Background and Purpose-Pretreatment with angiotensin II AT 1 receptor antagonists protects against cerebral ischemia.We studied whether modulation of cerebral blood flow (CBF) and morphometric changes in brain arteries participated in this protective mechanism. Methods-We pretreated adult spontaneously hypertensive rats with equally antihypertensive doses of candesartan (0.1 or 0.3 mg/kg per day), nicardipine (0.1 mg/kg per day), or captopril (3.0 mg/kg per day) for 3 or 28 days via subcutaneous osmotic minipumps followed by permanent left middle cerebral artery (MCA) occlusion distal to the origin of the lenticulostriate arteries. We measured CBF by autoradiography with 4-iodo-[N-methyl-14 C]antipyrine 3 hours after operation and the areas of infarct and tissue swelling 24 hours after operation. Morphometric changes in the MCA were studied after antihypertensive treatment. Results-Twenty-eight days of candesartan pretreatment decreased the infarct area by 31%; reduced the CBF decrease at the peripheral area of ischemia and the cortical volume of severe ischemic lesion, where CBF was Ͻ0.50 mL/g per minute; increased the MCA external diameter by 16%; and reduced the media thickness of the MCA by 23%. Captopril pretreatment for 28 days decreased the infarct area by 25%. Pretreatment with candesartan for 3 days or nicardipine for 28 days was ineffective. Conclusions-Angiotensin II system inhibition protects against neuronal injury more effectively than calcium channel blockade. Protection after AT 1 receptor blockade is not directly correlated with blood pressure reduction but with normalization of MCA media thickness, leading to increased arterial compliance and reduced CBF decrease during ischemia at the periphery of the lesion.

dra. Anti-inflammatory effects of angiotensin II AT 1 receptor antagonism prevent stress-induced gastric injury. Am J Physiol Gastrointest Liver Physiol 285: G414-G423, 2003. First published April 9, 2003 10.1152/ajpgi.00058.2003.-Stress reduces gastric blood flow and produces acute gastric mucosal lesions. We studied the role of angiotensin II in gastric blood flow and gastric ulceration during stress. Spontaneously hypertensive rats were pretreated for 14 days with the AT 1 receptor antagonist candesartan before cold-restraint stress. AT 1 receptors were localized in the endothelium of arteries in the gastric mucosa and in all gastric layers. AT 1 blockade increased gastric blood flow by 40-50%, prevented gastric ulcer formation by 70-80% after coldrestraint stress, reduced the increase in adrenomedullary epinephrine and tyrosine hydroxylase mRNA without preventing the stress-induced increase in adrenal corticosterone, decreased the stress-induced expression of TNF-␣ and that of the adhesion protein ICAM-1 in arterial endothelium, decreased the neutrophil infiltration in the gastric mucosa, and decreased the gastric content of PGE 2. AT1 receptor blockers prevent stress-induced ulcerations by a combination of gastric blood flow protection, decreased sympathoadrenal activation, and anti-inflammatory effects (with reduction in TNF-␣ and ICAM-1 expression leading to reduced neutrophil infiltration) while maintaining the protective glucocorticoid effects and PGE 2 release. Angiotensin II has a crucial role, through stimulation of AT 1 receptors, in the production and progression of stress-induced gastric injury, and AT 1 receptor antagonists could be of therapeutic benefit. gastric blood flow; prostaglandins; tumor necrosis factor STRESS INDUCES ACUTE GASTRIC mucosal lesions (33) by complex psychological factors influencing individual vulnerability, stimulation of specific brain pathways regulating autonomic function, decreased blood flow to the mucosa, increase in muscular contractility, mast cell degranulation, leukocyte activation, and increased free radical generation resulting in increased lipid peroxidation (2, 33, 49, 55).Cold-restraint stress is a commonly used and clinically relevant experimental model for acute gastric damage (44). A sudden blood flow reduction to the gastric mucosa and increased free radical formation play fundamental roles in ulcer production (49). Maintenance of gastric blood flow is important to protect the mucosa from endogenous and exogenous damage factors.Angiotensin II (ANG II) is a stress hormone (40), the levels of which dramatically increase in plasma and tissues, including stomach, during stress (10, 54). ANG II not only regulates vascular tone in resistance arteries (16) and in the brain (31) but also constricts the gastric vasculature through AT 1 receptor stimulation (19). In addition, ANG II generates reactive oxygen species with cellular damage and inflammation (36). The mucosal vasoconstriction and proinflammatory effects of ANG II could contribute to the production of...

Long-term pretreatment with an angiotensin II AT 1 antagonist blocks angiotensin II effects in brain and peripheral organs and abolishes the sympathoadrenal and hypothalamic-pituitary-adrenal responses to isolation stress. We determined whether AT 1 receptors were also important for the stress response of higher regulatory centers. We studied angiotensin II and corticotropin-releasing factor (CRF) receptors and benzodiazepine binding sites in brains of Wistar Hannover rats. Animals were pretreated for 13 days with vehicle or a central and peripheral AT 1 antagonist (candesartan, 0.5 mg/kg/day) via osmotic minipumps followed by 24 h of isolation in metabolic cages, or kept grouped throughout the study (grouped controls). In another study, we determined the influence of a similar treatment with candesartan on performance in an elevated plus-maze. AT 1 receptor blockade prevented the isolation-induced increase in brain AT 1 receptors and decrease in AT 2 binding in the locus coeruleus. AT 1 receptor antagonism also prevented the increase in tyrosine hydroxylase mRNA in the locus coeruleus. Pretreatment with the AT 1 receptor antagonist completely prevented the decrease in cortical CRF 1 receptor and benzodiazepine binding produced by isolation stress. In addition, pretreatment with candesartan increased the time spent in and the number of entries to open arms of the elevated plus-maze, measure of decreased anxiety. Our results implicate a modulation of upstream neurotransmission processes regulating cortical CRF 1 receptors and the GABA A complex as molecular mechanisms responsible for the anti-anxiety effect of centrally acting AT 1 receptor antagonists. We propose that AT 1 receptor antagonists can be considered as compounds with possible therapeutic anti-stress and anti-anxiety properties.

MMPs (matrix metalloproteinases) play a major role in the pathogenesis of hypertension by altering the extracellular matrix during cardiovascular remodelling. In the present study we show that MMP-2, but not MMP-9, cleaves the vasodilator peptide AM (adrenomedullin). Addition of the AM-binding protein, complement factor H, prevents this cleavage, providing a hitherto unknown mechanism of action for this binding protein. We identified the signature cleavage fragments and found some of them in human urine, suggesting that MMP-2 processing of AM may occur in vivo. Synthetic AM fragments regulated blood pressure in rats. The larger peptides are vasodilators, as is intact AM, whereas intermediate fragments did not affect blood pressure. In contrast, AM(11-22) elicited vasoconstriction. Studies of AM receptor activation in Rat2 cells confirm that the larger AM cleavage peptides activated this receptor, whereas AM(11-22) did not. The present study defines a new mechanism through which MMP-2 may regulate blood pressure by simultaneously eliminating a vasodilator and generating a vasoconstrictor.