Background and Purpose--There is growing evidence that pharmacologic interference with the renin-angiotensin system may reduce risk of stroke, although the mechanism is unclear. Impaired reactivity of cerebral vessels has recently been recognized as a risk factor for stroke. We examined the effect of the angiotensin-converting enzyme (ACE) inhibitor perindopril on cerebral vasomotor reactivity to acetazolamide in patients with lacunar cerebral infarction.

Methods--We studied a cohort of male patients between 3 and 12 months after lacunar infarction confirmed on computed tomography (CT). Each patient received perindopril 4 mg daily or matching placebo for 2 weeks in a randomized, double-blind, placebo-controlled crossover fashion. A 1-week washout period was observed between dosing periods. Cerebral vasomotor reactivity (increase in middle cerebral artery mean flow velocity in response to intravenous injection of 15 mg/kg acetazolamide) was measured before and after each dosing period using standard Doppler ultrasound techniques.

Results--Twelve patients (mean age 63.2±2.3 years) completed the protocol. There was no treatment order effect. Cerebral vasomotor reactivity was significantly greater after perindopril treatment (percent change from baseline +18.8±10.1% after perindopril, -4.6±4.1% after placebo; P=0.032). Dosing with perindopril did not affect resting cerebral blood flow velocity (CBFV) (percent change from baseline +3.1±9.5% after perindopril, -0.6±5.4% after placebo), nor was there a change in resting blood pressure (+1.8 mm Hg±3.1 after perindopril, +1.4 mm Hg±2.5 after placebo).

Conclusion--This study provides evidence of a significant improvement in CVR induced by perindopril, beyond any effect on blood pressure. The results suggest a possible mechanism for the beneficial effect of ACE inhibition on stroke risk observed in recent clinical trials, and suggest a role for the renin-angiotensin axis in the pathophysiology of subcortical small vessel disease.