Abstract
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 (N ω-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.
Highlights
Cigarette smoking is among the top ten contributors of morbidity and mortality in the world [1]
The current study investigated the interesting possibility that the interruption of the nitric oxide synthase (NOS)/Nitric oxide (NO) and heme oxygenase (HO)/carbon monoxide (CO) pathways accounts for the baroreflex depressant effect of nicotine
The data showed that the interruption of NOS signaling contributes, at least partly, to the inhibitory effect of nicotine on baroreflex gain because (i) pharmacologic NOS inhibition by L-NAME mimicked the baroreflex depressant effect of nicotine, and (ii) concomitant exposure to nicotine and L-NAME elicited no additional reductions in baroreflex sensitivity (BRS), and (iii) supplementation with the NOS substrate L-arginine mitigated the BRS depressant effect of nicotine
Summary
Cigarette smoking is among the top ten contributors of morbidity and mortality in the world [1] It predisposes to several cardiovascular diseases including hypertension, coronary heart disease and myocardial infarction [2]. NO increases the expression of HO-1 in endothelial and vascular smooth muscle cells [19] Unlike this seemingly synergistic interaction between NO and CO, contrasting biological effects for the two systems have been described [20]. Despite the importance of NOS/HO signaling in the control of arterial baroreflexes as detailed earlier, there has been no study to our knowledge that evaluated whether the interruption of these pathways or their mutual interactions contributes to the nicotineevoked baroreflex dysfunction. 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]
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