Effect of ondansetron on the contractile responses to positive inotropic agents in electrically driven left atria of rats.

Abstract

We studied the interaction of ondansetron with positive inotropic agents, including serotonin (5-hydroxytryptophane, 5-HT), noradrenaline, 4-aminopyridine (4-AP), calcium chloride, or with reserpine in isolated electrically driven rat atria. Concentrations of 5-HT ranging from 1 to 64 microg/ml increased atrial contractions in a dose-dependent manner. The inotropic effect of 5-HT in the right atria appeared to be weaker than that in the left atria. Ondansetron (30 microg/ml) depressed the positive inotropic effect of lower 5-HT concentrations . This effect was thought to be due to the local anesthetic action of ondansetron or its agonistic interaction with inhibitory imidazoline receptors on the sympathetic nerve endings that reduce noradrenaline release. The positive inotropic effect of 5-HT was abolished almost completely by cyproheptadine (2 microg/ml) and was reversed only partially by pretreatment with reserpine (1 or 3 mg/kg). This result was considered as evidence for the participation of pre- and post-junctional 5-HT2A receptors and the involvement of the sympathetic nervous system in the positive inotropic action of 5-HT in rat atria. Experiments with atropine (1 microg/ml) in atria from reserpine-pretreated rats revealed that the parasympathetic component of the autonomic nervous system is not involved in the inotropic action of 5-HT. Ondansetron (30 microg/ml) tended to increase the positive inotropic effects of noradrenaline, 4-AP, and calcium chloride, which were partially significant at certain concentrations. This result might be due to the activation of both pre- and post-junctional 5-HT2A receptors or due to the inhibition of noradrenaline reuptake into the sympathetic nerve endings through the activation of imidazoline receptors. From these findings, we conclude that the positive inotropic effect of 5-HT in the electrically driven rat atria seems to be mediated primarily by its interaction with 5-HT2A receptors, which are likely to be found on the pre- and post-junctional structures. Other mechanisms that might be involved in this relation are also discussed.