Inhibitory action of niflumic acid on noradrenaline- and 5-hydroxytryptamine-induced pressor responses in the isolated mesenteric vascular bed of the rat

1 The effects of niflumic acid, an inhibitor of calcium-activated chloride currents, were compared with the actions of the calcium channel blocker nifedipine on noradrenaline and 5-hydroxytryptamine (5-HT)-induced presser responses of the rat perfused isolated mesenteric vascular bed. 2 Bolus injections of noradrenaline (1 and 10 nmol) increased the perfusion pressure in a dose-dependent manner. Nifedipine (1 mu M) inhibited the increase in pressure produced by 1 nmol noradrenaline by 31+/-5%. Niflumic acid (10 and 30 mu M) also inhibited the noradrenaline-induced increase in perfusion pressure and 30 mu M niflumic acid reduced the presser response to 1 nmol noradrenaline by 34+/-6%. 3 The increases in perfusion elicited by 5-HT (0.3 and 3 nmol) were reduced by niflumic acid (10 and 30 mu M) in a concentration-dependent manner and 30 mu M niflumic acid inhibited responses to 0.3 and 3 nmol 5-HT by, respectively, 49+/-8% and 50+/-7%. Nifedipine (1 mu M) decreased the presser response to 3 nmol 5-HT by 44+/-9%. 4 In the presence of a combination of 30 mu M niflumic acid and 1 mu M nifedipine the inhibition of the presser effects of noradrenaline (10 nmol) and 5-HT (3 nmol) was not significantly greater than with niflumic acid (30 mu M) alone. Thus the effects of niflumic acid and nifedipine were not additive. 5 In Ca-free conditions the transient contractions induced by 5-HT (3 nmol) were not reduced by 30 mu M niflumic acid, suggesting that this agent does not inhibit calcium release from the intracellular store or the binding of 5-HT to its receptor. 6 Niflumic acid 30 mu M did not inhibit the presser responses induced by KCI (20 and 60 mu mol) which were markedly reduced by 1 mu M nifedipine. In addition, 1 mu M levcromakalim decreased presser responses produced by 20 mu mol KCl. These data suggest that niflumic acid does not block directly calcium channels or activate potassium channels. 7 It is concluded that niflumic acid selectively reduces a component of noradrenaline- and 5-HT-induced presser responses by inhibiting a mechanism which leads to the opening of voltage-gated calcium channels. Our data suggest that the Ca2+-activated chloride conductance may play a pivotal role in the activation of voltage-gated calcium channels in agonist-induced constriction of resistance blood vessels.