Phentolamine and structurally related compounds selectively antagonize the vascular actions of the K+ channel opener, cromromakalim.

1. The effects of cromakalim, a novel vasodilator agent believed to open K+ channels, were studied in a range of large and small arteries in vitro. In dog isolated coronary artery, precontracted with U46619 (a thromboxane A2-mimetic), cromakalim caused concentration-dependent relaxation which could be inhibited by phentolamine (10-100 microM). 2. The ability of phentolamine to antagonize cromakalim was selective since it did not affect responses to a number of other vasodilators including isoprenaline, nitroprusside or nicorandil. 3. The effect of phentolamine was not related to its alpha-adrenoceptor blocking actions since other alpha-adrenoceptor antagonists (prazosin 10 microM, rauwolscine 10 microM and phenoxybenzamine 1 microM) failed to influence the action of cromakalim. 4. A number of compounds structurally related to phentolamine were also able to block the vaso-relaxant response to cromakalim in the dog isolated coronary artery. The rank order of potency was alinidine = phentolamine = ST91 greater than tramazoline = naphazoline. Clonidine and tolazoline were inactive. The most potent compounds (alinidine and phentolamine) were effective only at concentrations above 1 microM. 5. Electrophysiological studies, in which resting membrane potential and tension were measured simultaneously, were carried out on rat isolated femoral artery. Phentolamine (30 microM) antagonized both the vasorelaxation and hyperpolarization caused by cromakalim. 6. These results suggest that phentolamine and some structurally related compounds, may inhibit K+ channel opening, an action which would account for their ability to antagonize the actions of cromakalim. Such compounds may prove useful in determining the role of K+ channels in regulating vascular smooth muscle tone in vivo and in vitro.