Abstract
It has been demonstrated in isolated organs that angiotensin II mediates catecholamine release via presynaptically located AT<sub>1</sub> receptor subtypes. In the present study, the relevance of AT<sub>1</sub>-mediated noradrenaline and adrenaline release in a whole-animal model, which reflects the peripherally sympathetic system (pithed rat), was investigated. Furthermore, the effects of a new AT<sub>1</sub> antagonist, HR 720, are demonstrated with respect to its pre- and postsynaptic actions in comparison to the AT<sub>1</sub> antagonist losartan. Dose-response curves to angiotensin II of blood pressure show a tenfold higher potency for HR 720 to compete for angiotensin II, thereby decreasing the maximum effects when compared with losartan. The electrically induced sympathetic outflow resulted in a dose-dependent increase after angiotensin II infusions. It could markedly be reduced with both AT<sub>1</sub> antagonists, whereby HR 720 again was ten times more potent than losartan. Neither with HR 720 nor with losartan an agonistic activity could be demonstrated. The results indicate an AT<sub>1</sub> receptor subtype mediated release of catecholamines in a whole-animal model. HR 720 is ten times more potent than the AT<sub>1</sub> antagonist losartan and acts in a noncompetitive manner.
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