“…The potencies of cromakalim, RP 49356 and pinacidil in the isolated uterus against oxytocin-induced spasms were similar to those observed in vascular smooth muscle (Southerton et al, 1988;Cavero et al, 1989;Eltze, 1989 Glibenclamide is a blocker of ATP-dependent K+ channels in pancreatic fl-cells (Sturgess et al, 1988) and in smooth muscle (Standen et al, 1989). Glibenclamide has been used in smooth muscle as a pharmacological tool to demonstrate that cromakalim and related compounds act via ATP-dependent K+ channels (Quast & Cook, 1989b Eltze, 1989;Quast & Cook, 1989a;Wilson, 1989).…”
Section: In Vivosupporting
confidence: 53%
“…Glibenclamide has been used in smooth muscle as a pharmacological tool to demonstrate that cromakalim and related compounds act via ATP-dependent K+ channels (Quast & Cook, 1989b Eltze, 1989;Quast & Cook, 1989a;Wilson, 1989). The pA2 value for the interaction of glibenclamide with pinacidil was lower than that for cromakalim or RP 49356 and there was a Schild slope of greater than -1.…”
Section: In Vivomentioning
confidence: 99%
“…However, in the uterus of the term-pregnant rat, in contrast to other smooth muscles, cromakalim does not increase the efflux of 86Rb+ or 42K+, produce a marked hyperpolarization or augment the outward K + current in isolated myometrial cells (Hollingsworth et al, 1987;. Recently, it has been shown that glibenclamide is a selective antagonist of these K + channel openers in vitro (Buckingham et al, 1989;Cavero et al, 1989;Eltze, 1989;Wilson, 1989;Winquist et al, 1989;Newgreen et al, 1990).…”
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 (10p1M). (0.01-1lpM) inhibited spasm evoked by all concentrations of KCl (10-80mM). Suppression of spasm evoked by KCI (10-80mM) by cromakalim (100pM) and pinacidil (100pMm) was insensitive to glibenclamide (10pM).4 Cromakalim (0.1mgkg-1) and RP 49356 (0.1mgkg-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 (20mgkg-'), 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 100puM) and cromakalim (100pM) 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.
“…The potencies of cromakalim, RP 49356 and pinacidil in the isolated uterus against oxytocin-induced spasms were similar to those observed in vascular smooth muscle (Southerton et al, 1988;Cavero et al, 1989;Eltze, 1989 Glibenclamide is a blocker of ATP-dependent K+ channels in pancreatic fl-cells (Sturgess et al, 1988) and in smooth muscle (Standen et al, 1989). Glibenclamide has been used in smooth muscle as a pharmacological tool to demonstrate that cromakalim and related compounds act via ATP-dependent K+ channels (Quast & Cook, 1989b Eltze, 1989;Quast & Cook, 1989a;Wilson, 1989).…”
Section: In Vivosupporting
confidence: 53%
“…Glibenclamide has been used in smooth muscle as a pharmacological tool to demonstrate that cromakalim and related compounds act via ATP-dependent K+ channels (Quast & Cook, 1989b Eltze, 1989;Quast & Cook, 1989a;Wilson, 1989). The pA2 value for the interaction of glibenclamide with pinacidil was lower than that for cromakalim or RP 49356 and there was a Schild slope of greater than -1.…”
Section: In Vivomentioning
confidence: 99%
“…However, in the uterus of the term-pregnant rat, in contrast to other smooth muscles, cromakalim does not increase the efflux of 86Rb+ or 42K+, produce a marked hyperpolarization or augment the outward K + current in isolated myometrial cells (Hollingsworth et al, 1987;. Recently, it has been shown that glibenclamide is a selective antagonist of these K + channel openers in vitro (Buckingham et al, 1989;Cavero et al, 1989;Eltze, 1989;Wilson, 1989;Winquist et al, 1989;Newgreen et al, 1990).…”
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 (10p1M). (0.01-1lpM) inhibited spasm evoked by all concentrations of KCl (10-80mM). Suppression of spasm evoked by KCI (10-80mM) by cromakalim (100pM) and pinacidil (100pMm) was insensitive to glibenclamide (10pM).4 Cromakalim (0.1mgkg-1) and RP 49356 (0.1mgkg-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 (20mgkg-'), 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 100puM) and cromakalim (100pM) 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.
“…This has also been observed with 7 various other K channel openers (Hamilton et al, 1986;Weir 8 & Quast & Cook, 1989). Recently, sulphonyl-9 ureas like glibenclamide have been shown to block cromakalim-induced electrical and mechanical changes in cardiac (Escande et al, 1988;Fosset et al, 1988;Sanguinetti et al, 1988;Satoh et al, 1990) and in vascular smooth muscle (Buckingham et al, 1989;Eltze, 1989;Quast & Cook, 1989 (Figure 8), a supposed guanylate cyclase vel. The force of contraction was increased in inhibitor (Ignarro et al, 1981).…”
“…The relaxations induced by cromakalim and nitroglycerin were inhibited by glibenclamide (10-6 M) and oxyhaemoglobin (10-5 M), respectively ( Figure 4). Glibenclamide (10-6 M) and oxyhaemoglobin (10' M) had no effect on the relaxations induced by nitroglycerin and cromakalim, respectively (Figure 4 te and a K+ nitrate action and a K+ channel opening action, respectively, dilator actions because oxyhaemoglobin, a pharmacological antagonist of pi-and midnitrovasodilators (Martin et al, 1985), and glibenclamide, a be based on a pharmacological antagonist of K+ channel openers (Cavero et al, 1989;Eltze 1989), had no effect on cromakalim-and nitroglycerin-induced responses, respectively. The difference in the relaxation response between epi-and mid-myocardial coronary arteries is likely to be important in the redistribution of coronary blood flow.…”
1 The relaxant mechanisms of action of KRN2391, a novel vasodilator, and nicorandil on epimyocardial coronary artery (2.5-3.0 mm outer diameter) and mid-myocardial coronary artery (0.8-1.0 mm outer diameter) were investigated in porcine isolated coronary arteries. In addition, the vasorelaxant responses of KRN2391 and nicorandil were compared with those of nitroglycerin and cromakalim, a K+ channel opener, in epi-and mid-myocardial coronary arteries. 2 Nitroglycerin showed a more potent relaxant effect on epi-myocardial coronary arteries than on mid-myocardial coronary arteries, whereas cromakalim produced greater relaxation responses in midmyocardial coronary arteries. There was no difference between epi-and mid-myocardial coronary arteries in terms of the relaxant effect of KRN2391 and nicorandil. 3 Relaxation induced by KRN2391 in epi-and mid-myocardial coronary arteries was inhibited by oxyhaemoglobin, a pharmacological antagonist of nitrovasodilators, and glibenclamide, a pharmacological antagonist of K+ channel opening drugs. However, the inhibitory effect of glibenclamide on KRN2391-induced relaxation was greater in mid-myocardial coronary artery than in epi-myocardial coronary artery. 4 Relaxation induced by nicorandil was inhibited by oxyhaemoglobin alone in epi-myocardial coronary arteries and by both oxyhaemoglobin and glibenclamide in mid-myocardial coronary arteries. 5 In epi-and mid-myocardial coronary arteries, relaxation induced by cromakalim was inhibited by glibenclamide but not by oxyhaemoglobin, whereas relaxation induced by nitroglycerin was inhibited by oxyhaemoglobin but not by glibenclamide. 6 These results suggest that KRN2391 and nicorandil exhibit a dual mechanism of action acting partly as a nitrate and partly as a K+ channel opener. The mechanism of action of these drugs depend on the segment of coronary artery studied. Furthermore, the dual mechanism of action of KRN2391 and nicorandil seems to contribute to the equipotent relaxant effect between epi-and mid-myocardial coronary arteries.
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