Mechanism of the chronotropic action and noradrenaline release induced by a high concentration of 5‐hydroxytryptamine in the rat isolated atria

Abstract

1 High concentrations of 5-hydroxytryptamine (5-HT) were shown to produce a positive chronotropic effect in the rat isolated atria associated with an increase in [3H] release when the atria were preloaded with [3H]-noradrenaline ([3H]-NA). The present study investigates the mechanism of this [3H] release using different antagonists.2 In atria preloaded with ['HI-NA (37 kBq ml-l, 0.4 pM, 20 min), 5-HT induced a rise in [3H] release values which appeared at the concentration of 2.5 pM and increased slightly with concentration ( 5 , 10, 20 and 50 p~) .However, 5-HT (2.5 pM) had no chronotropic effect while the different concentrations of 5, 10,20 and 50 pM induced the same increase in atrial rate (AR). By contrast, when MA0 activity was blocked by pargyline, 5-HT (2.5 pM) induced an increase in AR.3 In the absence of 5-HT, the 5-HT2 receptor antagonist, ketanserin, largely increased the spontaneous [3H] release without modifying the AR. The AR was increased by ketanserin in the presence of pargyline. The NA uptake inhibitor, desipramine, increased both [3H] release and AR. On the other hand, the incubation of atria with the 5-HT, and 5-HT2 receptor antagonist, methiothepin, the 5-HT3 receptor antagonist, zacopride or with one of the two specific 5-HT uptake inhibitors, fluvoxamine or indalpine, did not modify neither the [3H] efflux nor the AR. 4 In the presence of 5-HT (50 pM), methiothepin decreased the 5-HT-induced [3H] release and had no effect on the increase in AR due to 5-HT. By contrast, ketanserin reduced the [3H] increase induced by 5-HT. Zacopride did not modify the 5-HT-induced increases in [3H] release and in AR, while desipramine abolished completely these effects. Fluvoxamine and indalpine had no effect on the 5-HT chronotropic action. However, indalpine but not fluvoxamine decreased the 5-HT-induced [3H] release.5 It is concluded that a tyramine-like effect is the main mechanism of the 5-HT-induced chronotropic action at high concentrations. This effect is not modulated by the 5-HT3 receptors but involves the 5-HT, and/or the 5-HT2 receptor activity. The high concentrations of 5-HT protect the NA released from inactivation by MAO.