Antagonism by lipophilic quaternary ions of the K+ channel opener, levcromakalim, in vascular smooth muscle.

1. The aim of this study was to characterize the interaction between the K+ channel opener levcromakalim (LKM) and several quaternary ions, in vascular smooth muscle, in vitro. Segments of isolated, thoracic aorta of the rat were suspended in organ baths filled with Krebs solution at 37 degrees C. Cumulative concentration-response curves to LKM were obtained in the absence and in the presence of increasing concentrations of quaternary ions using a number of agents to pre-constrict the vessel. The ions tested were tetraphenylphosphonium (chloride TPP-Cl and bromide TPP-Br salts), tetrapentylammonium (TPeA), tetraethylammonium (TEA), tetraphenylarsonium (TPAs) and tetraphenylboron (TPB). 2. For the compounds which antagonized the vasorelaxation responses of LKM, 'apparent pKB' values were estimated on the basis of a single concentration of antagonist. These were then used to obtain the following order of potency: TPP-Br (7.22 +/- 0.25) = TPAs (7.12 +/- 0.04) = TPP-Cl (7.11 +/- 0.15) > TPeA (6.23 +/- 0.20). TEA and TPB were both found to be inactive at the maximum concentrations used. 3. The interaction between the cationic TPP and anionic TPB was also investigated. The shift in the LKM concentration-response curve constructed in the presence of both of these compounds was compared to that when each agent was present separately. We found that TPB, at concentrations greater than 1 microM, reversed the blockade of the LKM-mediated relaxation induced by TPP (3 microM). 4. Similar experiments were undertaken combining TPB with either alinidine or glibenclamide (both functional antagonists of K+ channel openers). It was found that TPB (10 microM) partially reversed the antagonism induced by alinidine (30 and 100 microM) but had no effect on the action of glibenclamide(3 microM).5. These studies show that lipophilic cations such as TPP and TPAs are potent antagonists of levcromakalim-mediated vasorelaxation responses in the rat thoracic aorta. The mechanism by which these compounds cause their antagonism is not known. However, given the lipophilicity of these compounds, it is possible they may act at a number of sites including the KATP channel itself or possibly via some other intracellular mechanism.