The effect of angiotensin AT1 receptor blockade in the brain on the maintenance of blood pressure during haemorrhage in sheep

The effect of systemic or intracerebroventricular (ICV) infusion of the angiotensin AT1 receptor antagonist losartan on blood pressure during hypotensive haemorrhage was investigated in five conscious sheep. Mean arterial pressure (MAP) was measured during haemorrhage (15 mL kg-1 body wt). Losartan (1 or 0.33 mg h-1) was given to sheep by ICV, intravenous or intracarotid administration, beginning 60 min before and continuing during the haemorrhage. During control infusion of ICV artificial cerebrospinal fluid, MAP was maintained until 13.16 +/- 0.84 mL kg-1 blood loss, when a rapid reduction of at least 15 mmHg in arterial pressure occurred (the decompensation phase). ICV infusion of losartan at 1 mg h-1 caused an early onset of the decompensation phase after only 9.8 +/- 0.8 mL kg-1 of blood loss compared with control. Intravenous infusion of losartan (1 mg h-1) also caused an early onset (P < 0.05) of the decompensation phase at 10.2 +/- 1.0 mL kg-1 blood loss. This dose of losartan inhibited the pressor response to ICV angiotensin II, but not to intravenously administered angiotensin II, indicating that only central AT1 receptors were blocked. Bilateral carotid arterial administration of losartan at 0.33 mg h-1 caused an early onset of the decompensation phase during haemorrhage at 11.06 +/- 0.91 mL kg-1 blood loss (P < 0.05), which did not occur when infused by intravenous or ICV routes. The results indicate that an angiotensin AT1-receptor-mediated mechanism is involved in the maintenance of MAP during haemorrhage in sheep. The locus of this mechanism appears to be the brain.