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 oxygenase-1 (HO-1) pathway is imperative for the nicotine counteraction of hemodynamic and renovascular dysfunction caused by acute endotoxemia in rats. Renal vasodilations were induced by cumulative bolus injections of acetylcholine (ACh, 0.01 nmol-7.29 nmol) or ethylcarboxamidoadenosine (NECA, adenosine receptor agonist, 1.6 nmol-100 nmol) in isolated phenylephrine-preconstricted perfused kidneys. The data showed that 6-h treatment with lipopolysaccharide (LPS, 5 mg/kg i.p.) decreased systolic blood pressure and renal vasodilations caused by NECA but not Ach. The endotoxic insult also increased the mortality rate and elevated serum urea and creatinine. These LPS effects were sex-unrelated, except hypotension, and enhanced mortality which were more evident in male rodents, and abrogated after co-administration of nicotine (0.5, 1 mg/kg and 2 mg/kg) in a dose-dependent fashion. The advantageous effects of nicotine on NECA vasodilations, survivability, and kidney biomarkers in endotoxic male rats disappeared upon concurrent exposure to methyllycaconitine citrate (α7-nAChR blocker) or zinc protoporphyrin (HO-1 inhibitor) and were reproduced after treatment with bilirubin, but not hemin (HO-1 inducer) or tricarbonyldichlororuthenium (II) dimer (carbon monoxide-releasing molecule). Together, 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 renal vasodilator capacity in endotoxic rats.

Nicotine Improves Survivability, Hypotension, and Impaired Adenosinergic Renal Vasodilations in Endotoxic Rats: Role of α7-nAChRs/HO-1 Pathway.

As an anti-inflammatory alkaloid, nicotine plays dual roles in treating diseases. Here we reviewed the anti-inflammatory and pro-inflammatory effects of nicotine on inflammatory diseases, including inflammatory bowel disease, arthritis, multiple sclerosis, sepsis, endotoxemia, myocarditis, oral/skin/muscle inflammation, etc., mainly concerning the administration methods, different models, therapeutic concentration and duration, and relevant organs and tissues. According to the data analysis from recent studies in the past 20 years, nicotine exerts much more anti-inflammatory effects than pro-inflammatory ones, especially in ulcerative colitis, arthritis, sepsis, and endotoxemia. On the other hand, in oral inflammation, nicotine promotes and aggravates some diseases such as periodontitis and gingivitis, especially when there are harmful microorganisms in the oral cavity. We also carefully analyzed the nicotine dosage to determine its safe and effective range. Furthermore, we summarized the molecular mechanism of nicotine in these inflammatory diseases through regulating immune cells, immune factors, and the vagus and acetylcholinergic anti-inflammatory pathways. By balancing the “beneficial” and “harmful” effects of nicotine, it is meaningful to explore the effective medical value of nicotine and open up new horizons for remedying acute and chronic inflammation in humans.

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Nicotine in Inflammatory Diseases: Anti-Inflammatory and Pro-Inflammatory Effects

Nicotine reverses the enhanced renal vasodilator capacity in endotoxic rats: Role of α7/α4β2 nAChRs and HSP70.

Experiments on outbred albino mice have shown that proserine (reversible cholinesterase inhibitor) and nicotine (nicotinic receptor agonist) in a equivalent dose of 0.2 DL(50)injected 2 h before sepsis induction significantly reduced animal mortality from experimental infection due to reduction of blood concentrations of proinflammatory cytokines TNF-α, IL-1β, and IL-6.

Effects of reversible inhibition of cholinesterase and nicotine on mouse mortality and blood levels of proinflammatory cytokines during the early phase of sepsis.

P. F. Zabrodskii

Papers

Effects of reversible inhibition of cholinesterase and nicotine on mouse mortality and blood levels of proinflammatory cytokines during the early phase of sepsis.