Effect of the cardioactive drug AR-L 57 on free intracellular calcium and ouabain-insensitive ion fluxes in the squid giant axon
Honerjäger, P.; Reiter, M.; Baker, P.F.
Molecular Pharmacology 19(1): 68-77
1981
ISSN/ISBN: 0026-895X PMID: 6163073 Document Number: 169078
The cardioactive drug AR-L 57 [6-(2,4-dimethoxyphenyl)-imidazo(4,5-b)pyridine] causes a rapid and reversible reduction of Ca efflux and light output from axons of L. forbesi which received microinjections of both 45Ca and the Ca-sensitive photoprotein aequorin. The light output from aequorin injected into extruded axoplasm is reduced by AR-L 57, but the drug does not inhibit the light from an aqueous buffer solution containing aequorin. The effect on Ca efflux is prevented if the axon is injected with enough Ca-ethylene glycol bis(.beta.-aminoethyl ether)-N,N'-tetraacetic acid to buffer the intracellular ionized Ca close to the physiological level. The large Nao[extracellularNa]- and Cao[extracellular Ca]-dependent Ca efflux from axons poisoned with cyanide or carbonylcyanide p-trifluoromethoxyphenyl-hydrazone is insensitive to AR-L 57. AR-L 57 inhibits the Ca efflux from unpoisoned axons by increasing intracellular Ca binding. AR-L 57 has no noticeable direct effect on the axolemmal Ca pump of unpoisoned axons or on the Ca efflux system operating in poisoned axons. AR-L 57 inhibits the Ca influx from Li-artificial sewater and the Cao-dependent Na efflux from axons injected with 22Na and superfused with Na-poor Li or K) seawater. The light response evoked in axons injected with aequorin by a K depolarization in the presence of a high external Ca concentration is reversibly reduced by AR-L 57. AR-L 57 inhibits Ca entry both via Na-Ca exchange and through the voltage-sensitive late Ca channel. AR-L 57 does not affect the 86Rb efflux at 10 mmol/l [K]o [extracelluar K concentration] but reversibly inhibits the increased Rb efflux from axons depolarized by 410 mmol of K/l. The outward (K) current is inhibited by the drug both with time and voltage during a voltage-clamp depolarization, but the transient inward (Na) current is unaffected. AR-L 57 does inhibit the maintained tetrodotoxin-sensitive 22Na efflux through Na channels kept open by veratridine. The normal Na inactivation mechanism appears to protect the Na channels from blockade by AR-L 57. None of the effects on the axolemma reported here, if applied to the sarcolemma of myocardial cells, provides an obvious explanation for the cardiotonic action of AR-L 57. AR-L 57 inhibits the Na pump but the present results show that the drug affects a number of ion transport processes that are insensitive to cardiac glycosides.