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-ch olinergic excitatory nerves in guinea-pig isolated bronchi are due to the release of substance P (SP) and related tachykinins. Release of su ch neuropeptides are thought to play a pathophysiological role in asth ma. Two K+ channel openers cromakalim (pD(2)=6.45; E(max)=95%) and pin acidil (pD(2)=6.06; E(max)=87%) were shown to concentration-dependentl y inhibit non-cholinergic nerve-mediated contractions in guinea-pig br onchi 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 a s found against contractile responses to non-cholinergic neurostimulat ion. Also the a-adrenoceptor agonist terbutaline (pD(2)=8.29; E(max)=8 3%), the xanthine derivative theophylline (pD(2)=4.19; E(max)=100%) an d the Ca2+ blocker verapamil (pD(2)=5.55; E(max)=100%) suppressed resp onses 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 a s found against nerve-mediated contractions. Glibenclamide (1 mu M) re versed 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-cholin ergic excitatory neurotransmission in guinea-pig bronchi and suggest t hat they act preferentially at a pre-junctional site.