Effect of Noradrenaline on Radioprotective Effect of Calcium Channel Blockers

Abstract

Calcium channel blockers can be classified into three main subgroups on the basis of their pharmacologic features. In earlier work the radioprotective effect of dilthiazem and nifedipine was proved, when these antagonists were given to mice s.c. or i.p. In this work mechanism of radioprotective activity was studied.

For indirect investigation of the cardiovascular effects leading to hypoxia in mice, measurements of rectal temperature were used with assumption that hypothermic response reflects hypometabolic effects which are considered as compensatory reaction of the organism to hypoxia. I.p. administration of Diacordin (diltiazem hydrochlorid, Léciva, Praha) in the doses of 25-100 mg/kg to mice led to a significant decrease rectal temperature at the interval of 15 minutes to 2 hours after injection. This decrease was influenced by Noradrenaline administration. The dose of 2.8 mg/kg was optimal for significant inhibition of the hypothermic response first hour after administration of Diacordin. Administration of Noradrenaline before Diacordin reduced radioprotective effect of Diacordin. We studied radioprotective effect on:

• survival of lethal irradiated mice

• hematological indicators (number of CFU-S, CFU-GM in the bone marrow and the spleen).

Our experiment suported hypothesis that radioprotective activity of Diacordin is induced by at least two mechanisms. These two mechanisms are:

• protection by means of hypoxia as a result of the effect of treatment on cardiovascular system

• inhibition of the influx of Ca²⁺ through specialized channels into cells.

Abbreviations: CFU-GM - colony-forming unit-granulocyte/macrophage, CFU-S - colony-forming unit-spleen, E-CFU-S - endogenous colony-forming unit-spleen, Di -Diacordin, Na - Noradrenaline, Di + Na Diacordin and Noradrenaline, C- nonirradiated group marrow of the femur. A significant increase in comparison with Na group was only seen in the group protected by Diacordin. It is seen in the table that in the case of Noradrenaline application the number of endogenous colonies on the spleens is very small. Diacordin application led to the increase which was not influenced by Noradrenaline application before Diacordin application.

Interestingly, although there was a significant reduction in the quickness of regeneration of the number of CFU-S and CFU-GM in the bone marrow induced by Noradrenaline, the survival rate of mice in the area of lethal doses was influenced substantially less. The results of Pospísil et al. [2] concerning the influencing of radioprotective effect of Dipyridamole and AMP by Noradrenaline had a different character. Noradrenaline did not practically influenced the quickness of hemopoietic regeneration but it reduced significantly the survival of irradiated mice. One of the possible hypothesis is that the damage caused by whole-body irradiation has a complex character where a number of systems is damaged, which means above all gastrointestinal system where different mechanisms of radioprotective effect of Diacordin can act. These mechanisms are significant from the point of view of survival of irradiated mice.