Chronic 5-HT 2 receptor blockade unmasks the role of 5-HT 1F receptors in the inhibition of rat cardioaccelerator sympathetic outflow.

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-HT ₂ receptors is beneficial in several cardiovascular pathologies, this study investigated whether sarpogrelate (a 5-HT ₂ 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 (C ₇ -T ₁ ) 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.