Blockade of 5-HT receptors with sarpogrelate uncovers 5-HT receptors inhibiting the tachycardic sympathetic drive in pithed rats.

Our group has previously shown in pithed rats that the cardiac sympathetic drive, which produces tachycardic responses, is inhibited by 5-HT via the activation of prejunctional 5-HT receptors. Interestingly, when 5-HT receptors are chronically blocked with sarpogrelate, the additional role of cardiac sympatho-inhibitory 5-HT receptors is unmasked. Although 5-HT receptors mediate tachycardia in rats, and the chronic blockade of 5-HT receptors unmasked 5-HT receptors mediating cardiac vagal inhibition, the role of 5-HT receptors in the modulation of the cardiac sympathetic tone remains virtually unexplored. On this basis, male Wistar rats were pretreated during 14 days with sarpogrelate (a 5-HT receptor antagonist) in drinking water (30 mg/kg/day; sarpogrelate-pretreated group) or equivalent volumes of drinking water (control group). Subsequently, the rats were pithed to produce increases in heart rate by either electrical preganglionic spinal (C -T ) stimulation of the cardiac sympathetic drive or iv administration of exogenous noradrenaline. The iv continuous infusion of AS-19 (a 5-HT receptor agonist; 10 µg/kg/min) (i) inhibited the tachycardic responses to sympathetic stimulation, but not those to exogenous noradrenaline only in sarpogrelate-pretreated rats. This inhibition was completely reversed by SB258719 (a selective 5-HT receptor antagonist; 1 mg/kg, iv) or glibenclamide (an ATP-sensitive K channel blocker; 20 mg/kg, iv). These results suggest that chronic 5-HT receptor blockade uncovers a cardiac sympatho-inhibitory mechanism mediated by 5-HT receptors, involving a hyperpolarization due to the opening of ATP-sensitive K channels. Thus, these findings support the role of 5-HT receptors in the modulation of the cardiac sympathetic neurotransmission.