Effects of Phorbol 12,13-Diacetate and Its Influence on Spasmogenic Responses in Normal and Sensitized Guinea-pig Trachea

Abstract

Abstract We have studied the effects of phorbol 12,13-diacetate (PDA) and its influence on a variety of spasmogenic responses in trachea isolated in from normal and sensitized guinea-pigs. Tracheal preparations were denuded of epithelium, treated with indomethacin (2·8 μm), and cooled to 20°C. In these experimental conditions, tracheal strips contracted to PDA (0·1 nm-1 μm). Contractions to PDA (1 μm) were greater in sensitized tissues. In normal trachea, contractions to PDA (0·1 μm) were depressed by H-7, 1-(5-isoquinolinyl-sulphonyl)-2-methylpiperazine, (50 μm), amiloride (10 μm), verapamil (10 μm) and Ca2+-free exposure. Similar effects were obtained in sensitized trachea except that PDA-induced contraction was resistant to verapamil and Ca2+-free exposure. Cooling (20°C) of normal trachea substantially depressed the response to CaCl2 (in K+-depolarized tissues), KC1, histamine and 5-hydroxytryptamine without affecting the spasm induced by acetylcholine. This inhibitory effect of cooling was not observed in sensitized trachea. PDA (0·1 μm) did not affect spasmogenic responses at 37°C but counteracted the inhibitory effect of cooling in normal trachea. PDA had no effect on sensitized tissues. PDA (0·1-1μm) did not alter Ca2+-induced contraction of skinned normal and sensitized trachea. These results support the hypothesis that intracellularly stored Ca2+ plays an important role in the activation of sensitized tracheal muscle.