Systemic and coronary effects of the angiotensin II receptor antagonist EXP3174 in dogs.
The effects of EXP3174 (0.03-0.3 mg/kg), the active metabolite of the angiotensin II (AII) receptor antagonist losartan, on systemic and coronary hemodynamics as well as on regional myocardial blood flow (radioactive microspheres) were evaluated in anesthetized, open-chest dogs with or without preactivated renin-angiotensin system (RAS) (furosemide treatment). These effects were compared with those of the angiotensin-converting enzyme (ACE) inhibitor enalaprilat (0.1-1 mg/kg). In dogs without preactivated RAS, EXP3174 or enalaprilat did not exert marked hemodynamic effects other did not exert marked hemodynamic effects other than a significant decrease in mean arterial blood pressure (MAP) at the highest doses. In dogs with preactivated RAS, EXP3174 induced a marked, dose-dependent decrease in MAP (maximum decrease -23 +/- 7%), associated with a significant decrease in total peripheral resistance (TPR), whereas cardiac output (CO), heart rate (HR), and left ventricular dP/dt remained unchanged. At the coronary level, EXP3174 induced a decrease in mean coronary resistance that paralleled that of AP. Similar systemic and coronary hemodynamic effects were obtained with enalaprilat administered at doses three times higher. However, regional myocardial tissue perfusion, assessed by the microspheres technique (whether subendocardial, subepicardial, or transmural) or its transmural distribution (endo/epi ratios) was not affected by EXP3174 or enalaprilat. Thus, these results indicate that blockade of the AT1 receptor of AII by EXP3174 induces hemodynamic modifications similar to those evoked by the ACE inhibitor enalaprilat. The lack of effect of EXP3174 or enalaprilat on regional myocardial blood flow (RMBF) suggests, however, that the RAS does not play a role in regulation of myocardial tissue perfusion.
Richard
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V
Département de Pharmacologie, Faculté de Médecine Paris Sud, Le Kremlin-Bicêtre, France.
Berdeaux
A
A
Giudicelli
J F
JF
D000803:Angiotensin I / Q000032:analysis; D000804:Angiotensin II / Q000032:analysis; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D003326:Coronary Circulation / Q000187:drug effects*; D004285:Dogs; D015773:Enalaprilat / Q000494:pharmacology; D005260:Female; D005665:Furosemide / Q000494:pharmacology; D006439:Hemodynamics / Q000187:drug effects*; D007093:Imidazoles / Q000494:pharmacology*; D019808:Losartan; D008297:Male; D012084:Renin-Angiotensin System / Q000187:drug effects; D013777:Tetrazoles / Q000494:pharmacology*
D057911:Angiotensin Receptor Antagonists; D007093:Imidazoles; D013777:Tetrazoles; D000804:Angiotensin II; D005665:Furosemide; D000803:Angiotensin I; C066026:losartan carboxylic acid; D015773:Enalaprilat; D019808:Losartan