Inhibition of angiotensin II-induced facilitation of sympathetic neurotransmission in the pithed rat: a comparison between losartan, irbesartan, telmisartan and captopril

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ObjectiveNumerous studies have shown that angiotensin II enhances sympathetic nervous transmission. The objective of the present study was to quantify the inhibitory effect of the angiotensin II type 1 (AT1) receptor blockers losartan, irbesartan and telmisartan and the angiotensin converting enzyme (ACE) inhibitor captopril on sympathetic neurotransmission and to compare the potency of these agents both at the presynaptic and the postsynaptic levels.DesignIn the male, normotensive pithed rat model, we studied the effect of losartan (1, 3, 10 and 30 mg/kg), irbesartan (3, 10, 30 and 60 mg/kg), telmisartan (0.3, 1, 3 and 10 mg/kg) and captopril (1.5, 5, 15 and 45 mg/kg) on electrical stimulation of the thoraco-lumbar spinal cord. To investigate the interaction between postsynaptic AT1-receptors and α-adrenoceptors, the effects of these compounds on pressor responses to exogenous noradrenaline were studied.ResultsStimulation of the thoracolumbar spinal cord caused a stimulation-frequency dependent rise in diastolic blood pressure (DBP) that could be dose-dependently reduced by both AT1 receptor blockade and ACE inhibition. Interestingly, the highest doses of the AT1 antagonists caused less than maximal reduction in the rise in DBP. This phenomenon was not observed after ACE inhibition by captopril. In experiments with exogenous noradrenaline, no effect of AT1 blockade or ACE inhibition on α-adrenoceptor-mediated blood pressure responses was seen.ConclusionWe conclude that, in the pithed rat model, the effects of stimulation of the thoraco-lumbar spinal cord on DBP are counteracted by blockade of presynaptically located AT1 receptors. The order of potency concerning sympatico-inhibition is telmisartan > losartan > irbesartan. Regarding the inhibition of angiotensin II-induced facilitation of sympathetic neurotransmission, marked differences were observed between selective AT1 blockade and ACE inhibition. The finding that all three AT1 blockers cause less than maximal inhibition in their highest doses, as opposed to captopril, suggests that this is a class effect of the AT1 antagonists.

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