First, an update of the vascular systemic and tissue renin-angiotensin-aldosterone system is provided to explain how it is regulated at the systemic and tissue levels, and how many
angiotensin peptides and receptors can be modulated by the various
antihypertensive drugs. Second, experimental data is presented to support the hypothesis that
antihypertensive drugs that increase
angiotensin II formation, such as
diuretics, AT1-receptor blockers and
dihydropyridines, may have greater brain anti-ischemic effects than
antihypertensive drugs that decrease
angiotensin II formation, such as beta-blockers and
angiotensin-converting enzyme inhibitors, because they increase activation of
angiotensin AT2 and
AT4 receptors. Indeed, these trigger brain anti-ischemic mechanisms by favouring cerebral blood flow (angiogenesis and recruitment of pre-existing collateral circulation, specifically in the ischemic brain where AT2 receptors are overexpressed) or by directly increasing neuronal resistance to
anoxia. Third, we review most of the large primary and secondary
stroke prevention trials as well as the ACCESS
acute stroke trial in which
antihypertensive drugs were evaluated. With the exception of the secondary
stroke prevention trial PRoFESS, most trials support the hypothesis that
angiotensin II-increasing drugs confer specific blood pressure-independent
brain ischemia protection when compared with
angiotensin II-decreasing drugs or placebo. A careful analysis of the PRoFESS trial, however, reveals study design limitations, the main one being that diastolic BP (<80 mmHg) in the first month post-
stroke may have been too low in at least one third of the population with baseline systolic blood pressure less than 130 mmHg, because a high dose of
telmisartan was given after a very short post-
stroke delay (median 15 days) without discontinuation of the baseline
antihypertensive treatment.