Mechanism of the Indirect Sympathomimetic Effect of 5‐hydroxytryptamine on the Isolated Heart of the Rabbit

Abstract

1 Rabbit isolated hearts, perfused by the Langendorff technique, were used to investigate the indirect sympathomimetic effects of 5-hydroxytryptamine (5-HT). Comparisons were made with noradrenaline and with two indirectly acting sympathomimetic agents with entirely different mechanisms of action, tyramine and dimethylphenylpiperazinium (DMPP). 2 The cardiac stimulant effects of 5-HT, tyramine and DMPP were inhibited by propranolol and practolol and the pA2 values obtained were similar to those obtained with noradrenaline as the agonist. 3 Responses to 5-HT, tyramine and DMPP were greatly reduced on hearts from rabbits pretreated with 6-hydroxydopamine. Such hearts had less than 7% of their normal catecholamine concentration and no fluorescence characteristic of noradrenaline in the cardiac sympathetic nerves could be demonstrated. 4 Rapid, reversible and selective tachyphylaxis to 5-HT was demonstrated during perfusion with 5-HT. In hearts desensitized to DMPP by perfusion with DMPP, responses to 5-HT were also reduced. S Perfusion of hearts with colchicine inhibited stimulant responses to 5-HT and DMPP but had little effect on responses to noradrenaline or tyramine. 6 Desmethylimipramine enhanced cardiac stimulant responses to noradrenaline and to a lesser extent, those to 5-HT and DMPP. Responses to tyramine were consistently inhibited by desmethylimipramine. 7 Tetrodotoxin abolished responses of the heart to electrical nerve stimulation but left responses to noradrenaline, 5-HT and DMPP unaffected. 8 5-HT, tyramine and DMPP evoked 3H-release from hearts whose neuronal noradrenaline stores had been labelled by perfusion with [3HI-(-)-noradrenaline. The pattern of release evoked by 5-HT was similar to that of DMPP but differed from that of tyramine.9 Reducing the calcium concentration in the Tyrode solution from 3.6 to 0.2 mEq/l did not affect 3H-overflow after tyramine but greatly inhibited that evoked by 5-HT and DMPP.10 The results confirm that the stimulant effects of 5-HT on the rabbit isolated heart are the result of noradrenaline release. They further suggest that the site of the release is the terminal sympathetic nerve network. The mechanism of release shows more similarities to that of DMPP (calcium-dependent depolarization and exocytosis) than to that of tyramine (neuronal uptake and stoichiometric displacement).

An operational model of pharmacological agonism: the effect of E/[A] curve shape on agonist dissociation constant estimation

“…All washes (indicated by W in the protocol) were by exchange of bath contents for fresh Krebs solution. Benextramine tetrahydrochloride (BHC) was included in order to avoid possible confounding of 5-HT responses due to direct or indirect a-adrenoreceptor stimulation by the agonist (Innes, 1962;Fozard & Mwaluko, 1976;Apperley et al, 1976;Marin et al, 1981). The sighting dose of 10 mM 5-HT was used only to establish tissue viability.…”

An operational model of pharmacological agonism: the effect of E/[A] curve shape on agonist dissociation constant estimation

“…All washes (indicated by W in the protocol) were by exchange of bath contents for fresh Krebs solution. Benextramine tetrahydrochloride (BHC) was included in order to avoid possible confounding of 5-HT responses due to direct or indirect a-adrenoreceptor stimulation by the agonist (Innes, 1962;Fozard & Mwaluko, 1976;Apperley et al, 1976;Marin et al, 1981). The sighting dose of 10 ,uM 5-HT was used only to establish tissue viability.…”

Inhibitory 5‐hydroxytryptamine receptors involved in pressor effects obtained by stimulation of sympathetic outflow from spinal cord in pithed rats

“…The participation of 5-HT in the control of blood pressure (Cohen, 1984;Grading et al, 1985;Saxena et al, 1987; Dabire, 1990) and the modulation of cardiac and vascular sympathetic transmission has also been demonstrated. For this modulation, potentiating and inhibitory actions have been proposed, however in both cases there is a disparity between mechanisms postulated to account for such actions (Fozard & Mwaluko, 1976;Fozard, 1984b;Coote et al, 1987;Docherty, 1988;Bom et al, 1989;Shepheard et al, 1991;Done & Sharp, 1992).…”