Correolide, a nor-triterpenoid blocker of Shaker-type Kv1 channels elicitstwitches in guinea-pig ileum by stimulating the enteric nervous system andenhancing neurotransmitter release

1 Correolide (1-10 muM), a nortriterpene purified from Spachea correae and a selective blocker of Kv1 potassium channels, elicits repetitive twitching in guinea-pig ileum. This effect is not seen in guinea-pig duodenum, porta l vein, urinary bladder or uterine strips, nor in rat or mouse ileum. 2 The time course and amplitude of the correolide-induced twitches in guine a-pig ileum are similar to those elicited by electrical stimulation of the enteric nervous system. 3 The correolide-induced twitching is not affected by pre-treatment with ca psaicin (1 muM), but is facilitated by the NO synthase inhibitor, NG-nitro- L-arginine methyl esther (L-NAME, 200 muM). 4 The correolide-induced twitching is abolished by tetrodotoxin (1 muM) or hexamethonium (100 muM), and is markedly inhibited by nifedipine (0.3 muM) or atropine (0.2 muM). The atropine-resistant component is inhibited by sel ective antagonists of NK1 and NK2 tachykinin receptors, namely GR 82334 and GR 94800(1 muM each). The former compound is more effective in inhibiting the correolide-induced, atropine-resistant activity. 5 Correolide intensified the twitching of ileum segments exposed to saturat ing concentrations of margatoxin (MgTX), which suggests that Kv1 sub-types other than Kv1.1 (Kv1.4 or Kv1.5) are involved in the relatively greater de gree of stimulation of the enteric nervous system by correolide, as compare d to MgTX. 6 We propose that blockade of Kv1 channels by correolide increases the exci tability of intramural nerve plexuses promoting release of acetylcholine an d tachykinins from excitatory motor neurons. This, in turn, leads to Ca2+-d ependent action potentials and twitching of the muscle fibres.