Effect of 3-arylamino-1,2-dihydro-3H-1,4-benzodiazepine-2-ones on the bradykinin-induced smooth muscle contraction

Damage to tissue, inflammation and disruption of normal functioning of organs are often accompanied by pain. In pain perceptions, the kinin-kallikrein system with bradykinin as mediator is very important. Regulatory activity of the kininkallikrein system permits the control of inflammation, pain, vascular tone and other functions. A new group of substances that may used for this purpose are 3-substituted 1,4-benzdiazepinones. We analyzed the effect of 3-arylamino-1,2-dihydro-3H- 1,4-benzodiazepine-2-ones derivatives on the normalized maximal rate of bradykinin-induced smooth muscle contraction of the stomach in the presence of calcium channel blockers verapamil (1 mu M) and gadolinium (300 mu M). The levels of bradykinin and 3-arylamino-1,2-dihydro-3H-1,4-benzodiazepine-2-ones in the incubation solution were 10(-)6 M. Data processing on the dynamics of contraction was performed according to the method of T. Burdyha and S. Kosterin. Statistically significant changes were found for MX-1828. This compound reduced the maximal normalized rate of bradykinin-induced smooth muscle contraction in the presence of Gd3+ and verapamil by 19.3% and 32.0%, respectively. Also, MX-1828 demonstrated effects similar to those of the competitive inhibitor bradykinin B-2-receptor - des-Arg9-bradykinin-acetate, which is possible evidence of its interaction with the receptor or signal transduction pathways. MX-1828 additionally reduced the maximum normalized rate of relaxation by 6.2% in the presence of Gd3+. This effect was demonstrated for MX-1906 in the presence of verapamil with additional reduction of the maximal normalized rate of relaxation, which was 26.4%. The results suggest the presence of inhibitory interaction between MX-1828 and kininkallikrein system receptors or signal transduction pathways. The effects which were found for MX-1906 require further studies to clarify the mechanisms of influence on bradykinin-induced smooth muscle contraction.