Moving together: K+ channel openersand ATP-sensitive K+ channels

1 The aim of this study was to assess the role of endothelial cells in the modulation of vasocontractile responses to endothelin-1 (ET-1) of human placental vasculature.2 Isolated stem villi small arteries (diameter = 170-250 gm) were obtained from healthy parturients who underwent caesarean surgery during the 39th week of pregnancy for cephalo-pelvic disproportion. Isometric tension was measured in vascular rings mounted in a myograph system and challenged with ET-1 (10-12 to 10-6 M). 3 The vasocontractile response to ET-1 was significantly (P<0.0001) increased in endothelial-denuded (active tension= 1156 + 214 mN mm-') as compared with endothelial-preserved vascular rings (active tension = 458 ± 48 mN mm-1). This difference was significantly (P< 0.05) but only partly abolished by the NO synthase inhibitor N1'-nitro-L-arginine (L-NOARG, 10' M).4 In endothelial-preserved rings submaximally precontracted with 5-hydroxytryptamine (10-6 M), ET-1 (10-12 to 10-9 M) induced dose-dependent relaxation (maximum relaxation = 70 + 7%) at 10-9 M, which was followed, at higher doses (10-8 to 10-6 M), by a contraction. In contrast, no relaxation was seen in endothelial-denuded rings. The relaxation in rings with endothelium was significantly (P<0.001) reduced by L-NOARG (10-4 M). Moreover, it was totally abolished by combined pretreatment with L-NOARG (10-4 M) and the sulphonylurea glibenclamide (10' M). 5 In conclusion, endothelial cells modulate the vascular responses to ET-1 through the release of NO and a substance acting on the ATP-sensitive K+ channel of smooth muscle of stem villi small arteries from healthy parturients.

Section: Resultsmentioning

confidence: 99%

Endothelial modulation of vasoconstrictor responses to endothelin‐1 in human placental stem villi small arteries

Sabry

Mondon

Lévy

et al. 1995

“…Quast & Cook (1989) proposed that the action of potassium channel openers may also be enhanced under such conditions. Indeed, the vasorelaxant action of the K ATP channel opener levcromakalim, though not pinacidil, appears to be enhanced under such conditions, since levcromakalim was more potent in causing vasodilation of the rabbit ear artery in hypoxia or when oxidative metabolism was impaired (Randall & Gri th, 1993).…”

Section: E Ects Of Metabolic Inhibition On Nicorandil Relaxationsmentioning

confidence: 99%

Potassium channel activation and relaxation by nicorandil in rat small mesenteric arteries

Davie

Kubo

Standen

1998

1 We used whole-cell patch clamp to investigate the currents activated by nicorandil in smooth muscle cells isolated from rat small mesenteric arteries, and studied the relaxant e ect of nicorandil using myography. 2 Nicorandil (300 mM) activated currents with near-linear current-voltage relationships and reversal potentials near to the equilibrium potential for K + . 3 The nicorandil-activated current was blocked by glibenclamide (10 mM), but una ected by iberiotoxin (100 nM) and the guanylyl cyclase inhibitor LY 83583 (1 mM). During current activation by nicorandil, openings of channels with a unitary conductance of 31 pS were detected. 4 One hundred mM nicorandil had no e ect on currents through Ca 2+ channels recorded in response to depolarizing voltage steps using 10 mM Ba 2+ as a charge carrier. A small reduction in current amplitude was seen in 300 mM nicorandil, though this was not statistically signi®cant. 5 In arterial rings contracted with 20 mM K + Krebs solution containing 200 nM BAYK 8644, nicorandil produced a concentration-dependent relaxation with mean pD 2 =4.77+0.06. Glibenclamide (10 mM) shifted the curve to the right (pD 2 =4.32+0.05), as did 60 mM K + . LY 83583 caused a dosedependent inhibition of the relaxant e ect of nicorandil, while LY 83583 and glibenclamide together produced greater inhibition than either alone. 6 Metabolic inhibition with carbonyl cyanide m-chlorophenyl hydrazone (30 nM), or by reduction of extracellular glucose to 0.5 mM, increased the potency of nicorandil. 7 We conclude that nicorandil activates K ATP channels in these vessels and also acts through guanylyl cyclase to cause vasorelaxation, and that the potency of nicorandil is increased during metabolic inhibition.

“…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%

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

Piper

Minshall

Downing

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.