Modulation of membrane currents and mechanical activity by niflumic acid in rat vascular smooth muscle

Abstract

The effects of niflumic acid on whole-cell membrane currents and mechanical activity were examined in the rat portal vein. In freshly dispersed portal vein cells clamped at −60 mV in caesium (Cs +)-containing solutions, niflumic acid (1–100 μM) inhibited calcium (Ca 2+)-activated chloride currents ( I Cl(Ca)) induced by caffeine (10 mM) and by noradrenaline (10 μM). In a potassium (K +)-containing solution and at a holding potential of −10 mV, niflumic acid (10–100 μM) induced an outward K + current ( I K(ATP)) which was sensitive to glibenclamide (10–30 μM). At concentrations < 30 μM and at a holding potential of −2 mV, niflumic acid had no effect on the magnitude of the caffeine- or noradrenaline-stimulated current ( I BK(Ca)) carried by the large conductance, Ca 2+-sensitive K + channel (BK Ca). However, at a concentration of 100 μM, niflumic acid significantly inhibited I BK(Ca) evoked by caffeine (10 mM) but not by NS1619 (1-(2′-hydroxy-5′-trifluoromethylphenyl)-5-trifluorommethyl-2(3 H)benzimidazolone; 20 μM). In Cs +-containing solutions, niflumic acid (10–100 μM) did not inhibit voltage-sensitive Ca 2+ currents. In intact portal veins, niflumic acid (1–300 μM) inhibited spontaneous mechanical activity, an action which was partially antagonised by glibenclamide (1–10 μM), and contractions produced by noradrenaline (10 μM), an effect which was glibenclamide-insensitive. It is concluded that inhibition of I Cl(Ca) and stimulation of I K(ATP) both contribute to the mechano-inhibitory actions of niflumic acid in the rat portal vein.