STUDY OF IN-VITRO AND IN-VIVO EFFECTS OF ISRADIPINE IN SKELETAL-MUSCLES AND INTERACTION WITH SOME DRUGS

The effects of the calcium channel blocker isradipine were studied in the indirectly and directly stimulated mouse diaphragm and in the anes thetized rat to determine its potency, reversibility and interaction w ith a number of drugs. Initially, it potentiated both indirect and dir ect twitches followed by a reduction. With tetanic contractions, no po tentiation was obtained, only a reduction, which was complete or near complete at the highest concentration tested (10(-4) M). In combinatio n, isradipine reduced the IC50 and IC90 values for the antibiotics gen tamicin, polymyxin B and clindamycin, d-tubocurarine and magnesium ion s. Depression of contraction caused by isradipine or in combination co uld be reversed to varying degrees by washout elevated calcium ions, n eostigmine or 4-aminopyridine. Spontaneous recovery from the effects o f isradipine alone or in combination was slow and usually incomplete. For in vivo experiments, severe cardiovascular depressant effects of i sradipine limited its exposure to lower concentrations and for shorter periods. Under these conditions, it had no effect on heart rate. Howe ver both systolic and diastolic blood pressure were significantly redu ced, while pulse pressure was increased. After an initial potentiation , muscle contraction was maximally reduced to 55% of control. This stu dy indicates that acute administration of isradipine may aggravate neu romuscular effects of antibiotics, muscle relaxants or hypermagnesemia , although it is unlikely that spontaneous recovery or reversibility o f muscular activity by suitable reversal agents will be affected. Howe ver; prolonged use of the drug may be more difficult to reverse.