EFFECTS OF THE AT(1) ANTAGONIST HR-720 IN COMPARISON TO LOSARTAN ON STIMULATED SYMPATHETIC OUTFLOW, BLOOD-PRESSURE, AND HEART-RATE IN PITHED SPONTANEOUSLY HYPERTENSIVE RATS

It has been demonstrated in isolated organs that angiotensin II mediat es catecholamine release via presynaptically located AT, receptor subt ypes. In the present study, the relevance of AT(1)-mediated noradrenal ine and adrenaline release in a whole-animal model, which reflects the peripherally sympathetic system (pithed rat), was investigated. Furth ermore, the effects of a new ATI antagonist, HR 720, are demonstrated with respect to its pre- and postsynaptic actions in comparison to the AT(1) antagonist losartan. Dose-response curves to angiotensin II of blood pressure show a tenfold higher potency for MR 720 to compete for angiotensin II, thereby decreasing the maximum effects when compared with losartan. The electrically induced sympathetic outflow resulted i n a dose-dependent increase after angiotensin II infusions. It could m arkedly be reduced with both ATI antagonists, whereby HR 720 again was ten times more potent than losartan. Neither with HR 720 nor with los artan an agonistic activity could be demonstrated. The results indicat e an ATI receptor subtype mediated release of catecholamines in a whol e-animal model. HR 720 is ten times more potent than the AT(1) antagon ist losartan and acts in a noncompetitive manner.