Chronic Sarpogrelate Treatment Reveals 5-HT7 Receptor in the Serotonergic Inhibition of the Rat Vagal Bradycardia.
5-Hydroxytryptamine (5-HT) modulates the cardiac parasympathetic neurotransmission, inhibiting the bradyarrhythmia by 5-HT2 receptor activation. We aimed to determine whether the chronic selective 5-HT2 blockade (sarpogrelate) could modify the serotonergic modulation on vagal cardiac outflow in pithed rat. Bradycardic responses in rats treated with sarpogrelate (30 mg·kg·d; 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-HT7 receptor 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-HT1/7), 8-OH-DPAT (5-HT1A), or AS-19 (5-HT7) (50 μg/kg each) mimicked the 5-HT-induced inhibitory effect. Neither agonists CGS-12066B (5-HT1B), L-694,247 (5-HT1D), nor 1-phenylbiguanide (5-HT3) modified the electrically-induced bradycardic responses. Moreover, SB-258719 (5-HT7 antagonist) 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-HT7 receptor was expressed in both the vagus nerve and the right atrium. Our outcomes suggest that blocking chronically 5-HT2 receptors modifies the serotonergic influence on cardiac vagal neurotransmission exhibiting 5-HT as an exclusively inhibitory agent via prejunctional 5-HT7 receptor.
*Laboratory of Pharmacology, Department of Physiology and Pharmacology, Faculty of Pharmacy, University of Salamanca, Salamanca, Spain; †Biomedical Research Institute of Salamanca (IBSAL), University Hospital of Salamanca-USAL-CSIC, Salamanca, Spain; and ‡Unit of Cardiovascular and Renal Pathophysiology, Department of Physiology and Pharmacology, Research Institute of Nephrology "Reina Sofía," University of Salamanca, Salamanca, Spain.
José Ángel
JÁ
García-Pedraza
Mónica
M
García
María Luisa
ML
Martín
Nélida
N
Eleno
Asunción
A
Morán
D000818:Animals; D001919:Bradycardia / Q000209:etiology / Q000503:physiopathology*; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D006339:Heart Rate / Q000187:drug effects / Q000502:physiology; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D011985:Receptors, Serotonin / Q000502:physiology*; D012702:Serotonin Antagonists / Q000008:administration & dosage*; D013386:Succinates / Q000008:administration & dosage*; D016896:Treatment Outcome; D014630:Vagus Nerve / Q000187:drug effects / Q000502:physiology*; D055536:Vagus Nerve Stimulation / Q000009:adverse effects
D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D013386:Succinates; C104425:serotonin 7 receptor; C064294:sarpogrelate