Hemin blunts the depressant effect of chronic nicotine on reflex tachycardia via activation of central NOS/PI3K pathway in female rats

Background

Chronic nicotine administration impairs reflex chronotropic responses that follow arterial baroreceptor unloading in female rats with repleted, but not depleted (ovariectomized, OVX), estrogen (E₂). 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 E₂-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 E₂ but not vehicle. Baroreceptor dysfunction in nicotine-treated OVXE₂ 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 E₂ receptor blockade (ICI182780) failed to alter the hemin effect.

Conclusion

The activation of central NOS/PI3K signaling following HO upregulation improves the E₂-dependent depressant effect of nicotine on reflex tachycardia.