Effects of lemakalim on changes in Ca²⁺concentration and mechanical activity induced by noradrenaline in the rabbit mesenteric artery

Abstract

1 Effects of (-)-cromakalim (lemakalim) on tension and Ca2+ mobilization induced by noradrenaline (NA) were investigated by measuring intracellular Ca2" concentration ([Ca2"]), isometric tension and production of inositol-1,4,5-trisphosphate (IP3) in smooth muscle strips of the rabbit mesenteric artery.2 In thin smooth muscle strips, 1OpUM NA produced a large phasic, followed by a small tonic increase in [Ca2'ji, which correlated well with the evoked phasic and tonic contractions, respectively. Lemakalim (0. 4 In fl-escin-skinned strips, 1OMm NA increased [Ca2+]i in Ca2+-free solution containing 50pM EGTA, 3 pM guanosine triphosphate (GTP) and 2,pM Fura 2 after the storage sites were loaded by application of 0.3/iM Ca2+ for 2 min, suggesting that Ca2+ is released from intracellular storage sites following activation of the a-adrenoceptor. Lemakalim (1 pM) did not inhibit the Ca2+ release from storage sites induced by NA. 5 We conclude that lemakalim inhibits NA-induced Ca2 + release due to inhibition of NA-induced 'P3 production in a manner dependent on the membrane potential and causes inhibition of the phasic contraction induced by NA.

Comparative effects of BRL 38227, nitrendipine and isoprenaline on carbachol‐ and histamine‐stimulated phosphoinositide metabolism in airway smooth muscle

“…The failure to affect the initial rate of phosphoinositide hydrolysis is consistent with the poor anti-spasmogenic activity of K+-channel openers observed in some tissues (Allen et al, 1986;Cook et al, 1988;Bray et al, 1991;Raeburn & Brown, 1991). In contrast to the present findings, Ito et al (1991) (Clapham & Wilson, 1987), and suggests that the ability of K+-channel In many tissues a Ca2"-activated component of the phosphoinositide response can be discerned (Eberhard & Holz, 1988). Thus, in membranes prepared from airway smooth T T muscle, changes in calcium concentration within the physiological range have been shown to stimulate PIC activity (Murray et al, 1989b).…”

Effects of rubidium on responses to potassium channel openers in rat isolated aorta

“…In addition, levcromakalim inhibits the loading of 45Ca into inositol trisphosphate (InsP3)-sensitive calcium stores in rabbit cultured airways smooth muscle (Chopra et al, 1992) and antagonizes agonist-induced stimulation of InsP3 formation (Ito et al, 1991b;Challis et al, 1992;Itoh et al, 1992). Pinacidil and levcromakalim also reduce the noradrenaline-induced increase in [Ca2+]i as determined by fura-2 epifluorescence techniques (Ito et al, 1991b;Criddle et al, 1992;Itoh et al, 1992).…”

Effect of KC399, a newly synthesized K+ channel opener, on acetylcholine‐induced electrical and mechanical activities in rabbit tracheal smooth muscle

“…Following work on vascular smooth muscle, it was originally thought that such K+ channel openers might inhibit the activation of the L-type Ca2+ channel as a result of the membrane hyperpolarization they evoke and that this was responsible for their inhibition of agonist-induced contraction (Standen et al, 1989). Later, it was found, in vascular smooth muscle from various vessels, that the membrane hyperpolarization induced by such K+ channel openers also inhibits agonist-induced production of inositol 1,4,5-trisphosphate (InsP3) (Ito et al, 1991;Itoh et al, 1992) and/or lowers the sensitivity of the contractile machinery to Ca2" (Okada et al, 1993). Thus, it seems likely that these three mechanisms may all contribute to the K'channel opener-induced muscle relaxation in vascular smooth muscle.…”