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Background: Chronic nicotine administration impairs reflex chronotropic responses that follow arterial baroreceptor unloading in female rats with repleted, but not depleted (ovariectomized, OVX), estrogen (E 2 ). 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 2 -sensitive depressant effect of nicotine on reflex tachycardia., Methods: 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)., Results: Nicotine (2 mg/kg/day ip, 14 days) reduced BRS in OVX rats treated with E 2 but not vehicle. Baroreceptor dysfunction in nicotine-treated OVXE 2 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 ERK (PD98059), MAPK p38 (SB203580) or MAPK JNK (SP600125). Likewise, sGC inhibition (ODQ) or E 2 receptor blockade (ICI182780) failed to alter the hemin effect., Conclusion: The activation of central NOS/PI3K signaling following HO upregulation improves the E 2 -dependent depressant effect of nicotine on reflex tachycardia., (Copyright © 2017 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier B.V. All rights reserved.)

We have previously reported that estrogen (E2) exacerbates the depressant effect of chronic nicotine on arterial baroreceptor activity in female rats. Here, we tested the hypothesis that this nicotine effect is modulated by nitric oxide synthase (NOS) and/or heme oxygenase (HO) and their downstream soluble guanylate cyclase (sGC)/phosphatidylinositol 3-kinase (PI3K)/mitogen-activated protein kinases (MAPKs) signaling. We investigated the effects of (i) inhibition or facilitation of NOS or HO on the interaction of nicotine (2mg/kg/day i.p., 2 weeks) with reflex bradycardic responses to phenylephrine in ovariectomized (OVX) rats treated with E2 or vehicle, and (ii) central pharmacologic inhibition of sGC, PI3K, or MAPKs on the interaction. The data showed that the attenuation by nicotine of reflex bradycardia in OVXE2 rats was abolished after treatment with hemin (HO inducer) or l-arginine (NOS substrate). The hemin or l-arginine effect disappeared after inhibition of NOS (Nω-Nitro-l-arginine methyl ester hydrochloride, L-NAME) and HO (zinc protoporphyrin IX, ZnPP), respectively, denoting the interaction between the two enzymatic pathways. E2-receptor blockade (ICI 182,780) reduced baroreflexes in OVXE2 rats but had no effect on baroreflex improvement induced by hemin or l-arginine. Moreover, baroreflex enhancement by hemin was eliminated following intracisternal (i.c.) administration of wortmannin, ODQ, or PD98059 (inhibitors of PI3K, sGC, and extracellular signal-regulated kinases, MAPKERK, respectively). In contrast, the hemin effect was preserved after inhibition of MAPKp38 (SB203580) or MAPKJNK (SP600125). Overall, NOS/HO interruption underlies baroreflex dysfunction caused by nicotine in female rats and the facilitation of NOS/HO-coupled sGC/PI3K/MAPKERK signaling might rectify the nicotine effect., (Copyright © 2015 Elsevier Inc. All rights reserved.)

We recently reported that chronic nicotine impairs reflex chronotropic activity in female rats. Here, we sought evidence to implicate nitric oxide synthase (NOS) and/or heme oxygenase (HO) in the nicotine-baroreflex interaction. Baroreflex curves relating changes in heart rate to increases (phenylephrine) or decreases (sodium nitroprusside) in blood pressure were generated in conscious female rats treated with nicotine or saline in absence and presence of pharmacological modulators of NOS or HO activity. Compared with saline-treated rats, nicotine (2 mg/kg/day i.p., for 14 days) significantly reduced the slopes of baroreflex curves, a measure of baroreflex sensitivity (BRS). Findings that favor the involvement of NOS inhibition in the nicotine effect were (i) NOS inhibition (Nω-Nitro-L-arginine methyl ester, L-NAME) reduced BRS in control rats but failed to do so in nicotine-treated rats, (ii) L-arginine, NO donor, reversed the BRS inhibitory effect of nicotine. Alternatively, HO inhibition (zinc protoporphyrin IX, ZnPP) had no effect on BRS in nicotine- or control rats and failed to reverse the beneficial effect of L-arginine on nicotine-BRS interaction. Similar to female rats, BRS was reduced by L-NAME, but not ZnPP, in male rats and the L-NAME effect was not accentuated after concomitant administration of nicotine. Baroreflex dysfunction caused by nicotine in female rats was blunted after supplementation with hemin (HO inducer) but not tricarbonyldichlororuthenium(II) dimer (CORM-2), a carbon monoxide (CO) releasing molecule, or bilirubin, the breakdown product of heme catabolism. The facilitatory effect of hemin was abolished upon simultaneous treatment with L-NAME or 1H-[1], [2], [4] oxadiazolo[4,3-a] quinoxalin-1-one (inhibitor of soluble guanylate cyclase, sGC). The activities of HO and NOS in brainstem tissues were also significantly increased by hemin. Thus, the inhibition of NOS, but not HO, accounts for the baroreflex depressant of chronic nicotine. Further, hemin alleviates the nicotine effect through a mechanism that is NOS/sGC but not CO or bilirubin-dependent.

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 nicotine-baroreflex 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 nicotine-treated rats, blockade of β-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.

We have previously shown that acute exposure of male rats to nicotine preferentially attenuates baroreceptor-mediated control of reflex tachycardia in contrast to no effect on reflex bradycardia. Here, we investigated whether female rats are as sensitive as their male counterparts to the baroreflex depressant effect of nicotine and whether this interaction is modulated by estrogen. Baroreflex curves relating reflex chronotropic responses evoked by i.v. doses (1-16 μg/kg) of phenylephrine (PE) or sodium nitroprusside (SNP), were constructed in conscious freely moving proestrus, ovariectomized (OVX), and estrogen (50 μg/kg/day s.c., 5 days)-replaced OVX (OVXE₂) rats. Slopes of the curves were taken as a measure of baroreflex sensitivity (BRS(PE) and BRS(SNP)). Nicotine (100 μg/kg i.v.) reduced BRS(SNP) in OVX rats but not in proestrus or OVXE₂ rats. The attenuation of reflex tachycardia by nicotine was also evident in diestrus rats, which exhibited plasma estrogen levels similar to those of OVX rats. BRS(PE) was not affected by nicotine in all rat preparations. Experiments were then extended to determine whether central estrogenic receptors modulate the nicotine-BRS(SNP) interaction. Intracisteral (i.c.) treatment of OVX rats with estrogen sulfate (0.2 μg/rat) abolished the BRS(SNP) attenuating effect of i.v. nicotine. This protective effect of estrogen disappeared when OVX rats were pretreated with i.c. ICI 182,780 (50 μg/rat, selective estrogen receptor antagonist). Together, these findings suggest that central neural pools of estrogen receptors underlie the protection offered by E₂ against nicotine-induced baroreceptor dysfunction in female rats., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Baroreflex dysfunction contributes to increased cardiovascular risk in cigarette smokers. Given the importance of adenosinergic pathways in baroreflex control, the hypothesis was tested that defective central adenosinergic modulation of cardiac autonomic activity mediates the nicotine-baroreflex interaction. Baroreflex curves relating changes in heart rate (HR) to increases or decreases in blood pressure (BP) evoked by i.v. doses (1-16μg/kg) of phenylephrine (PE) and sodium nitroprusside (SNP), respectively, were constructed in conscious rats; slopes of the curves were taken as measures of baroreflex sensitivity (BRS). Nicotine (25 and 100μg/kg i.v.) dose-dependently reduced BRS(SNP) in contrast to no effect on BRS(PE). BRS(SNP) was also attenuated after intracisternal (i.c.) administration of nicotine. Similar reductions in BRS(SNP) were observed in rats pretreated with atropine or propranolol. The combined treatment with nicotine and atropine produced additive inhibitory effects on BRS, an effect that was not demonstrated upon concurrent exposure to nicotine and propranolol. BRS(SNP) was reduced in preparations treated with i.c. 8-phenyltheophylline (8-PT, nonselective adenosine receptor antagonist), 8-(3-Chlorostyryl) caffeine (CSC, A(2A) antagonist), or VUF5574 (A(3) antagonist). In contrast, BRS(SNP) was preserved after blockade of A(1) (DPCPX) or A(2B) (alloxazine) receptors or inhibition of adenosine uptake by dipyridamole. CSC or 8-PT abrogated the BRS(SNP) depressant effect of nicotine whereas other adenosinergic antagonists were without effect. Together, nicotine preferentially impairs reflex tachycardia via disruption of adenosine A(2A) receptor-mediated facilitation of reflex cardiac sympathoexcitation. Clinically, the attenuation by nicotine of compensatory sympathoexcitation may be detrimental in conditions such as hypothalamic defense response, posture changes, and ventricular rhythms., (Copyright © 2011 Elsevier Inc. All rights reserved.)