CENTRAL ANGIOTENSIN-II AT(1)-RECEPTOR ANTAGONISM IN NORMAL AND HEART-FAILED SHEEP

The role of the brain renin-angiotensin system (RAS) in heart failure was examined by administering intracerebroventricular (ICV) infusions of the angiotensin II (ANG II) type 1 (AT(1))-receptor antagonist losa rtan (0.1 followed by 0.5 mg . kg(-1). 3h(-1)) to six concious sheep b efore (nonpaced) and after induction of heart failure by rapid left ve ntricular pacing (paced). In both nonpaced and paced states, ICV losar tan abolished drinking, induced a significant diuresis (P < 0.05) and anti-natriuresis (P < 0.05), and increased plasma renin activity (P < 0.05) and ANG II (P < 0.01) and aldosterone levels (0.1 > P > 0.05). P lasma arginine vasopressin was suppressed by ICV losartan only in the paced state (P < 0.05). Hemodynamics were not altered by ICV losartan in the nonpaced animals. In the paced state, however, significant redu ctions in left ventricular systolic, mean arterial, and left atrial pr essures were observed (decrements of 13 +/- 7, 12 +/- 5, and 3.4 +/- 0 .7 mmHg, respectively, all P < 0.05). In conclusion, ANG II within the brain participates in the regulation of thirst and body electrolyte a nd fluid homeostasis in normal and heart-failed sheep and appears to p lay a role in regulating resting hemodynamic status in this model of h eart failure.