HISTAMINE H(1)-RECEPTOR-MEDIATED INOSITOL PHOSPHOLIPID HYDROLYSIS IN DDT(1)MF-2 CELLS - AGONIST AND ANTAGONIST PROPERTIES

1 The effect of histamine HI-receptor stimulation on inositol phospholipid hydrolysis has been investigated in the hamster vas deferens smooth muscle cell line, DDT1MF-2. 2 Histamine (EC50 = 27 muM) stimulated the accumulation of [H-3]-inositol phosphates in DDT1MF-2 cells prelabelled with [H-3]-myo-inositol. 2-Thiazolylethylamine (EC50 42 muM) produced a maximal response of similar magnitude to histamine while the maximal response obtained with N-methylhistamine (EC50 = 72 muM) and 2-pyridylethylamine (EC50 = 85 muM) were much lower (circa 65%, histamine = 100%). 3 The H-1-selective agonists 2-(3-fluorophenyl)-histamine (2-FPH) and 2-(3-chlorophenyl)-histamine (2-CPH) both appeared to act as partial H-1-agonists in this system. Both compounds produced maximal responses of only 30% (with respect to histamine = 100) and were able to antagonize the inositol phosphate response to histamine (estimated K(p) = 10.4 and 18.9 muM for 2-FPH and 2-CPH respectively). 4 The response to histamine was antagonized by the H-1-antagonists, mepyramine (K(D) 0.4 nM), (+)-chlorpheniramine (K(D) 1.2 nM) and promethazine (K(D) 0.3 nM). Furthermore, the (-)-isomer of chlorpheniramine was approx. three orders of magnitude less potent than the corresponding (+)-isomer. 5 The response to histamine (0.1 mM) was not altered by prior treatment of cells with pertussis toxin (100 ng ml-1; 24 h) whereas the inositol phosphate response to adenosine A1-receptor stimulation in this cell line was significantly attenuated under these conditions. 6 These data indicate that histamine-stimulated inositol phospholipid hydrolysis in DDT1MF-2 cells is mediated via a classical H-1-receptor. Furthermore, the results also suggest that histamine H-1- and adenosine A1-receptors activate phospholipase C in DDT1MF-2 cells via two different G-protein-coupled pathways.