151P Granada Congress and Exhibitions Centre
6th European Congress of Pharmacology (EPHAR 2012)

 

 

INFLUENCE OF 5-HT2 BLOCKADE IN THE SEROTONERGIC MODULATION OF SYMPATHETIC CARDIOVASCULAR RESPONSES IN PITHED RAT

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

 

Serotonin has been linked to the pathophysiology of diabetes and its micro and macrovascular complications, such as hypertension, which highly contributes to worsen this disease and its consequences1,2,3. Moreover, it is well known that 5-HT2 receptors are involved in vasoconstriction and hypertension. Therefore, our project aims to analyze whether 5-HT2 blockade may modify the regulation exerted by 5-HT at adrenergic level in pithed rats4,5, improving the vascular complications of this disease. In a first attempt, our work determines 5-HT receptors involved in the serotonergic effect on the pressor responses obtained by electrical stimulation (monophasic pulses, 1 ms duration and supramaximal intensity at increasing frequencies 0.1, 0.5, 1 and 5 Hz) of the sympathetic outflow from the spinal cord3 in normoglycaemic rats orally treated with the 5-HT2 antagonist, risperidone (2 mg/kg, dissolved in drink water for 7 and 14 days).

Electrical stimulation of both control and risperidone-treated pithed rats resulted in frequency-dependent increases in mean blood pressure (table 1). Treatment with risperidone for 7 or 14 days did not modify the increases in mean blood pressure compared with control group.

Table 1: Increases in mean blood pressure (mm Hg). *p<0.05 vs control.

Treatment groups 0.5 Hz 1 Hz
Control 13.98 ± 1.97 27.67 ± 3.29
Risperidone (7 days) 11.29 ± 1.31 21.25 ± 1.83
Risperidone (14 days) 16.39 ± 1.75* 31.89 ± 3.13*

Continuous i.v. infusion of 5-HT (10 and 20 µg/kg/min) inhibited the sympathetic pressor responses induced by electrical stimulation (Table 2) in a dose-dependent way both in control and risperidone-treated group. The serotonergic inhibitory effect was reproduced by continuous i.v. infusion of the selective 5-HT1/7 receptor agonist, 5-CT (5 µg/kg/min). The inhibitory effect induced by either 5-HT or 5-CT was more marked in animals treated with the 5-HT2 blocker than in control group.

Table 2: Inhibition (%) of pressor effects induced by infusion of 5-HT. *p<0.05 vs control.

Control Risperidone 14 days
Doses (µg/kg/min) 0.5 Hz 1 Hz 0.5 Hz 1 Hz
5-HT (10) 49 31 64* 42*
5-CT (5) 69 70 91* 76*

On the other hand, infusion of the selective 5-HT3 receptor agonist, 1-phenylbiguanide was able to potentiate the increases in mean blood pressure induced by electrical stimulation of the sympathetic outflow in a dose-dependent manner (5-20 µg/kg/min).

Selective blockade of 5-HT7 receptor with pimozide (1 mg/Kg, i.v.) did not modify the inhibition caused by infusion of 5-CT (5 µg/kg/min); therefore, 5-HT7 receptor subtype is devoid of this inhibitory effect. The potentiating effect induced by 1-phenylbiguanide was reversed in the presence of MDL-72222 (2 mg/kg, i.v.), a selective 5-HT3 receptor antagonist.

In summary, oral treatment with risperidone, a 5-HT2 receptor blocker, increases the 5-HT1-mediated inhibitory degree and attenuates the 5-HT3-induced potentiation on the pressor responses obtained by sympathetic stimulation.

1 Sandrini et al. 1997. Life Sci. 60(16):1393-7. 2 García et al. 2005. Br J Pharmacol. 145(5):593-601.3 Morán et al. 2010. Eur J Pharmacol. 643(1):70-7. 4 Gillespie & Muir. 1967. Br J Pharmacol Chemother. 30(1):78-87. 5 Morán et al. 1994. Br J Pharmacol. 113(4):1358-62.