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

Abstract

1 The ability of several potassium (K⁺) channel openers to inhibit spasm of the uterus of the nonpregnant rat and their susceptibility to antagonism by glibenclamide was assessed in vitro and in vivo. 2 In the isolated uterus exposed to oxytocin (0.2 nm), cromakalim, RP 49356 and pinacidil were of similar potency (mean pD₂ = 6.4, 6.0 and 6.2 respectively) while minoxidil sulphate was of lower potency (pD₂ = 4.7). Glibenclamide antagonized cromakalim and RP 49356 with the interactions consistent with competitive antagonism (mean pA₂ of 6.57 and 7.00 respectively). Glibenclamide also antagonized pinacidil (pA₂ = 6.22) but the slope of the Schild plot was significantly greater than −1. Neither salbutamol nor minoxidil sulphate was antagonized by glibenclamide (10 μm). 3 Cromakalim (1 and 10 μm), RP 49356 (1 and 10 μm), pinacidil (1 μm) and minoxidil sulphate (100 μm) suppressed spasm evoked by low (< 40 mm) but not high (≥ 40 mm) KCl concentrations. Glibenclamide (10 μm) prevented cromakalim (10 μm)-, RP 49356 (10 μm)- and pinacidil (10 μm)-induced suppression of KCl (20 mm)-evoked spasm. Pinacidil (10 and 100 μm), cromakalim (100 μm) and salbutamol (0.01–1 μm) inhibited spasm evoked by all concentrations of KCl (10–80 mm). Suppression of spasm evoked by KCl (10–80 mm) by cromakalim (100 μm) and pinacidil (100 μm) was insensitive to glibenclamide (10 μm). 4 Cromakalim (0.1 mg kg⁻¹) and RP 49356 (0.1 mg kg⁻¹), given by i.v. bolus injection, inhibited uterine contractions, produced a fall in blood pressure and a slight tachycardia in the conscious ovariectomized rat. Glibenclamide (20 mg kg⁻¹), given by i.v. infusion, antagonized the vascular and uterine smooth muscle relaxant properties of cromakalim and RP 49356. 5 Several K⁺ channel openers are uterine relaxants. The antagonism of cromakalim, RP 49356 and pinacidil, at low concentrations, by glibenclamide suggests their actions may involve an ATP-sensitive K⁺ channel. High concentrations of pinacidil (10 and 100 μm) and cromakalim (100 μm) may exert an additional action in the uterus. The low potency of minoxidil sulphate and its insensitivity to glibenclamide in the isolated uterus suggests that its mechanism of action may differ from that of the other K⁺ channel openers.