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Bicuculline but not SR 95531 and picrotoxinin enhances peristaltic activity of the guinea-pig ileum
385
Pharmacological Research Communications, VoL 20, Supplement 11. 1988
BICUCULLINEBUT NOT SR 95531 AND PICROTOXININENHANCES PERISTALTICACTIVITYOF THE GUINEA-PIG iLEUM M. Tonini, L. Onori, G. De Petris, L. Manzo, C.A. Rizzl, and A. Crema Department of Internal Medicine and Therapeutics, Pharmacology Division, University of Pavia Key Words: GABA-A receptors, GABA-A receptor antagonists, picrotoxinin, peristalsis An in vitro study was performed to establish the role of GABA-A receptor function on peristaltic activity of the guinea-pig ileum. The experiments were conducted using competitive antagonists such as (-)bicuculline methlodide and SR 95531, and picrotoxinin, a drug which is known to interfere with CI" conductance at the receptor-associated ionophore. Peristalsis was induced
by the method of Tonini et al.
(1981) with minor modifications, In keeping with the results of a recent report (Schworer and Kilbinger, 1988), bicucuiltne (1-30 p.M) facilitated peristalsis by increasing the number of propulsive contractions and the amount of fluid ejected during a 30 rain cycle. BV contrast, no influence on peristaltic parameters was observed with picrotoxinin (1-30 I~M) or SR 95531 (0.3-3 p.M). The latter agent has been shown to possess a 200-fold greater affinity for the GABA-A receptor than bicuculline (Wermuth and Bizi~re, 1986). Moreover, in experiments on myenteric plexus-longitudinal muscle preparations we observed an approximately 50-fold parallel shift to the right of the concentration-response curve to the GABA-A receptor agonist 3-aminopropane sulphonic
acid (1-300 pM) after addition of 3 p.M SR 95531. In the presence of either SR 95531 or picrotoxinin, bicucuiline was still able to potentiate peristaltic activity. Bicuculline (1-30 p.M), but not SR 95531 electrically-induced
and picrotoxinin,
(25 V, 0.5 msec, 0.1
enhanced the amplitude of
Hz) contractions
in the myenteric
plexus-longitudinal muscle without modifying those evoked by exogenously-applied acetyicholine (0.1 p.M). In unstimulated preparations, bicuculline (30, 50 p.M) induced a contractile response which was prevented by tetrodotoxin (1 p.M) and hyosclne (1 p.l~,,1). Taken together, these findings provide evidence for a facilitafory role of bicuculline on cholinergic transmission in the myenteric plexus of the guinea-pig ileum. The potentiating effect of bicuculline on peristaltic activity could be explained by this mechanism which appears to be independent of the GABA-A receptor blockade. REFERENCES: Schworer H. and Kilbinger H. (1988) Br. J. Pharmacol. 93:715-720 Tonini M., Frigo G.M., Lecchini S., D'Angelo L. and Crema A. (1981) Eur. J. Pharmacol. 71:375-381 Wermuth C.G. and Bizi~re K. (1986) TIPS 7:421-424
Pharmacological Research Communications, VoL 20, Supplement 11. 1988
BICUCULLINEBUT NOT SR 95531 AND PICROTOXININENHANCES PERISTALTICACTIVITYOF THE GUINEA-PIG iLEUM M. Tonini, L. Onori, G. De Petris, L. Manzo, C.A. Rizzl, and A. Crema Department of Internal Medicine and Therapeutics, Pharmacology Division, University of Pavia Key Words: GABA-A receptors, GABA-A receptor antagonists, picrotoxinin, peristalsis An in vitro study was performed to establish the role of GABA-A receptor function on peristaltic activity of the guinea-pig ileum. The experiments were conducted using competitive antagonists such as (-)bicuculline methlodide and SR 95531, and picrotoxinin, a drug which is known to interfere with CI" conductance at the receptor-associated ionophore. Peristalsis was induced
by the method of Tonini et al.
(1981) with minor modifications, In keeping with the results of a recent report (Schworer and Kilbinger, 1988), bicucuiltne (1-30 p.M) facilitated peristalsis by increasing the number of propulsive contractions and the amount of fluid ejected during a 30 rain cycle. BV contrast, no influence on peristaltic parameters was observed with picrotoxinin (1-30 I~M) or SR 95531 (0.3-3 p.M). The latter agent has been shown to possess a 200-fold greater affinity for the GABA-A receptor than bicuculline (Wermuth and Bizi~re, 1986). Moreover, in experiments on myenteric plexus-longitudinal muscle preparations we observed an approximately 50-fold parallel shift to the right of the concentration-response curve to the GABA-A receptor agonist 3-aminopropane sulphonic
acid (1-300 pM) after addition of 3 p.M SR 95531. In the presence of either SR 95531 or picrotoxinin, bicucuiline was still able to potentiate peristaltic activity. Bicuculline (1-30 p.M), but not SR 95531 electrically-induced
and picrotoxinin,
(25 V, 0.5 msec, 0.1
enhanced the amplitude of
Hz) contractions
in the myenteric
plexus-longitudinal muscle without modifying those evoked by exogenously-applied acetyicholine (0.1 p.M). In unstimulated preparations, bicuculline (30, 50 p.M) induced a contractile response which was prevented by tetrodotoxin (1 p.M) and hyosclne (1 p.l~,,1). Taken together, these findings provide evidence for a facilitafory role of bicuculline on cholinergic transmission in the myenteric plexus of the guinea-pig ileum. The potentiating effect of bicuculline on peristaltic activity could be explained by this mechanism which appears to be independent of the GABA-A receptor blockade. REFERENCES: Schworer H. and Kilbinger H. (1988) Br. J. Pharmacol. 93:715-720 Tonini M., Frigo G.M., Lecchini S., D'Angelo L. and Crema A. (1981) Eur. J. Pharmacol. 71:375-381 Wermuth C.G. and Bizi~re K. (1986) TIPS 7:421-424