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Nicotinic Acetylcholine Receptors of α7 and α4β2 Types Mediate the Nicotine Counteraction of Impaired Baroreceptor Function in Endotoxic Rats

Autonomic dysfunction and reduced arterial baroreceptor activity are prominent features of sepsis. Given the defensive role of the cholinergic antiinflammatory pathway against endotoxic manifestations, agonist and antagonist studies were employed in the current study to identify the roles of α7 and α4β2 nAChRs in impaired reflex chronotropic function caused by endotoxemia in conscious male rats. Endotoxemia was induced by i.v. administration of lipopolysaccharides (LPS, 10 mg/kg) and baroreflex activity was measured by the vasoactive method. The latter involves the assessment of reflex chronotropic responses evoked by increases (phenylephrine, PE) or decreases (sodium nitroprusside, SNP) in blood pressure. Slopes of baroreflex curves were taken as a measure of baroreflex sensitivity (BRS). The data showed that the shifts caused by LPS in baroreflex curves generated by PE or SNP as well as the associated decreases in slopes of the curves (BRSPE, from −2.0±0.2 to −1.2±0.1 beats/min/mmHg; BRSSNP, from −3.7±0.3 to −2.1±0.2 beats/min/mmHg) were dose‐dependently reversed by subsequent i.v. administration of nicotine (25, 50, or 100 μg/kg). Such nicotine effects disappeared after selective blockade of α7‐nAChRs or α4β2‐nAChRs by intracisternal administration of methyllycaconitine (MLA) and dihydro‐β‐erythroidine (DHβE), respectively. We also report that the corrective effects of nicotine on BRSPE were replicated in rats treated with i.v. PHA‐543613 (α7‐nAChR agonist; 0.2–2.0 mg/kg) or 5‐iodo‐A‐85380 (5IA, α4β2‐nAChRs agonist; 0.01–0.1 mg/kg) in dose‐related fashions. Conversely, while the depressed BRSSNP of endotoxic rats was preserved after individual treatment with PHA or 5IA, improved BRSSNP was only seen after the combined exposure to the two drugs. Collectively, functional α7 or α4β2 nAChRs is essential for the demonstration of the alleviation by nicotine of baroreflex dysfunction induced by endotoxemia. Moreover, the precise roles of the homomeric α7 and heteromeric α4β2 nAChRs depend on the nature of the reflex chronotropic response (bradycardia vs. tachycardia).