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.
Häuser
W
W
Institute of Pharmacology, Medical University of Lübeck, Germany.
Dendorfer
A
A
Nguyen
T
T
Dominiak
P
P
D000803:Angiotensin I / Q000037:antagonists & inhibitors*; D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001713:Biphenyl Compounds / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D002395:Catecholamines / Q000097:blood; D003655:Decerebrate State; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D006339:Heart Rate / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects*; D006973:Hypertension / Q000097:blood / Q000188:drug therapy / Q000503:physiopathology*; D007093:Imidazoles / Q000494:pharmacology*; D019808:Losartan / Q000494:pharmacology*; D008297:Male; D051381:Rats; D011918:Rats, Inbred SHR; D013564:Sympathetic Nervous System / Q000187:drug effects / Q000502:physiology*
D000959:Antihypertensive Agents; D001713:Biphenyl Compounds; D002395:Catecholamines; D007093:Imidazoles; C094626:fonsartan; D000804:Angiotensin II; D000803:Angiotensin I; D019808:Losartan