Angiotensin II Type 1 Receptor Blockade Prevents Lethal Malignant Hypertension

Abstract

Background-Angiotensin II is elevated in malignant hypertension. We tested the hypothesis that angiotensin II type 1 receptor blockade can prevent the development of malignant hypertension even in the absence of a blood pressure-lowering effect. Methods and Results-Two-kidney, 1-clip rats were followed up for 28 days; blood pressure was measured by tail-cuff plethysmography and intra-arterially. After a 2-week run-in phase, rats received valsartan at a dose of 0.3 (nϭ14) or 3 (nϭ12) mg · kg Ϫ1 · d Ϫ1 or solvent (nϭ27). Only the higher dose of valsartan, but not the lower dose, decreased blood pressure. Both doses of valsartan prevented the development of lethal malignant hypertension. Twenty of 27 solvent-treated renovascular hypertensive rats died, but only 3 of 14 rats treated with the low dose and 1 of 12 rats treated with the high dose of valsartan died. Histological signs of malignant nephrosclerosis were found in all rats examined that had died throughout the study and in 6 of 7 surviving solvent-treated renovascular hypertensive animals. Increased expression of monocyte chemoattractant protein-1 and prominent interstitial influx of macrophages occurred in the nonclipped kidneys exposed to high pressure in solvent-treated rats. These alterations were prevented by valsartan at both doses, irrespective of blood pressure effects. Conclusions-Angiotensin II type 1 receptor blockade by valsartan prevents lethal malignant hypertension independently of blood pressure. The results suggest that reduction of angiotensin-induced inflammation in the kidney may contribute to the protective effects of valsartan.

Angiotensin II AT1 Receptor Blockade Abolishes Brain Microvascular Inflammation and Heat Shock Protein Responses in Hypertensive Rats

“…Members of the HSP family are able to stimulate cells of the innate immune system directly and act as dangersignaling molecules (Hilgers et al, 2001). Proinflammatory cytokines induce activation of HSF1-DNA binding followed by induction of HSP70 expression (Schett et al, 1998).…”

Effects of Renin-Angiotensin System Blockade on Macrophage Infiltration in Patients with Hypertensive Nephrosclerosis

“…Activation of the renin-angiotensin system is a major cause of systemic hypertension and local activation in the kidneys induces renal tissue damage via immunological mechanisms such as the activation of nuclear factor κB (NFκB) (6). In addition, renal monocyte chemoattractant protein-1 expression is increased in an experimental rat model of renin-angiotensin system-dependent hypertension, and angiotensin II type 1 receptor blocker inhibits the production of monocyte chemoattractant protein-1 protein and decreases macrophage infiltration (7). Furthermore, large clinical trials have confirmed that angiotensin-converting enzyme inhibitors inhibit the renin-angiotensin system, and that angiotensin II type 1 receptor blockers have renoprotective effects in diabetic and non-diabetic renal diseases, with some of these renoprotective effects appearing to be independent of the blood pressure-lowering effects (8,9).…”

“…In this study, all 16 patients were clinically and histologically diagnosed with benign hypertensive nephrosclerosis. Human benign hypertensive nephrosclerosis is thought to develop gradually as a consequence of long-term hypertension, and thus shows a considerably different progression from experimental hypertension, which is generally rapid and short-term (4,5,7). The present data are interesting, because they suggest that, in addition to the role played by the renin angiotensin system, an inflammatory process could also contribute to the progression of human benign hypertensive nephrosclerosis, although the mechanisms are not likely to completely correspond with those in experimental models.…”

Antihypertensive effects of Ocimum basilicum L. (OBL) on blood pressure in renovascular hypertensive rats

“…2,3 Hypertension is with dyslipidemia and platelet activation a major contributor to cardiovascular risk 4 with clinical consequences, such as heart failure, acute coronary syndrome and ischemic stroke. 5,6 It was therefore thought useful to test whether OBL also had any effects on blood pressure in a model of experimental hypertension and cardiac hypertrophy. …”