Tolerance to cromakalim in the rat uterus in vivo

Abstract

1 Cromakalim (0.1 and mgkg 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.

Influence of ovarian steroids on myometrial sensitivity and tolerance to relaxin in the rat in vivo: lack of cross-tolerance between relaxin, salbutamol and cromakalim

“…Cromakalim inhibits uterine contractions in vivo, is antagonized competitively by glibenclamide, a rela¬ tively selective blocker of ATP-sensitive potassium channels, and exhibits tolerance with repeated admin¬ istration (Downing et al 1989;Piper et al 1990;Downing & Hollingsworth, 19926). Potassium chan¬ nel opening may be part of the mechanism by which relaxin induces myometrial relaxation in vivo.…”

“…infusion of relaxin to non-pregnant ovariectomized rats (Cheah & Sherwood, 1981), suggesting that tolerance to relaxin may occur. ß-adrenoceptor agonists such as salbutamol (Abel & Hollingsworth, 1986;Downing & Hollingsworth, 1990, 19926) and potassium channel openers such as cromakalim (Downing, Miller & Hollingsworth, 1989 ; Downing Piper, Downing & Hollingsworth, 1991). It has been suggested that the development of tolerance to ß-adrenoceptor agonists may be due to three mechanisms: (i) phosphorylation of receptors, (ii) internalization and loss of membrane receptors and (iii) uncoupling of the membrane receptor from the adenylate cyclase complex with consequent loss of production of the second messenger, cyclic AMP (cAMP) (Harden, 1983 ;Lefkowitz, Hausdorff& Caron, 1990).…”

Antagonism of relaxin by glibenclamide in the uterus of the rat in vivo

“…Glibenclamide was also effective in reversing established uterine inhibition by cromakalim and appears to have stimulated uterine contractions above control values in these animals. Cromakalim has a prolonged duration of inhibition of uterine contractions (Downing et al, 1989). At 5 h after the control high dose of cromakalim (0.25mgkg-1), there may have been some residual effect of the drug.…”

Effects of several potassium channel openers and glibenclamide on the uterus of the rat

“…Intrauterine pressure and its integral or blood pressure and heart rate were measured in conscious unrestrained rats and recorded on a Grass polygraph as described previously Downing et al, 1989 The same experimental design was adopted to measure the effects of cromakalim (0.1 mgkg-1) and RP 49356 (0.1 mgkg-') on blood pressure (BP) and heart rate (HR) before and after glibenclamide or vehicle infusion. Data are expressed as % change from pre-injection control values.…”

“…The surgical technique was based on that of and Downing et al (1989). Rats were anaesthetized with tribromoethanol (240mgkg-1, i.p.…”