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

Abstract

We recently reported that acute nicotine impairs reflex tachycardic activity in estrogen-depleted, but not estrogen-repleted, female rats, suggesting a restraining influence for estrogen against the nicotine effect. In this study, we tested whether the baroreflex-protective effect of estrogen can be replicated when nicotine was administered chronically. We also report on the dose dependence and autonomic modulation of the nicotinebaroreflex interaction. The effects of nicotine (0.5, 1, or 2 mg/ kg/day for 14 days) on baroreflex curves relating changes in heart rate to increases [phenylephrine (PE)] or decreases [sodium nitroprusside (SNP)] in blood pressure were evaluated in sham-operated (SO), ovariectomized (OVX), and estrogen-replaced OVX (OVXE 2 ) rats. Slopes of the curves were taken as a measure of baroreflex sensitivity (BRS PE and BRS SNP ). In SO rats, both reflex bradycardic and tachycardic responses were attenuated by nicotine in a dose-related fashion. In nicotinetreated rats, blockade of ␤-adrenergic (propranolol), but not muscarinic (atropine), receptors caused additional reductions in reflex chronotropic responses, implying that nicotine selectively impairs reflex vagal activity. OVX selectively decreased BRS PE but not BRS SNP and abolished the nicotine-induced impairment of either response. These effects of OVX were reversed after treatment with estrogen or the estrogen receptor modulator raloxifene. In atropine-treated rats, comparable BRS values were demonstrated in all rat preparations regardless of the estrogen or nicotine milieu. Collectively, the inhibition of vagal activity accounts for the depressant effect of chronic nicotine on baroreflex activity. Furthermore, contrary to nicotine's acute effects, the baroreflex-attenuating effect of chronic nicotine is exacerbated by estrogen.

Celecoxib, but not indomethacin, ameliorates the hypertensive and perivascular fibrotic actions of cyclosporine in rats: Role of endothelin signaling

“…SBP of rats was measured before, and 5 and 10 days after administration of drugs using a computerized data acquisition system with LabChart-7 pro software (Power Lab 4/30, model ML866/P, AD Instruments, Bella Vista, Australia) as in our previous studies (El-Mas et al, 2012a). Heart rate (HR) was computed from BP waveforms and displayed on another channel of the recording system.…”

Impairment of Nitric Oxide Synthase but Not Heme Oxygenase Accounts for Baroreflex Dysfunction Caused by Chronic Nicotine in Female Rats

“…drug administration. A dose of 2 mg/kg/day of nicotine was given for two weeks, which has been shown in our previous studies to produce plasma cotinine levels [7] similar to those achieved in humans after moderate cigarette smoking [23], [24].…”

“…Baroreflex sensitivity was assessed by a modified Oxford (vasoactive) method [31] where changes in HR derived from BP waveforms were correlated to changes in MAP caused by vasopressor and vasodepressor agents [7], [10]–[12], [25]. This method measures the bradycardic or tachycardic responses to reciprocal peripherally-mediated BP changes evoked by bolus i.v.…”

“…The ratio ΔHR/ΔMAP was taken as a measure of BRS as described in our previous studies [7]. The data obtained from this experiment are included in file S1 and in figure S1.…”

“…Nicotine diminishes the baroreflex gain through direct interaction with central mechanisms integrating the baroreceptor input into autonomic responses [5] or via reducing arterial compliance and stretch receptor responsiveness [6]. In a recent study, we presented the first experimental evidence that chronic nicotine dose-dependently attenuated reflex heart rate (HR) responses in female rats through a mechanism that involved the inhibition of the estrogen-mediated vagal facilitation [7].…”