Central Cholinergic Pathways Diminish the Hypotensive and Cardiac Autonomic Depressant Effects of Endotoxemia in Male Rats: Role of Medullary NFκB/α7/α4β2 nAChR Signaling

Abstract

We have recently shown that systemically administered nicotine improves endotoxic manifestations of hypotension and cardiac autonomic dysfunction in rats. In this report, integrative and molecular studies were employed to investigate whether medullary antiinflammatory pathways of α7 and α4β2 nicotinic acetylcholine receptors (nAChRs) modulate cardiovascular derangements induced by endotoxemia. The i.v. administration of nicotine (50 mg/kg) to conscious rats abolished the lipopolysaccharide (LPS, 10 mg/kg i.v.)‐evoked: (i) falls in blood pressure, (ii) decreases in spectral measure of cardiac sympathovagal balance (ratio of the low‐frequency to high‐frequency power, LF/HF) and (iii) increases in the immunohistochemical protein expression of NFκB in medullary neurons of the nucleus tractus solitarius (NTS). These favorable influences of nicotine were replicated in rats treated intracisternally (i.c.) with PHA‐543613 (selective α7 nAChR agonist; 2 μg/rat), or 5‐iodo‐A‐85380 (5IA, selective α4β2 nAChRs agonist; 0.1 μg/rat). Measurement of arterial baroreflex activity by the vasoactive method revealed that nicotine, PHA, or 5IA reversed the depressant effect of LPS on reflex bradycardic, but not tachycardic, activity. Pharmacologic antagonist studies showed that the reversing effect of nicotine on LPS hypotension was partly inhibited in rats treated concomitantly with i.c. methyllycaconitine citrate salt hydrate (α7 nAChR antagonist, 10 μg/rat) or dihydro‐β‐erythroidine hydrobromide (α4β2 nAChR antagonist, 10 μg/rat), whereas the associated increases in LF/HF ratio remained unaltered. The data signifies the importance of the NTS inflammatory pathways in cardiovascular endotoxic manifestations and the capacity of brainstem circuits of α7 and α4β2 nAChRs in ameliorating these responses.Support or Funding InformationSupported by the Science and Technology Development Fund, Egypt (STDF Grant No. 14895)This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.