hemin (HO inducer) but not l-arginine (NOS substrate) denoting the importance of reduced availability of carbon monoxide, but not NO, in the nicotine effect. The favorable BRS effect of hemin was abolished after intracisternal (ic) administration of L-NAME (NOS inhibitor) or wortmannin (PI3 K inhibitor). Central circuits of MAPKs do not seem to contribute to the baroreflex facilitatory effect of hemin because the latter was preserved after central inhibition of MAPK (PD98059), MAPK (SB203580) or MAPK (SP600125). Likewise, sGC inhibition (ODQ) or E receptor blockade (ICI182780) failed to alter the hemin effect.
The activation of central NOS/PI3K signaling following HO upregulation improves the E-dependent depressant effect of nicotine on reflex tachycardia.
慢性尼古丁给药会损害雌性大鼠在动脉压力感受器去负荷后的反射性变时反应，而这种作用在补充（卵巢切除，OVX）而不是耗竭（OVX）雌激素（E）的雌性大鼠中被抑制。本研究旨在探究一氧化氮合酶（NOS）和/或血红素氧合酶（HO）产物以及相关的可溶性鸟苷酸环化酶（sGC）/磷酸肌醇 3-激酶（PI3K）/丝裂原激活蛋白激酶（MAPK）信号转导是否介导了 E 敏感的尼古丁对反射性心动过速的抑制作用。
在清醒雌性大鼠中建立与血压（BP）下降相关的反射性心动过速反应的压力感受器反射曲线，并将曲线的斜率作为压力感受器敏感性（BRS）的衡量标准。
在给予 E 的 OVX 大鼠中，尼古丁（2mg/kg/天，ip，14 天）降低了 BRS，但在给予载体的大鼠中没有。在给予静脉注射血红素（HO 诱导剂）后，在给予尼古丁的 OVXE 大鼠中，压力感受器功能障碍被消除，但给予 l-精氨酸（NOS 底物）后并未消除，这表明在尼古丁的作用中，一氧化碳的可用性降低，而不是 NO。血红素对 BRS 的有利影响在给予 cisternal（ic）L-NAME（NOS 抑制剂）或wortmannin（PI3K 抑制剂）后被消除。MAPK 的中枢回路似乎对血红素的压力感受器易化作用没有贡献，因为后者在 MAPK（PD98059）、MAPK（SB203580）或 MAPK（SP600125）的中枢抑制后仍然存在。同样，sGC 抑制（ODQ）或 E 受体阻断（ICI182780）也未能改变血红素的作用。
HO 上调后中枢 NOS/PI3K 信号的激活改善了 E 依赖性的尼古丁对反射性心动过速的抑制作用。
