Interactions between phorbol esters and agents which increase cytosolic calcium in the guinea pig parenchymal strip: direct and indirect effects on the contractile response

AW Obianime, SJ Hirst and MM Dale

Department of Pharmacology, University College London, England.

In the guinea pig parenchymal strip the cumulative concentration- response curve to 4 beta-phorbol dibutyrate (4 beta-PDBu) occurred over the range 10 nM to 10 microM, the response to 10 microM being 246 +/- 22% of the mean maximum histamine response. A "cocktail" of agents which inhibit synthesis and/or release of mediators (mepyramine, 1 microM; indomethacin, 1 microM; mepacrine, 300 microM; atropine, 10 microM; cimetidine, 10 microM; phentolamine, 10 microM; and quercetin, 50 microM) had no effect on the cumulative 4 beta-PDBu concentration- response curve, indicating that the response was not due to the release of noradrenaline, acetylcholine, histamine, platelet activating factor or eicosanoids. When the cumulative curves to vanadate and A23187 were measured in the presence of the cocktail of inhibitors, the vanadate response was unaffected, but the response to A23187 was reduced marginally. Threshold concentrations of four agents which increase cytosolic calcium (Bay K 8644, 1 and 10 nM; ionomycin, 100 nM; A23187, 100 nM; and vanadate, 3 microM) shifted the cumulative 4 beta-PDBu curve to the left. A threshold concentration of 4 beta-PDBu (30 nM) shifted the cumulative-response curve of vanadate to the left, had no effect on the Bay K 8644 response and left-shifted the A23187 curve whether the tissue was immersed in cocktail-containing Krebs' solution or not. Threshold concentrations of A23187 and 4 beta-PDBu added together in the inhibitory cocktail caused only a transient contraction as compared to a sustained contraction with 1 microM 4 beta- PDBu.(ABSTRACT TRUNCATED AT 250 WORDS)

Volume 247, Issue 1, pp. 262-270, 10/01/1988
Copyright © 1988 by American Society for Pharmacology and Experimental Therapeutics