[Reduction of the pressor effect of fluoxetine after V1A-vasopressin receptor blockade in the conscious rats].
Pharmacovigilance data have reported some cases of arterial hypertension in patients treated with serotonin reuptake inhibitors. This side effect is now called serotonin syndrome. Moreover, some authors have shown that these drugs could reduce, at least in part, the fall in blood pressure (BP) observed in experimental models or in human forms of orthostatic hypotension, suggesting a modulation of the autonomic nervous system by these drugs. These data led us to study in freely moving Wistar rats the mechanisms involved and the putative involvement of autonomic nervous system. Intracerebroventricular (i.c.v.) administration of fluoxetine (5-50 micrograms) induced an increase in BP similar to which was obtained following central administration of serotonin (5-HT) (0.5-5 micrograms). After 5-HT, the pressor effect was immediate (1 min following injection) and involved the baroreflex pathway (bradycardia). The fluoxetine-induced pressor response reached its maximal 1 hour after injection without any significant change in heart rate (HR). At the dose of 10 micrograms i.c.v., fluoxetine significantly increased mean BP by 16 +/- 4 mmHg. This pressor response was partially but significantly reduced by a pretreatment by the alpha 1-adrenoreceptor antagonist, prazosin (500 micrograms.kg-1 i.v.) (+7 +/- 4 mmHg, p < 0.05) or by a V1A-vasopressin receptor antagonist (20 micrograms.kg-1 i.v.) (+5 +/- 3 mmHg, p < 0.05). However, pretreatment by the beta-adrenoreceptor antagonist, propranolol (1 mg.kg-1 i.v.) and the antagonist 5-HT2, ketanserine (5 mg.kg-1 i.v.) did not modify the fluoxetine-induced pressor response. In freely moving rats receiving fluoxetine (10 micrograms i.c.v.), vasopressin plasma levels were significantly higher (+39 +/- 5 pg.mL-1) than in rats receiving saline (100 microL i.c.v.) (+14 +/- 4 pg.mL-1), thus confirming the involvement of vasopressinergic mechanisms in the fluoxetine-induced pressor response. These data suggest that in freely moving Wistar rats, central acute administration of fluoxetine induces a pressor response mediated by both an increase in sympathetic tone and a vasopressin release. This observation could suggest the putative use of alpha 1-adrenoreceptors antagonists and/or V1A-vasopressin receptor antagonists in the treatment of the serotonin syndrome.
Lazartigues
E
E
Laboratoire de pharmacologie médicale et clinique, INSERM U317, centre Midi-Pyrénées de pharmacovigilance, de pharmaco-epidémiologie ets d'informations sur le médicament, faculte de médecine, Toulouse.
Costes
S
S
Brefel-Courbon
C
C
Gharib
C
C
Tran
M A
MA
Senard
J M
JM
Montastruc
J L
JL
D000704:Analysis of Variance; D000818:Animals; D065092:Antidiuretic Hormone Receptor Antagonists; D001341:Autonomic Nervous System / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects*; D005473:Fluoxetine / Q000037:antagonists & inhibitors*; D007276:Injections, Intraventricular; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D017367:Selective Serotonin Reuptake Inhibitors
D065092:Antidiuretic Hormone Receptor Antagonists; D005473:Fluoxetine; D017367:Selective Serotonin Reuptake Inhibitors