Effects of the AT₁ 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 mediates catecholamine release via presynaptically located AT₁ receptor subtypes. In the present study, the relevance of AT₁-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 AT₁ antagonist, HR 720, are demonstrated with respect to its pre- and postsynaptic actions in comparison to the AT₁ 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 AT₁ 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 AT₁ receptor subtype mediated release of catecholamines in a whole-animal model. HR 720 is ten times more potent than the AT₁ antagonist losartan and acts in a noncompetitive manner.