Correolide, a nor-triterpenoid blocker ofShaker-type Kv1 channels elicits twitches in guinea-pig ileum by stimulating the enteric nervous system and enhancing neurotransmitter release

Abstract

1 Correolide (1 ± 10 mM), a nortriterpene puri®ed from Spachea correae and a selective blocker of Kv1 potassium channels, elicits repetitive twitching in guinea-pig ileum. This eect is not seen in guinea-pig duodenum, portal vein, urinary bladder or uterine strips, nor in rat or mouse ileum. 2 The time course and amplitude of the correolide-induced twitches in guinea-pig ileum are similar to those elicited by electrical stimulation of the enteric nervous system. 3 The correolide-induced twitching is not aected by pre-treatment with capsaicin (1 mM), but is facilitated by the NO synthase inhibitor, N G -nitro-L-arginine methyl esther (L-NAME, 200 mM). 4 The correolide-induced twitching is abolished by tetrodotoxin (1 mM) or hexamethonium (100 mM), and is markedly inhibited by nifedipine (0.3 mM) or atropine (0.2 mM). The atropineresistant component is inhibited by selective antagonists of NK1 and NK2 tachykinin receptors, namely GR 82334 and GR 94800 (1 mM each). The former compound is more eective in inhibiting the correolide-induced, atropine-resistant activity. 5 Correolide intensi®ed the twitching of ileum segments exposed to saturating 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 degree of stimulation of the enteric nervous system by correolide, as compared to MgTX. 6 We propose that blockade of Kv1 channels by correolide increases the excitability of intramural nerve plexuses promoting release of acetylcholine and tachykinins from excitatory motor neurons. This, in turn, leads to Ca 2+ -dependent action potentials and twitching of the muscle ®bres.