Effects of calcium antagonistic drugs on the stimulation by carbamoylcholine and histamine of phosphatidylinositol turnover in longitudinal smooth muscle of guinea pig ileum

A number of drugs classed as calcium antagonists, spasmolytics, non specific receptor antagonists or receptor antagonists with multiple sites of action were tested to determine whether they prevent the stimulation of phosphatidylinositol turnover caused in various tissues by the activation of receptors which increase cell surface Ca²⁺ permeability. The experiments were done with fragments of longitudinal smooth muscle from guinea pig ileum; these were incubated in vitro with ³²P(i) and either 100μM carbamoylcholine or 100μM histamine, in the presence of antagonistic drugs at concentrations at least sufficient to cause complete blockade of smooth muscle contraction. The phosphatidylinositosol response to carbamoylcholine was not changed by cinchocaine, papaverine, nifedipine, dibenamine, amethocaine, cinnarizine, lidoflazine, methoxyverapamil, prenylamine or two antimuscarinic alkane bis ammonium compounds, and the response to histamine was unaffected by the first 4 drugs. In contrast, phenoxybenzamine prevented the increase in phosphatidylinositol labelling caused by either carbamoylcholine or histamine. The insensitivity of the phosphatidylinositol response to most of the drugs provides further experimental support for the conclusion that the receptor stimulated phosphatidylinositol breakdown which initiates the increase in phosphatidylinositol turnover is not caused by an an in intracellular Ca²⁺. The simplest interpretation of the available information appears to be that phosphatidylinositol breakdown plays a role in the coupling between the receptor agonist interaction and the opening of cell surface Ca²⁺ gates (Mitchell, R.H. (1975) Biochim. Biophys. Acta 415, 81-147). If this is correct, then phenoxybenzamine must exert its inhibitory effects on phosphatidylinositol breakdown early in this sequence of events, but the other drugs must act at a stage later than phosphatidylinositol breakdown. The unexpected difference in the effects of dibenamine and phenoxybenzamine, which are chemically very similar, may provide a useful experimental tool with which to explore the way in which activated receptors provoke the opening of cell surface Ca²⁺ gates.