The effects of long-term infusion of salbutamol, diltiazem and nifedipine on uterine contractions in the ovariectomized, post-partum rat.

The sensitivity of the uterus to the inhibition of contractions by salbutamol, diltiazem or nifedipine was assessed in the ovariectomized, post-partum rat by dose-response curves following bolus intravenous (i.v.) administration. These tests were performed before (day 1), immediately after a 20 h i.v. infusion of salbutamol, diltiazem, nifedipine or appropriate control infusate (day 2) and after a further 20 h infusion of saline (day 3). In a further group of animals sensitivity to nifedipine was assessed before and after a 20 h infusion of salbutamol. Uterine contractions were monitored throughout infusions. Infusion of salbutamol (2 micrograms kg-1 min-1) produced an initial marked inhibition of uterine contractions, an effect which was not maintained despite continued infusion. Contractions reappeared after 2 h of infusion and reached pre-infusion levels by 5 h. The dose-response curve to salbutamol on day 2 was shifted more than 100 fold to the right compared with that on day 1. Sensitivity of the uterus on day 3 did not differ from that on day 1. Nifedipine (25 micrograms kg-1 min-1) produced sustained inhibition of uterine contractions throughout the 20 h of infusion. Sensitivity of the uterus to nifedipine could not, therefore, be tested on day 2; sensitivity on day 3 did not differ from that on day 1. In addition, there was no change in sensitivity of the uterus to nifedipine after a 20 h infusion of salbutamol. 4 Diltiazem (200 Ig kg-' min-') produced a marked initial inhibition of uterine contractions, with a partial return of contractions during continued infusion in 7 out of 12 animals so that mean integral values reached 40% of those pre-infusion. The dose-response curve to diltiazem on day 2 showed a 25 fold shift to the right compared with that on day 1 in 4 out of 12 animals where the test could be performed. Sensitivity of the uterus on day 3 did not differ from that on day 1. 5 These findings suggest that marked but reversible tolerance to the inhibitory actions of salbutamol on uterine contractions occurs during long-term infusion. There was no evidence of tolerance to the uterine actions of nifedipine, but there was evidence of tolerance to diltiazem in some animals.