Mechanisms of the Anti-Ischemic Effect of Angiotensin II AT( 1 ) Receptor Antagonists in the Brain.
1. Circulating and locally formed Angiotensin II regulates the cerebral circulation through stimulation of AT(1) receptors located in cerebrovascular endothelial cells and in brain centers controlling cerebrovascular flow. 2. The cerebrovascular autoregulation is designed to maintain a constant blood flow to the brain, by vasodilatation when blood pressure decreases and vasoconstriction when blood pressure increases. 3. During hypertension, there is a shift in the cerebrovascular autoregulation to the right, in the direction of higher blood pressures, as a consequence of decreased cerebrovascular compliance resulting from vasoconstriction and pathological growth. In hypertension, when perfusion pressure decreases as a consequence of blockade of a cerebral artery, reduced cerebrovascular compliance results in more frequent and more severe strokes with a larger area of injured tissue. 4. There is a cerebrovascular angiotensinergic overdrive in genetically hypertensive rats, manifested as an increased expression of cerebrovascular AT(1) receptors and increased activity of the brain Angiotensin II system. Excess AT(1) receptor stimulation is a main factor in the cerebrovascular pathological growth and decreased compliance, the alteration of the cerebrovascular eNOS/iNOS ratio, and in the inflammatory reaction characteristic of cerebral blood vessels in genetic hypertension. All these factors increase vulnerability to brain ischemia and stroke. 5. Sustained blockade of AT(1) receptors with peripheral and centrally active AT(1) receptor antagonists (ARBs) reverses the cerebrovascular pathological growth and inflammation, increases cerebrovascular compliance, restores the eNOS/iNOS ratio and decreases cerebrovascular inflammation. These effects result in a reduction of the vulnerability to brain ischemia, revealed, when an experimental stroke is produced, in protection of the blood flow in the zone of penumbra and substantial reduction in neuronal injury. 6. The protection against ischemia resulting is related to inhibition of the Renin-Angiotensin System and not directly related to the decrease in blood pressure produced by these compounds. A similar decrease in blood pressure as a result of the administration of beta-adrenergic receptor and calcium channel blockers does not protect from brain ischemia. 7. In addition, sustained AT(1) receptor inhibition enhances AT(2) receptor expression, associated with increased eNOS activity and NO formation followed by enhanced vasodilatation. Direct AT(1) inhibition and indirect AT(2) receptor stimulation are associated factors normalizing cerebrovascular compliance, reducing cerebrovascular inflammation and decreasing the vulnerability to brain ischemia.8. These results strongly suggest that inhibition of AT(1) receptors should be considered as a preventive therapeutic measure to protect the brain from ischemia, and as a possible novel therapy of inflammatory conditions of the brain.
Saavedra
Juan M
JM
Section on Pharmacology, Division of Intramural Research Programs, National Institute of Mental Health, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland, USA. saavedrj@mail.nih.gov
Benicky
Julius
J
Zhou
Jin
J
D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D000818:Animals; D001794:Blood Pressure; D001921:Brain / Q000098:blood supply / Q000187:drug effects* / Q000378:metabolism; D002545:Brain Ischemia / Q000517:prevention & control*; D002560:Cerebrovascular Circulation / Q000502:physiology; D006801:Humans; D006973:Hypertension / Q000503:physiopathology; D008954:Models, Biological; D051381:Rats; D011918:Rats, Inbred SHR; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism / Q000502:physiology; D044139:Receptor, Angiotensin, Type 2 / Q000502:physiology; D012084:Renin-Angiotensin System / Q000187:drug effects; D020521:Stroke / Q000517:prevention & control
D047228:Angiotensin II Type 1 Receptor Blockers; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2