Serotonin (5-hydroxytryptamine; 5-HT) inhibits the rat cardioaccelerator sympathetic outflow by 5-HT_1B/1D/5 receptors. Because chronic blockade of sympatho-excitatory 5-HT₂ receptors is beneficial in several cardiovascular pathologies, this study investigated whether sarpogrelate (a 5-HT₂ receptor antagonist) alters the pharmacological profile of the above sympatho-inhibition. Rats were pretreated for 2 weeks with sarpogrelate in drinking water (30 mg/kg per day; sarpogrelate-treated group) or equivalent volumes of drinking water (control group). Animals were pithed and prepared for spinal stimulation (C₇-T₁) of the cardioaccelerator sympathetic outflow or for intravenous (i.v.) bolus injections of noradrenaline. Both procedures produced tachycardic responses remaining unaltered after saline. Continuous i.v. infusions of 5-HT induced a cardiac sympatho-inhibition that was mimicked by the 5-HT receptor agonists 5-carboxamidotryptamine (5-CT; 5-HT_1/5A), CP 93,129 (5-HT_1B), or PNU 142633 (5-HT_1D), but not by indorenate (5-HT_1A) in both groups; whereas LY344864 (5-HT_1F) mimicked 5-HT only in sarpogrelate-treated rats. In sarpogrelate-treated animals, i.v. GR 127935 (310 μg/kg; 5-HT_1B/1D/1F receptor antagonist) attenuated 5-CT-induced sympatho-inhibition and abolished LY344864-induced sympatho-inhibition; while GR 127935 plus SB 699551 (1 mg/kg; 5-HT_5A receptor antagonist) abolished 5-CT-induced inhibition. These results confirm the cardiac sympatho-inhibitory role of 5-HT_1B, 5-HT_1D, and 5-HT_5A receptors in both groups; nevertheless, sarpogrelate treatment specifically unmasked a cardiac sympatho-inhibition mediated by 5-HT_1F receptors.

5-Hydroxytryptamine (5-HT) modulates the cardiac parasympathetic neurotransmission, inhibiting the bradyarrhythmia by 5-HT₂receptor activation. We aimed to determine whether the chronic selective 5-HT₂blockade (sarpogrelate) could modify the serotonergic modulation on vagal cardiac outflow in pithed rat. Bradycardic responses in rats treated with sarpogrelate (30 mg·kg⁻¹·d⁻¹; orally) were obtained by electrical stimulation of the vagal fibers (3, 6, and 9 Hz) or intravenous (IV) injections of acetylcholine (1, 5, and 10 μg/kg). 5-HT₇receptor expression was quantified by Western blot in vagus nerve and right atrium. The IV administration of 5-HT (10–200 μg/kg) dose dependently decreased the vagally induced bradycardia, and agonists 5-CT (5-HT_1/7), 8-OH-DPAT (5-HT_1A), or AS-19 (5-HT₇) (50 μg/kg each) mimicked the 5-HT–induced inhibitory effect. Neither agonists CGS-12066B (5-HT_1B), L-694,247 (5-HT_1D), nor 1-phenylbiguanide (5-HT₃) modified the electrically-induced bradycardic responses. Moreover, SB-258719 (5-HT₇antagonist) abolished the 5-HT–, 5-CT–, 8-OH-DPAT–, and AS-19–induced bradycardia inhibition; 5-HT or AS-19 did not modify the bradycardia induced by IV acetylcholine; and 5-HT₇receptor was expressed in both the vagus nerve and the right atrium. Our outcomes suggest that blocking chronically 5-HT₂receptors modifies the serotonergic influence on cardiac vagal neurotransmission exhibiting 5-HT as an exclusively inhibitory agent via prejunctional 5-HT₇receptor.