INHIBITION BY CROMAKALIM, PINACIDIL, TERBUTALINE, THEOPHYLLINE AND VERAPAMIL OF NONCHOLINERGIC NERVE-MEDIATED CONTRACTIONS OF GUINEA-PIG ISOLATED BRONCHI

Contractions induced by electrical field stimulation of sensory non-cholinergic excitatory nerves in guinea-pig isolated bronchi are due to the release of substance P (SP) and related tachykinins. Release of such neuropeptides are thought to play a pathophysiological role in asthma. Two K+ channel openers cromakalim (pD(2)=6.45; E(max)=95%) and pinacidil (pD(2)=6.06; E(max)=87%) were shown to concentration-dependently inhibit non-cholinergic nerve-mediated contractions in guinea-pig bronchi in vitro. Cromakalim (pD(2)=6.27; E(max)=25%) and pinacidil (pD(2)=6.03; E(max)=25%) each had a much lower inhibitory efficacy against contractions induced by exogenously applied SP but the same potency as found against contractile responses to non-cholinergic neurostimulation. Also the a-adrenoceptor agonist terbutaline (pD(2)=8.29; E(max)=83%), the xanthine derivative theophylline (pD(2)=4.19; E(max)=100%) and the Ca2+ blocker verapamil (pD(2)=5.55; E(max)=100%) suppressed responses to non-cholinergic neurostimulation. Terbutaline (pD(2)=6.32; E(max)=74%), theophylline (pD(2)=3.25; E(max)=71%) and verapamil (pD(2)=4.01; E(max)=100%) had a 10-100-fold lower inhibitory potency against SP-induced contractions but each drug showed about the same efficacy as found against nerve-mediated contractions. Glibenclamide (1 mu M) reversed the inhibitory effects of cromakalim and pinacidil on neurally-mediated contractions but did not influence the effects of terbutaline, theophylline and verapamil. The results demonstrate that cromakalim, pinacidil, terbutaline, theophylline and verapamil inhibit non-cholinergic excitatory neurotransmission in guinea-pig bronchi and suggest that they act preferentially at a pre-junctional site.