Big Conductance Calcium-activated Potassium Research Articles

Some structural changes on triazolyl-benzotriazoles and triazolyl-benzimidazolones as potential potassium channel activators. III

This paper reports the synthesis and pharmacological evaluation of some compounds, obtained by structural modifications of 1,2,3-triazolyl-benzotriazoles and 1,2,3-triazolyl-benzimidazolones, which had shown activity as potential activators of the big-conductance calcium-activated potassium channels (BK Ca). Changes have concerned the introduction of a hinderer substituent in the 5-position of the benzimidazolone ( 4a, b) and benzotriazole ( 5a, b) rings, opening of the benzimidazolone ring ( 7) and substitution of the 1,2,3-triazole ring with a 2-hydroxyphenyl ring ( 10). Furthermore a series of 3-aryl-benzotriazin-4-one derivatives ( 13a– e) has been studied, which appears as a modification and/or combination of the benzimidazolone and benzotriazole rings. Only compound 10 shows interesting activity, while the other structural modifications either do not increase (compounds 4 and 5) or reduce (compounds 7 and 13) the pharmacological activity. However, these results provide useful information about structure–activity relationships.

Triazolyl–benzimidazolones and triazolyl–benzotriazoles: new potential potassium channel activators. II

This paper reports the synthesis and pharmacological evaluation of a series of 5-substituted-triazolyl–benzotriazoles ( 2a–f) and the corresponding series of 5-substituted-triazolyl–benzimidazolones ( 6a–f), as potential activators of the big-conductance calcium-activated potassium channels (BK Ca). The synthesis and structure demonstration of the stock compounds of the two series have been described in our previous works, as well as the common starting compounds 4-carboxamido-5-(4-substituted-2-amino-anilino)-1,2,3-triazoles ( 1a–f). The triazolyl–benzotriazoles were obtained by diazotization, while the triazolyl–benzimidazolones were obtained by thermal intramolecular cyclization of ethoxycarbonylamino derivatives or directly with phosgene. Benzimidazolone compounds generally showed little effect whilst the compounds with a benzotriazole ring showed full efficacy, with vasorelaxing properties and potency parameters a little lower than that of the reference compound NS 1619. These effects were significantly reduced by an increased membrane depolarization. This depolarization-sensitive response is in agreement with the pharmacodynamic hypothesis of activation of potassium channels.

17-beta-estradiol modulation of area postrema potassium currents.

The purpose of this study was to determine the effects of 17-beta-estradiol on area postrema neuronal activity in vivo and on area postrema potassium currents (IK) in vitro. In anesthetized rats, intravenous injection of 17-beta-estradiol (10 ng/kg bw) -inhibited area postrema neuronal activity in 8/8 neurons tested. The averaged firing rate decreased from 2.9 +/- 1.1 to 1.1 +/- 0.3 Hz. The inhibitory effects of 17-beta-estradiol on area postrema neuronal activity were rapid in onset (within 1 min) and long-lasting (>8 min). To study the cellular mechanisms involved in this response, the effects of 17-beta-estradiol were examined in dissociated area postrema neurons. In these cells, 17-beta-estradiol (0.5 nM) increased the averaged peak IK 27 +/- 8%. The time course for the potentiation was observed within approximately 0.5-1 min after the application of 17-beta-estradiol. Full recovery from the potentiation usually occurred within approximately 3-4 min after the washout of 17-beta-estradiol. The biologically inactive 17-alpha-estradiol had no effect on area postrema IK and the 17-beta-estradiol antagonist, ICI 182,780 blocked the effects of 17-beta-estradiol on area postrema IK. Finally, big conductance calcium-activated potassium current (MaxiK(+)) was identified in area postrema neurons (n = 12/12). Blockade of MaxiK(+) with 100 nM iberiotoxin blocked the effects of 17-beta-estradiol on IK. These results suggested 17-beta-estradiol might modulate area postrema neuronal activity by increasing MaxiK(+) current.

The Chemical Modification of KCa Channels by Carbon Monoxide in Vascular Smooth Muscle Cells

The chemical modification of big conductance calcium-activated potassium (KCa) channels in rat tail artery smooth muscle cells by carbon monoxide (CO) was investigated using the cell-free single channel recording technique. Exposure of the internal surface of cell membranes to diethyl pyrocarbonate (DEPC) neither affected the characteristics of KCa channels nor modified the stimulatory effect of CO on KCa channels. However, when DEPC was applied to the external surface of cell membranes, the open probability of KCa channels was reduced. The pH and concentration dependence of the effect of DEPC indicated the specific modification of histidine residues. Kinetic analysis suggested that one externally located histidine residue was modified by DEPC. Treatment of the external surface of cell membranes with DEPC abolished the CO-induced increase in the open probability of KCa channels. Likewise, the presence of CO partially protected KCa channels from inhibition by DEPC. Moreover, photooxidation of the histidine residue located on the external membrane surface abolished the CO-induced activation of KCa channels. Our study demonstrates that the CO-induced increase in the open probability of KCa channels may rely specifically on the structure and topological locations of histidine residues.