Delayed inhibition of angiotensin II receptor type 1 reduces secondary brain damage and improves functional recovery after experimental brain trauma

Objective: To investigate the regulation of the cerebral renin angiotensin system and the effect of angiotensin II receptor type 1 inhibition on secondary brain damage, cerebral inflammation, and neurologic outcome after head trauma. Design: The expression of renin angiotensin system components was determined at 15 mins, 3 hrs, 6 hrs, 12 hrs, and 24 hrs after controlled cortical impact in mice. Angiotensin II receptor type 1 was inhibited using candesartan (0.1, 0.5, 1 mg/kg) after trauma to determine its effect on secondary brain damage, brain edema formation, and inflammation. The window of opportunity was tested by delaying angiotensin II receptor type 1 inhibition for 30 mins, 1 hr, 2 hrs, and 4 hrs. The long-term effect was tested by single and daily repeated treatment with candesartan for 5 days after controlled cortical impact. Setting: University research laboratory. Subjects: Male C57BI/6N mice. Interventions: Brain trauma by use of a controlled cortical impact device. Measurements and Main Results: Expression of angiotensin II receptor type 1A decreased by 42% within 24 hrs after controlled cortical impact, whereas angiotensin II receptor type 1B expression increased to 220% between 6 and 12 hrs. Blockage of angiotensin II receptor type 1with 0.1 mg/kg candesartan within 4 hrs of injury significantly reduced secondary brain damage (30 mins: 25 mm(3) vs. vehicle: 41 mm(3)) and improved neurologic function after 24 hrs but failed to reduce brain edema formation. Daily treatment with candesartan afforded sustained reduction of brain damage and improved neurologic function 5 days after traumatic brain injury compared with single and vehicle treatment. Inhibition of angiotensin II receptor type 1 significantly attenuated posttraumatic inflammation (interleukin-6: -56%; interleukin-1 beta: -42%; inducible nitric oxide synthase: -36%; tumor necrosis factor-alpha: -35%) and microglia activation (vehicle: 163 +/- 25/mm(2) vs. candesartan: 118 +/- 13/mm(2)). Higher dosages (0.5 and 1 mg/kg) resulted in prolonged reduction in blood pressure and failed to reduce brain lesion. Conclusions: The results indicate that angiotensin II receptor type 1 plays a key role in the development of secondary brain damage after brain trauma. Inhibition of angiotensin II receptor type 1 with a delay of up to 4 hrs after traumatic brain injury effectively reduces lesion volume. This reduction makes angiotensin II receptor type 1 a promising therapeutic target for reducing cerebral inflammation and limiting secondary brain damage. (Crit Care Med 2012; 40:935-944)