Endothelin modulates the cardiovascular effects of clonidine in the rat

Clonidine decreases mean arterial pressure (MAP) by acting as an α2-adrenergic receptor (AR) agonist in the central nervous system; it also acts on peripheral α-ARs to produce vasoconstriction. Endothelin (ET) has been shown to modulate the action of ARs. The present study was conducted to determine the involvement of ET in cardiovascular effects of clonidine. Intravenous administration of clonidine (10, 30 and 90 μg kg−1) produced a dose-dependent decrease in MAP and heart rate (HR). Treatment with ET-1 (100, 300 and 900 ng kg−1) significantly attenuated clonidine (10 μg kg−1) induced fall in MAP and HR. Rats treated with ET-1 (900 ng kg−1) showed an increase in MAP and HR after clonidine administration compared to untreated rats, while ETA/B antagonist, TAK-044 (1 mg kg−1) and ETA antagonist, BMS-182874 (9 mg kg−1) potentiated the hypotensive effect of clonidine. ETB receptor agonist, IRL-1620 (5 μg kg−1) produced significant attenuation of clonidine induced fall in MAP and HR, while ETB receptor antagonist, BQ-788 (0.3 mg kg−1), potentiated the hypotensive effect of clonidine. Prazosin (0.1 mg kg−1) completely blocked ET-1 induced changes in cardiovascular effects of clonidine. Clonidine-induced contraction of rat abdominal aortic ring was potentiated by ET-1, which was completely blocked by prazosin. Clonidine produced an increase in ETA receptor expression in the brain and abdominal aorta while ETB receptors were not affected. It is concluded that ET enhances the responsiveness of vascular ARs to the constrictor effect of clonidine and ET antagonists potentiate the hypotensive effect of clonidine suggesting that a combination of ET antagonist with clonidine may be a useful option to treat hypertension.

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