The Compromised Renal Vasodilations of Adenosinergic Origin in Endotoxic Rats is Reversed by Nicotine: Role of the nAChRs/Heme Oxygenase‐1 Pathway

Abstract

The nicotinic/cholinergic antiinflammatory pathway protects against acute kidney injury and other end organ damages induced by endotoxemia. In this study we tested the hypothesis that functional α7‐nAChRs/heme oxygnase (HO) pathway is imperative for the nicotine counteraction of renovascular dysfunction caused by endotoxemia in rats. Renal vasodilations were induced by cumulative bolus injections of acetylcholine (ACh, 0.01–7.29 nmol) or ethylcarboxamidoadenosine (NECA, adenosine receptor agonist, 1.6–100 nmol) in isolated phenylephrine‐preconstricted perfused kidneys. The data showed that 6‐hr treatment with i.p. lipopolysaccharide (LPS, 5 mg/kg) elevated biochemical indices of renal function (serum urea and creatinine) and reduced renal vasodilations caused by NECA. The specificity of the LPS interaction with NECA responses was indicated by the lack of similar attenuation in renal vasodilations induced by ACh. Additionally, the LPS effects were not sex‐related because they were observed in both male and female preparations. The attenuated vasodilatory action of NECA and elevated biomarkers of kidney function in endotoxic rats were reversed upon concurrent treatment with bilirubin (5 mg/kg), but not hemin (HO‐1 inducer, 10 mg/kg) or tricarbonyldichlororuthenium (II) dimer (carbon monoxide‐releasing molecule, 10 mg/kg). Likewise, the LPS effects were dose‐dependently abrogated by nicotine co‐treatment (0.5, 1 and 2 mg/kg). The blockade of α7‐nAChRs (methyllycaconitine citrate, 2 mg/kg) or inhibition of HO‐1 (zinc protoporphyrin, 10 mg/kg) blunted the advantageous effects of nicotine on renal endotoxic manifestations. The Kaplan‐Meier survival curve analysis showed that the increase in mortality rate caused by LPS disappeared in the presence of nicotine or bilirubin. Together, the current biochemical and pharmacological evidence suggests key roles for α7‐nAChRs and the bilirubin byproduct of the HO‐1 signaling in the nicotine counteraction of renal dysfunction and reduced adenosinergic vasodilator capacity.Support or Funding InformationSupported by the Science and Technology Development Fund, Egypt (STDF Grant No. 14895)This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.