Nerme V, Abrahamsson T, Vauquelin G
Department of Cardiovascular Pharmacology, Hässle Research Laboratories, Mölndal, Sweden.
J Pharmacol Exp Ther. 1990 Mar;252(3):1341-6.
Chronic administration of isoproterenol caused major changes in the molecular and functional characteristics of lung beta adrenoceptors. The dose of isoproterenol delivered by the minipumps over 7 days corresponded to approximately 60 micrograms.kg-1h-1. The agonist treatment produced an 80% decrease in the number of beta adrenoceptors in lung membranes. However, a significant proportion of the remaining receptors could still form complexes with the nucleotide regulatory protein (Gs) in the presence of agonist. This was demonstrated by the persistence of high affinity sites (42% versus 53% in controls, P less than .01) in isoproterenol competition binding curves and of the tight binding of isoproterenol in the presence of the reagent N-ethylmaleimide (44% versus 60% in controls, P less than .01). However, part of the receptor population displaying high affinity toward the agonist was insensitive to guanosine 5'-triphosphate. These changes were associated with a decrease in the Gs activity, as demonstrated by the lower degree of cholera toxin-mediated adenosine diphosphate ribosylation. Moreover, chronic against treatment caused a 50% reduction in the maximal relaxing effect of isoproterenol in the isolated lung parenchymal strip, whereas the tissue sensitivity to beta adrenoceptor stimulation was unchanged. It is concluded that chronic administration of isoproterenol to guinea pigs caused marked changes in beta adrenoceptor function in the lung tissue. The molecular events involved in beta adrenoceptor desensitization by chronic in vivo administration of relatively low catecholamine doses appear to differ from those reported for cultured cells, as well as those mediated by acute in vivo catecholamine administration.
长期给予异丙肾上腺素会导致肺β肾上腺素能受体的分子和功能特性发生重大变化。微型泵在7天内输送的异丙肾上腺素剂量相当于约60微克·千克⁻¹·小时⁻¹。激动剂处理使肺膜中β肾上腺素能受体数量减少了80%。然而，在存在激动剂的情况下，相当一部分剩余的受体仍能与核苷酸调节蛋白（Gs）形成复合物。这在异丙肾上腺素竞争结合曲线中高亲和力位点的持续存在（对照组为42%，处理组为53%，P＜0.01）以及在试剂N-乙基马来酰亚胺存在下异丙肾上腺素的紧密结合（对照组为60%，处理组为44%，P＜0.01）中得到了证明。然而，对激动剂表现出高亲和力的部分受体群体对鸟苷5'-三磷酸不敏感。这些变化与Gs活性降低有关，霍乱毒素介导的二磷酸腺苷核糖基化程度较低证明了这一点。此外，长期拮抗剂处理使分离的肺实质条带中异丙肾上腺素的最大舒张作用降低了50%，而组织对β肾上腺素能受体刺激的敏感性未改变。结论是，对豚鼠长期给予异丙肾上腺素会导致肺组织中β肾上腺素能受体功能发生显著变化。长期体内给予相对低剂量儿茶酚胺导致β肾上腺素能受体脱敏所涉及的分子事件似乎与培养细胞中报道的不同，也与急性体内给予儿茶酚胺所介导的不同。
