Lymphocyte cytochrome c oxidase, cyclic GMP and cholinergic muscarinic receptors as peripheral indicators of carbon monoxide neurotoxicity after acute and repeated exposure in the rat

Changes in cerebral cytochrome oxidase (COX) activity, nitric oxide (NO)–cyclic GMP (cGMP) pathway and cholinergic muscarinic receptors (MRs) have been reported in rodents acutely exposed to carbon monoxide (CO). These endpoints measurable in lymphocytes may serve as peripheral markers of CO neurotoxicity. The early and delayed effects of repeated and acute in vivo CO inhalation were investigated on COX activity, cGMP formation and MR binding in rat brain and lymphocytes to assess whether each endpoint was similarly affected both centrally and peripherally. Male Wistar rats either inhaled 500 ppm CO, 6 h/day, 5 days/week, 4 weeks (repeated exposure) or 2400 ppm, 1 h (single exposure). Neither treatment altered brain or lymphocyte COX activity 1 and 7 days post-treatment. Also ineffective were repeated and acute CO treatments towards 3H-quinuclidinyl benzilate (QNB) binding to MRs in cerebral cortex, hippocampus, striatum, cerebellum (respective controls, meanTS.D.: 171T45, 245T53, 263T14 and 77T7 fmol/mg protein) and lymphocytes (24T10 fmol/million cells) at the same time points. In lymphocytes control cGMP levels averaged 1.98T0.99 pmol/mg protein under basal conditions, and 3.94T0.55 pmol/mg protein after NO-stimulation. One day after chronic treatment cessation, the CO-treated group displayed about a 50% decrease in both basal and NOstimulated cGMP values, which persisted up to 7 days after, compared to air-exposed rats. Acutely, CO caused a delayed enhancement (+140%) of NO-induced activation of soluble guanylate cyclase. The finding that the NO–cGMP pathway is a target for the delayed effects of CO in peripheral blood cells is in accordance with our data in brain. In vivo exposure to carbon monoxide causes delayed impairment of activation of soluble guanylate cyclase by nitric oxide in rat brain cortex and cerebellum.