Tolerance to cromakalim in the rat uterus in vivo

1. Cromakalim (0.1 and 1 mg kg-1) produced inhibition of uterine contractions and falls in mean blood pressure in ovariectomized, non-pregnant rats, the durations of which were dose-dependent. Frequency of contractions was inhibited selectively compared to amplitude. 2. The durations of the uterine effect of cromakalim (1 mg kg-1), when given at 12 h intervals, were less after the second, third and fourth doses compared to the first dose in non-pregnant rats. In ovariectomized rats treated from day 18 of pregnancy, using the same experimental design, no uterine relaxant effects were seen to the third and fourth doses. The timing of delivery and foetal viability were unaffected by cromakalim. 3. The sensitivity of the uterus to cromakalim was tested using small doses before and after three cromakalim doses (1 mg kg-1) given at 8 h intervals in non-pregnant rats. This regime resulted in a 25 fold decrease in the sensitivity of the uterus to cromakalim. 4. Cromakalim can produce long-lasting inhibition of uterine contractions in the rat after bolus i.v. dose but it exhibits little selectivity relative to its vasodepressor action and there appears to be tolerance to the uterine relaxant action of cromakalim in vivo.