Phosphoinositides and cicletanine

In vascular smooth muscle cells, the activation of histaminergic receptors of the H1 subtype induces an increase in cytosolic free calcium. This has been shown to involve the metabolism of inositol-containing lipids. Since according to its pharmalogical characteristics, cicletanine could be considered as an H1 antagonist, it was of interest to check whether the drug behaved as such with regard to phosphoinositide metabolism. Phosphoinositide metabolism was studied by measuring the 32P labelling of phosphatidylinositol (PI) and of its phosphorylated derivatives in cultured smooth muscle cells isolated from guinea-pig aorta and incubated in the presence or absence of various histaminergic agonists and/or antagonists. The results clearly demonstrate that the increase in 32P-PI could be selectively induced by treatment of cells with histamine or 2-pyridylethylamine dihydrochloride (2-PEA) (an H1 agonist) but not with the H2 agonist dimaprit. In addition, histamine- or 2-PEA-induced 32P-PI increase was inhibited by pretreatment of cells with the H1 antagonist mepyramine, whereas the H2 antagonist cimetidine was without effect. These data demonstrate that the histamine-induced 32P-PI increase is mediated through H1 receptors. Under the same experimental conditions, cicletanine was as effective as mepyramine with an IC50 value of 10(-6) M. The development of tension in arterial smooth muscle is under the control of variations of calcium concentration in the intracellular space. Therefore, the blockade by cicletanine of histamine-enhanced phosphoinositide turnover may participate in the mechanism by which the drug exerts its antihypertensive action.