Abstract
Cardiac autonomic neuropathy is a prominent feature of endotoxemia. Given the defensive role of the cholinergic pathway in inflammation, we assessed the roles of central homomeric α7 and heteromeric α4β2 nAChRs in arterial baroreceptor dysfunction caused by endotoxemia in rats. Endotoxemia was induced by i.v. administration of lipopolysaccharides (LPS, 10 mg/kg), and baroreflex activity was measured by the vasoactive method, which assesses reflex chronotropic responses to increments (phenylephrine, PE) or decrements (sodium nitroprusside, SNP) in blood pressure. Shifts caused by LPS in PE/SNP baroreflex curves and associated decreases in baroreflex sensitivity (BRS) were dose-dependently reversed by nicotine (25–100 μg/kg, i.v.). The nicotine effect disappeared after intracisternal administration of methyllycaconitine (MLA) or dihydro-β-erythroidine (DHβE), selective blockers of α7 and α4β2 receptors, respectively. The advantageous effect of nicotine on BRSPE was replicated in rats treated with PHA-543613 (α7-nAChR agonist) or 5-iodo-A-85380 (5IA, α4β2-nAChRs agonist) in dose-dependent fashions. Conversely, the depressed BRSSNP of endotoxic rats was improved after combined, but not individual, treatments with PHA and 5IA. Central α7 and α4β2 nAChR activation underlies the nicotine counteraction of arterial baroreflex dysfunction induced by endotoxemia. Moreover, the contribution of these receptors depends on the nature of the reflex chronotropic response (bradycardia vs. tachycardia).
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Supporting raw data are publicly available in the Mendeley repository, as part of this record: https://data.mendeley.com/datasets/9mz3rbyppy/1 (El-Mas et al. 2022).
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ME and SE conceived and designed research. MS conducted experiments. MS and ME analyzed data. MS, SE, and ME wrote the manuscript. All authors read and approved the manuscript. The authors declare that all data were generated inhouse and that no paper mill was used.
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Sallam, M.Y., El-Gowilly, S.M. & El-Mas, M.M. Central α7 and α4β2 nicotinic acetylcholine receptors offset arterial baroreceptor dysfunction in endotoxic rats. Naunyn-Schmiedeberg's Arch Pharmacol 395, 1587–1598 (2022). https://doi.org/10.1007/s00210-022-02289-1
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DOI: https://doi.org/10.1007/s00210-022-02289-1