The α7‐nAChRs/heme oxygenase/carbon monoxide pathway arbitrates nicotine counteraction of the inflammatory and renal vasoconstrictor hyporeactivity in endotoxic rats

Abstract

The nicotinic/cholinergic antiinflammatory pathway plays integral roles in physiological and pathological regulation of inflammation. In this study, we tested the hypotheses that (i) nicotine guards against hemodynamic and renal vasoconstrictor dysfunction induced by endotoxemia in rats, and (ii) the α7‐nAChRs/heme oxygnase (HO) pathway constitutes a go‐between for the LPS‐nicotine interaction. Hemodynamic or renovascular functions were assessed 6 hr after i.p. administration of lipopolysaccharide (LPS, 5 mg/kg) with or without nicotine. LPS caused significant falls in systolic blood pressure (SBP) and reductions in cumulative renal vasoconstrictions induced by bolus injections of phenylephrine (PE, 0.002 – 4.42 nmol) or vasopressin (VP, 0.00092 – 0.27 nmol) into isolated perfused kidneys. LPS hypotension was demonstrated in both male and female rats, whereas the attenuation of renal vasoconstrictions was seen in male rats only. The reduced PE or VP responsiveness was reversed in preparations pretreated with nicotine (0.5, 1 and 2 mg/kg) in a dose‐dependent manner. This favorable action of nicotine disappeared after blockade of α7‐nAChRs (methyllycaconitine citrate, 2 mg/kg) or inhibition of HO‐1 (zinc protoporphyrin, 10 mg/kg). Moreover, the LPS attenuation of renal vasoconstrictions was improved upon concurrent treatment with pentoxfylline (TNFα inhibitor, 3 mg/kg), hemin (HO‐1 inducer, 10 mg/kg), tricarbonyldichlororuthenium (II) dimer (carbon monoxide‐releasing molecule, 10 mg/kg), in contrast to no effect for bilirubin (5 mg/kg). These data establish the first evidence that implicate the α7‐nAChRs/HO‐1/CO in the nicotine counteraction of renal vasoconstrictor hyporeactivity in endotoxemia.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.