The effect of smooth muscle relaxants working through different transduction mechanisms on the phorbol dibutyrate-induced contraction of the guinea-pig lung parenchymal strip: possible relevance for asthma.

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.