Effects of alkylating antagonists on the stimulated turnover of phosphatidylinositol produced by a variety of calcium-mobilising receptor systems

We have investigated the effects of two halogenoalkylamine drugs, dibenamine and phenoxybenzamine, on the stimulated phosphatidylinositol turnover that is produced by neurotransmitters and hormones which interact with receptors to bring about an increase in cell surface Ca²⁺ permeability. The phosphatidylinositol responses we have investigated were those evoked by muscarinic cholinergic stimuli (parotid gland and pancreas), by α-adrenergic stimuli (parotid gland, vas deferens smooth muscle), by pancreozymin or caerulein (pancreas), by phytohaemagglutinin (lymphocytes) and by either 5-hydroxytryptamine or elevation of the extracellular K⁺ concentration (ileum smooth muscle). Phenoxybenzamine inhibited the muscarinic cholinergic, α-adrenergic, 5-hydroxytryptamine and high K⁺ responses, but not the responses to phytohaemagglutinin and to pancreozymin (or caerulein). Dibenamine was less effective than phenoxybenzamine in inhibiting the α-adrenergic response and the high K⁺ response, and it did not inhibit the responses to muscarinic cholinergic stimuli, to 5-hydroxytryptamine or to the polypeptides. N,N-dimethyl-2-bromo-2-phenylethylamine (DMPEA) inhibited the α-adrenergic response, but not the response to muscarinic cholinergic stimulation. The specificity of DMPEA for the α-adrenergic response agrees with its postulated site of action at the noradrenaline-binding site of this receptor system, whereas dibenamine and phenoxybenzamine are less specific drugs which inhibit a variety of the 'physiological' responses of cells, including those to muscarinic cholinergic, H₁-histaminergic, α-adrenergic and 5-hydroxytryptamine stimuli. Previously, we suggested that dibenamine and phenoxybenzamine might show a constant pattern of effects on the phosphatidylinositol responses evoked through different receptors, phenoxybenzamine being inhibitory and dibenamine without effect [Jafferji & Michell (1976) Biochem. J. 160, 163-169]. However, this pattern has not been sustained throughout the present study of a larger range of Ca²⁺-mobilising stimuli.