Rapid Desensitization and Uncoupling of Human β-Adrenergic Receptors in anin VitroModel of Lactic Acidosis*

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Abstract
Adrenergic responsiveness in many tissues may be impaired in the presence of lactic acidosis. The purpose of this study was to examine how human neutrophil β2-adrenergic receptors may be altered in an in vitro model of lactic acidosis. Receptor coupling was assessed by constructing curves for the competition of isoproterenol with [125I]iodocyanopindolol for β-adrenergic receptors. Receptors were exposed to control (2 mM lactate, pH 7.4), lactic acidosis (16 mM lactate, pH 7.1), lactate excess (16 mM lactate, pH 7.4), and low pH (2 mM lactate, pH 7.1) conditions. Prior exposure of 0-adrenergic receptors on whole cells to lactic acidosis resulted in a 61% reduction in isoproterenol-stimulated cAMP accumulation (P < 0.05). This desensitization was not accompanied by down-regulation. After exposure to lactic acidosis, β-adrenergic receptors were uncoupled sufficiently that a high affinity state could not be detected. Both lactate excess and low pH were necessary to fully express the desensitization and uncoupling defects. The uncoupling was rapid (40 min) and occurred in cell-free membrane preparations. Thus, in an in vitro model of lactic acidosis, rapid desensitization and uncoupling occur which do not appear to require protein synthesis.