Obianime A W, Hirst S J, Dale M M
Department of Pharmacology, University College London, UK.
Pulm Pharmacol. 1989;2(4):191-200. doi: 10.1016/0952-0600(89)90020-3.
It has been suggested that protein kinase C activation may have a role in the maintained, 'latch-bridge' phase of smooth muscle contraction. We have examined the effects of a range of smooth muscle relaxants on the maintained contraction produced in the guinea-pig parenchymal lung strip by the protein kinase C activator, 4 beta-phorbol dibutyrate (4 beta-PDBu). The maximum histamine contraction (produced by 10 microM) was used as a standard and the effects of the smooth muscle relaxants were also studied on this histamine-induced contraction. After 4 beta-PDBu, 1 microM, had produced contraction, enprofylline, forskolin and papaverine caused concentration-dependent relaxation, producing total reversal of the contraction, while prostaglandin E2 and prostacyclin caused a concentration-dependent relaxation but less than total reversal. The concentrations required for the effects on the phorbol ester contraction were 10 to 100-fold higher than were necessary for relaxation of the maximum contraction produced by histamine. Isoprenaline, 1 microM, a concentration which caused total reversal of the histamine-induced contraction, caused only 22% decrease of the phorbol dibutyrate-induced contraction and no further relaxation occurred with higher concentrations. Cromakalim--a potassium channel activator proposed as a therapy for nocturnal asthma--had virtually no effect on preparations pre-contracted with 4 beta-PDBu, 1 microM, or histamine, 10 microM, but caused about 70% and 20% reversal of the contraction produced by 3 microM histamine and 100 nM 4 beta-PDBu respectively. When single doses of the relaxants were administered before a series of doses of 4 beta-PDBu given cumulatively, enprofylline, 1 microM, and aminophylline, 100 microM and 1 microM, caused a moderate right-shift of the phorbol dibutyrate concentration-response curve, but isoprenaline, 1 microM, was less effective, while cromakalim had no discernible effect. These results are discussed in the light of suggestions that inappropriate activation of protein kinase C in smooth muscle cells, may contribute to the pathogenesis of the late phase of asthma.
有人提出蛋白激酶C激活可能在平滑肌收缩的持续“闩锁桥”阶段起作用。我们研究了一系列平滑肌松弛剂对蛋白激酶C激活剂4β-佛波醇二丁酸酯（4β-PDBu）在豚鼠肺实质条带中产生的持续收缩的影响。以最大组胺收缩（由10μM产生）作为标准，并研究了平滑肌松弛剂对这种组胺诱导收缩的影响。在1μM的4β-PDBu产生收缩后，恩丙茶碱、福斯可林和罂粟碱引起浓度依赖性松弛，使收缩完全逆转，而前列腺素E2和前列环素引起浓度依赖性松弛，但未完全逆转。对佛波酯收缩产生作用所需的浓度比松弛组胺产生的最大收缩所需的浓度高10至100倍。1μM的异丙肾上腺素可使组胺诱导的收缩完全逆转，但仅使佛波醇二丁酸酯诱导的收缩降低22%，更高浓度时无进一步松弛作用。克罗卡林——一种被提议用于治疗夜间哮喘的钾通道激活剂——对预先用1μM的4β-PDBu或10μM的组胺预收缩的标本几乎没有影响，但分别使3μM组胺和100nM 4β-PDBu产生的收缩逆转约70%和20%。当在一系列累积给予的4β-PDBu剂量之前给予单剂量的松弛剂时，1μM的恩丙茶碱、100μM和1μM的氨茶碱使佛波醇二丁酸酯浓度-反应曲线适度右移，但1μM的异丙肾上腺素效果较差，而克罗卡林没有明显作用。根据平滑肌细胞中蛋白激酶C的不适当激活可能导致哮喘后期发病机制的观点，对这些结果进行了讨论。
