Evidence that BKCa channel activation contributes to K+ channel opener induced relaxation of the porcine coronary artery

Abstract

The rank order of potency of a series of benzopyran and cyanoguanidine K+ channel openers (KCOs) for causing relaxation of the PGF2 alpha-precontracted porcine coronary artery was determined. Glyburide, an inhibitor of KATP channels, showed an apparent competitive inhibition of the vasorelaxant activity of the KCOs. The pA2 values of glyburide when cromakalim and CGP 14877 (P1060) were used as vasorelaxants were 7.66 and 7.83, respectively. Charybdotoxin (40 nM), an inhibitor of BKCa channels, also caused a significant inhibition of the cromakalim mediated relaxation of the porcine coronary artery. In order to clarify the site of action of these KCOs, we identified a K+ channel current in single porcine coronary arterial cells and measured channel activity in the presence of these compounds. The prominent K+ ion current in these cells had characteristics typical of the conventional large Ca(2+)-activated K+ channel (BKCa) present in other smooth muscle cells. Using symmetrical K+ concentrations, the channel had a conductance of 214 pS and was found to be sensitive to [Ca2+]i and membrane potential. The KCOs were found to reversibly increase the open probability (P(o)) of the channel without changing channel conductance. The potency of the KCOs to increase K+ channel opening was similar to the potency of these compounds to cause coronary artery relaxation. These results indicate that the porcine coronary artery contains the BKCa channel and that this channel, along with other types of K+ channels (KATP), mediate the vasorelaxant effects of K+ channel openers.

Levosimendan Interacts with Potassium Channel Blockers in Human Saphenous Veins

“…Furthermore, the BK Ca channel revealed cation activation characteristics similar to troponin C (Latorre et al 1989), the latter being absent in smooth muscles, but comprising the primary target site for levosimendan in the heart (Haikala et al 1995). It is also worth mentioning that a prototype K ATP channel opener drug, cromakalim, also relaxes smooth muscles through activation of BK Ca channels, indicating a nonspecific potassium channel activating characteristics of this group of drugs (Balwierczak et al 1995). In the present study iberiotoxin, a selective inhibitor of BK Ca channels, antagonized the venodilating effect of levosimendan.…”

A K+ single channel and whole-cell clamp study on the effects of levcromakalim in guinea pig portal vein cells

“…This is not compatible with the upwardbent curvature predicted by the GHK current equation for purely resistive channels at high [K + ] i versus low [K + ] o . In conclusion, in the guinea pig portal vein cells, no evidence could be established for the hypotheses that KCOs may act via conversion of K v to K ATP (Beech and Bolton 1989;Edwards et al 1993) or by activation of BK Ca (Balwierczak et al 1995). In these cells, mild inward rectification of the levcromakalim-induced current was observed which underlines their relationship to K ATP in other tissues.…”

“…Particularly "big" calcium-dependent K + channels (BK Ca ) which abundantly exist in vascular smooth muscle have been suggested as the targets of KCOs (Klöckner et al 1989;Gelband et al 1989Gelband et al , 1990Hu et al 1990;Gelband and McCullough 1993;Balwierczak et al 1995). The casual activation of BK Ca in our experiments permitted us to study their dependence on levcromakalim and glibenclamide at the single channel level.…”

Vasodilating Mechanisms of Levosimendan: Involvement of K+ Channels

“…Hence, levosimendan and its metabolite may prefentially stimulate K V and BK Ca channels in large conductance vessels and the K ATP channel in small resistance vessels as it was previously suggested (13). It should also be noted that the prototype K ATP -channel-opener drug cromakalim relaxes smooth muscles through activation of BK Ca channels, indicating a non-specific potassium channel activating characteristic of this class of drugs (33). Obviously, additional studies in human arteries would be of interest to clarify the mechanism of the vasodilatory effect of levosimendan and its metabolite in different vascular beds.…”