BACKGROUND: A recent theory of anesthesia predicts that some endogenous compounds should have anesthetic properties. This theory raises the possibility that metabolites that are profoundly elevated in disease may also exert anesthetic effects. Because in pathophysiologic concentrations, ammonia reversibly impairs memory, consciousness, and responsiveness to noxious stimuli in a manner similar to anesthetics, we investigated whether ammonia had anesthetic properties. METHODS: The effect of ammonia was studied on alpha1beta2 and alpha1beta2gamma2s gamma-amino butyric acid type A, alpha1 glycine, and NR1/NR2A N-methyl-D-aspartate receptors, and the two-pore domain potassium channel TRESK. Channels were expressed in Xenopus laevis oocytes and studied using two-electrode voltage clamping. The immobilizing effect of ammonia in rats was evaluated by determining the reduction in isoflurane minimum alveolar concentration produced by IV infusion of ammonium chloride. The olive oil-water partition coefficient was measured to determine whether free ammonia (NH3) followed the Meyer-Overton relation. RESULTS: Ammonia positively modulated TRESK channels and glycine receptors. No effect was seen on alpha1beta2 and alpha1beta2gamma2s gamma-amino butyric acid type A receptors or NR1/NR2A N-methyl-d-aspartate receptors. Ammonia reversibly decreased the requirement for isoflurane, with a calculated immobilizing EC50 of 1.6 +/- 0.1 mM NH4Cl. The Ostwald olive oil-water partition coefficient for NH3 was 0.018. At a pH of 7.4, and at the anesthetic EC50, the NH3 concentration in bulk olive oil is 0.42 muM, approximately five orders of magnitude less than observed by anesthetics that follow the Meyer-Overton relation. CONCLUSIONS: These findings support the hypothesis that ammonia has anesthetic properties. Bulk oil concentration did not predict the potency of ammonia.
BACKGROUND: A recent theory of anesthesia predicts that some endogenous compounds should have anesthetic properties. This theory raises the possibility that metabolites that are profoundly elevated in disease may also exert anesthetic effects. Because in pathophysiologic concentrations, ammonia reversibly impairs memory, consciousness, and responsiveness to noxious stimuli in a manner similar to anesthetics, we investigated whether ammonia had anesthetic properties. METHODS: The effect of ammonia was studied on alpha1beta2 and alpha1beta2gamma2s gamma-amino butyric acid type A, alpha1 glycine, and NR1/NR2A N-methyl-D-aspartate receptors, and the two-pore domain potassium channel TRESK. Channels were expressed in Xenopus laevis oocytes and studied using two-electrode voltage clamping. The immobilizing effect of ammonia in rats was evaluated by determining the reduction in isoflurane minimum alveolar concentration produced by IV infusion of ammonium chloride. The oliveoil-water partition coefficient was measured to determine whether free ammonia (NH3) followed the Meyer-Overton relation. RESULTS:Ammonia positively modulated TRESK channels and glycine receptors. No effect was seen on alpha1beta2 and alpha1beta2gamma2s gamma-amino butyric acid type A receptors or NR1/NR2A N-methyl-d-aspartate receptors. Ammonia reversibly decreased the requirement for isoflurane, with a calculated immobilizing EC50 of 1.6 +/- 0.1 mM NH4Cl. The Ostwald oliveoil-water partition coefficient for NH3 was 0.018. At a pH of 7.4, and at the anesthetic EC50, the NH3 concentration in bulk oliveoil is 0.42 muM, approximately five orders of magnitude less than observed by anesthetics that follow the Meyer-Overton relation. CONCLUSIONS: These findings support the hypothesis that ammonia has anesthetic properties. Bulk oil concentration did not predict the potency of ammonia.
Authors: Robert J Brosnan; Kimberly Ramos; Antonio Jose de Araujo Aguiar; Alessia Cenani; Heather K Knych Journal: Pharmacology Date: 2022-01-31 Impact factor: 2.547