Histamine H1-receptors mediate phosphoinositide and calcium response in cultured smooth muscle cells-interaction with cicletanine (CIC)

Abstract

Smooth muscle cells were cultured from guinea-pig aorta and labelled with⁴⁵Ca⁺⁺ and³²P_i to investigate the possible effect of cicletanine, a new antihypertensive drug, on the release of intracellular Ca⁺⁺ and the metabolism of phosphoinositide induced by histamine. In⁴⁵Ca⁺⁺ labelled cells, histamine increased in a dose-dependent manner the⁴⁵Ca⁺⁺ efflux in the first two minutes. Stimulation of⁴⁵Ca⁺⁺ release was observed with H₁-agonist [2-pyridylethylamine dihydrochloride (2-PEA)] but not with H₂-agonist (dimaprit). In addition, histamine- or 2-PEA- induced⁴⁵Ca⁺⁺ efflux was inhibited by the H₁-antagonists (mepyramine and terfenadine) whereas the H₂-antagonist (cimetidine) was without effect. Similar results were obtained in³²P_i labelled cells; both H₁-agonists (Histamine and 2-PEA) increased the labelling of phosphoinositides. This effect was completely blocked by mepyramine. These results demonstrate that the histamine-induced stimulation of⁴⁵Ca⁺⁺ efflux and phosphoinositide metabolism are mediated through H₁-receptors. In the above systems, cicletanine was as effective as the H₁-antagonist (mepyramine) with an IC₅₀ of 10⁻⁶ M for both⁴⁵Ca⁺⁺ efflux and phosphoinositide metabolism. Blockade of these systems by cicletanine may be part of the mechanism by which this drug produces relaxation of blood vessels and may account for itsin vivo antihypertensive action.