Blockade of 5‐HT2 receptors with sarpogrelate uncovers 5‐HT7 receptors inhibiting the tachycardic sympathetic drive in pithed rats

• Published in: Clinical and experimental pharmacology & physiology Vol. 47; no. 3; pp. 403 - 411
• Main Authors: Hernández‐Abreu, Oswaldo I., García‐Pedraza, José Á., Rivera‐Mancilla, Eduardo, Villanueva‐Castillo, Belinda, Morán, Asunción, García‐Domingo, Mónica, Manrique‐Maldonado, Guadalupe, Altamirano‐Espinoza, Alain H., Villalón, Carlos M.
• Format: Journal Article
• Language: English
• Published: Richmond Wiley Subscription Services, Inc 01-03-2020
• Subjects: 5‐HT2 receptor blockade; 5‐HT7 receptors; AS‐19; ATP; cardiac sympatho‐inhibition; Drinking water; Glibenclamide; Heart rate; Hyperpolarization; Modulation; Neurotransmission; Noradrenaline; Norepinephrine; pithed rat; Potassium channels; Receptors; Rodents; sarpogrelate; SB258719; Stimulation; Sympathetic nervous system; Tachycardia; Vagus nerve
• ISSN: 0305-1870; 1440-1681
• DOI: 10.1111/1440-1681.13227

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‐HT1B/1D/5 receptors. Interestingly, when 5‐HT2 receptors are chronically blocked with sarpogrelate, the additional role of cardiac sympatho‐inhibitory 5‐HT1F receptors is unmasked. Although 5‐HT2 receptors mediate tachycardia in rats, and the chronic blockade of 5‐HT2 receptors unmasked 5‐HT7 receptors mediating cardiac vagal inhibition, the role of 5‐HT7 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‐HT2 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 (C7‐T1) stimulation of the cardiac sympathetic drive or iv administration of exogenous noradrenaline. The iv continuous infusion of AS‐19 (a 5‐HT7 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‐HT7 receptor antagonist; 1 mg/kg, iv) or glibenclamide (an ATP‐sensitive K+ channel blocker; 20 mg/kg, iv). These results suggest that chronic 5‐HT2 receptor blockade uncovers a cardiac sympatho‐inhibitory mechanism mediated by 5‐HT7 receptors, involving a hyperpolarization due to the opening of ATP‐sensitive K+ channels. Thus, these findings support the role of 5‐HT7 receptors in the modulation of the cardiac sympathetic neurotransmission.