A comparison of the effects of SCA40, NS 004 and NS 1619 on large conductance Ca²⁺‐activated K⁺ channels in bovine tracheal smooth muscle cells in culture

Abstract

1 The effects of imidazopyrazine derivative, SCA40, on the activity of single large conductance, Ca2+-activated K+ (BKCa) channels in inside-out and outside-out patches from bovine tracheal smooth muscle (BTSM) BKCa channels when applied to either inside-out or outside-out BTSM patches, thus confirming that these compounds are activators of the BKCa channel in this preparation. 4 SCA40 (0.1 -10 pM) had no effect on the activity of BKCa channels when applied to either inside-out or outside-out patches which subsequently responded to the application of NS 004 (10-20 pM). 5It is concluded that SCA40 does not have a direct effect on BKca channel activity in BTSM patches and that the previously reported relaxant action of SCA40 on tracheal smooth muscle is unlikely to be mediated by this mechanism.

Further analysis of the mechanisms underlying the tracheal relaxant action of SCA40

“…Quinine is a relatively non-selective inhibitor among Ca+-dependent K+-channels (Haylett & Jenkinson, 1990 (Figure 4; Table 2). Further support for this idea comes from patch clamp experiments performed on bovine trachealis where SCA40 (0.1-10tM) failed to modify the activity of BKCa channels recorded from either inside-out, outside-out or cell-attached plasmalemmal patches (MacMillan et al, 1994).…”

A Major Role for Prostacyclin in Nitric Oxide–Induced Ocular Vasorelaxation in the Piglet

“…Likewise, 6-keto PGF 1␣ synthesis by cultured retinal endothelial cells in response to SNP was nearly nullified by charybdotoxin and iberiotoxin but not by glibenclamide or 4-AP ( Figure 5C). In addition, the specific K Ca channel openers NS1619 and NS004 33 also stimulated synthesis of 6-keto PGF 1␣ ; this was virtually abolished by iberiotoxin. K ϩ channel blockers did not modify basal (in the absence of SNP, NS1619, or NS004) production of 6-keto PGF 1␣ .…”

Activation of large conductance potassium channels inhibits the afferent and efferent function of airway sensory nerves in the guinea pig.

“…Patch clamp studies have shown that in isolated smooth muscle cells from bovine trachea (21), rat portal vein (20), and basilar artery (22), NS1619 reversibly activates a hyperpolarising outward current resulting from the opening of BK Ca channels. A similar increase in the opening of BK Ca channels was seen in ventromedial hippocampal neurones (23).…”

“…In particular, the benzimidazolone compound, NS1619, has been shown to activate BK Ca channels in airways and vascular smooth muscle (20)(21)(22), and in hippocampal neurones (23). We have used this compound in combination with iberiotoxin, a highly selective blocker of BK Ca channels, to determine if the activation of these channels on sensory fiber endings in the guinea pig airways leads to an inhibition of fiber activity, using an in vitro model of single fiber recording (24).…”