4 beta-PDBu contracts parenchymal strip and synergizes with raised cytosolic calcium

The effect of various concentrations of 4 beta-phorbol dibutyrate, (4-beta PDBu) phorbol myristate acetate (PMA), and 4 beta-phorbol didecanoate (4 beta-PDD) were studied on the guinea-pig parenchymal strip. The order of potency, 4 beta-PDBu greater than PMA greater than 4 beta-PDD, was the inverse of their lipid solubility. 4 beta-PDBu, 10(-9)-10(-4) M, caused a powerful, slow, sustained contraction starting within 2-3 min and reaching maximum in approximately 45 min, the maximum being 170% of the maximum histamine contraction. The responses to PMA and 4 beta-PDD were slower and less marked. 4 alpha-Phorbol dibutyrate had no effect. These results differ from those reported for guinea-pig trachea. In calcium-free Krebs solution + EGTA (1 mM) the cumulative concentration-response curve to 4 beta-PDBu was still obtained but was slower and was diminished. A23187, ionomycin and vanadate also caused contraction, the respective concentration ranges being 10(-7)-10(-5), 10(-8)-10(-6) and 10(-6)-10(-3) M. When a low concentration of 4 beta-PDBu, which on its own produced no effect, was given with a low concentration of A23187, ionomycin or vanadate, marked synergism was seen. These results are consistent with the model of smooth muscle contraction in which it was proposed that the initial response to stimulation is mediated by both the trisphosphate/calcium and diacylglycerol/protein kinase C pathways, while the sustained response is mediated by the diacylglycerol/protein kinase C pathway, only.