Fluoxetine treatment changes the serotonergic cardiovascular inhibitory mechanisms in diabetic rats

C. López, M. García, J.A. García-Pedraza, M.L. Martín, L. San Román, A. Morán. Universidad de Salamanca, Departamento de Fisiología y Farmacología. Facultad de Farmacia. 37007. Salamanca, Spain

Alterations in monoamines (serotonin and noradrenalin), among other factors, constitutes one of the abnormalities documented in diabetic patients and in animal models that could explain the association between depression and diabetes(1). Depression in diabetic patients has been longly treated with selective serotonin reuptake inhibitors (SSRI), such as fluoxetin. Our previous results have suggested that 5-HT exerts a presynaptic inhibitory action on electrically induced pressor responses in normoglycaemic and diabetic rats(2,3,4). Treatment with fluoxetine in diabetic rats modifies the receptor subtype involved in the serotonergic inhibitory action on the pressor responses induced by electrical stimulation. This action is mediated by 5-HT1A and 5-HT1D receptor activation in fluoxetine-treated group while in control group only 5-HT1A receptors are involved in this action (5).

The present study was carried out to determine whether there is any indirect mechanism involved in the serotoninergic inhibitory effect on the pressor responses induced by sympathetic stimulation in fluoxetin-treated alloxan diabetic pithed rats.

Diabetes was induced in male Wistar rats by a single s.c. injection of alloxan. Animals were kept diabetic for 28 days, and treated the last 14 days with fluoxetin (10 mg/kg in drinking water). Electrical stimulation of the sympathetic outflow from the spinal cord (0.1, 0.5, 1.0 and 5.0 Hz) resulted in frequency-dependent increases in blood pressure. 5-HT (10 µg/kg/min) exerts an inhibitory effect on the pressor responses. That inhibitory effect was reproduced by 5-CT (5 µg/kg/min), a selective 5-HT1, 7 agonist, and that was partially reproduced by 8-OH-DPAT (5 µg/kg/min) and L-694,247 (5 µg/kg/min), selective 5-HT1A and 5-HT1D receptor subtype agonists, respectively.

Treatment with ODQ (10 μg/kg, i.v.), a guanylyl cyclase inhibitor or indomethacin (2 mg/kg, i.v.) a non-selective cyclooxygenase (COX) inhibitor partially reversed 5-HT action. However, the inhibitory action of 8-OHDPAT (5 μg/kg/min), was exclusively abolished blocking NO synthesis/pathway (in the presence of either ODQ (10 μg/kg, i.v.), or L-NAME (10 μg/kg, i.v.), a NO production inhibitor); but, prior i.v. bolus administration of indomethacin (2 mg/kg), failed to block the inhibition caused by the infusion of 8-OH-DPAT, in diabetic pithed rats treated with fluoxetin.

On the other hand, in the presence of indomethacin (2 mg/kg) or FR 122047 (1.5 mg/kg, a selective COX-1 inhibitor) L-694,247 did not modify the pressor responses induced by electrical stimulation. However, neither i.v, administration of L-NAME nor i.v. injection of nimesulide (1.5 mg/kg), a selective COX-2 inhibitor, were able to reverse L-694,247 inhibitory action.

In conclusion, 14-day fluoxetin treatment in diabetic rats changes both the receptor subtype and the indirect mechanisms involved in the serotonergic inhibitory action on the sympathetic cardiovascular actions. The inhibition on electrically induced sympathetic pressor responses produced by 5-HT1A activation is mediated by NO synthesis/pathway; and, the 5-HT1D inhibitory action is mainly due to COX-1 pathway activation.

1.- Castillo-Quan JI et al., Rev Neurol. 2010, 16;51 (6):347-59; 2.- Morán A et al., Br. J. Pharmacol. 1994, 113, 1358–1362; 3.- Morán A et al., Eur J Pharmacol. 2008 Sep 11;592 (1-3):133-7; 4.- García M et al., Br. J. Pharmacol. 2005, 145, 593–601; 5.- López C et al., European Journal of Clinical Pharmacology. 2010, 66 (suppl. 1): 69.