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• W2077202495 abstract "Ever since firm evidence began to emerge for the role of the renin–angiotensin system in high blood pressure in the first half of the twentieth century, the possibility that renin may damage vascular structures by non-haemodynamic mechanisms has been on the research agenda [1,2]. Wilson and Byrom [2] postulated that raised pressure in arterioles was the principal damaging phenomenon in models of hypertension. However, tracing the evolution of vascular changes in the kidneys of two kidney–one clip rats, they found that, after a time, the clipped kidney, apparently protected from the effects of high blood pressure, began to show similar vascular changes to the unclipped kidney. At the same time, it was observed that renin infusion caused proteinuria, apparently as a result of changes in glomerular permeability rather than renal perfusion pressure [3,4]. Fifty or 60 years later, there is still uncertainty about the relative role in vessel wall damage of high blood pressure itself in contrast to the metabolic effects of humoral factors whose initial functions were defined in terms of vascular smooth muscle tone. Dual vasomotor and inflammatory modulating functions have been found for angiotensin II, bradykinin [5], endothelin [6] and prostaglandins [7]. A thorough review of these functions for the renin–angiotensin system appeared recently [8] and concluded that they were important in vascular remodelling and inflammation. In this issue of the journal, Johanssen et al. [9] attempt to address the issue of multiple roles for angiotensin II in a genetically hyperlipidaemic mouse model made hypertensive by suprarenal aortic constriction. This is generally accepted to be a high renin form of hypertension, an expectation confirmed in their study. They conclude that pressure is the dominant factor in generating atheromatous changes assessed by plaque area. (The distinction between atherogenesis and other arterial wall pathology associated with high blood pressure should be born in mind, even though there are cellular and molecular processes that appear to be common to all.) The roles of different angiotensin II functions were assessed by ultrasound studies of aortic blood flow and direct blood pressure measurement above and below the constriction. Johanssen et al. [9] also measured the effects of angiotensin II type 1 receptor (AT1R) blockade with losartan, given throughout the experimental period, on pressures and plasma renin activity, as well as angiotensin II type 2 receptor protein and messenger RNA in the plaques generated. Some of their results were unexpected. Losartan lowered blood pressure more in the unoperated control animals than in the high renin hypertensive mice, although the efficacy of blockade in raising circulating renin concentration was comparable in both groups. Most studies have reported enhanced blood pressure sensitivity to angiotensin blockade in the high renin state [10]. There was a weak correlation between AT2 receptor expression and plaque area in the aorta. Whether this was related to increased circulating angiotensin II or a response by the arterial wall to the process of atherogenesis is uncertain. The conclusions of their study rest on finding increased plaque area in those parts of the arterial tree exposed to high blood pressure and no apparent response to concurrent angiotensin II blockade throughout the whole observation period. If anything, this conclusion is strengthened by the paradoxical failure of losartan to lower blood pressure while apparently producing angiotensin II antagonism of a degree that might be considered adequate to mitigate inflammatory responses. However, there are experimental reasons not to accept the authors' conclusion without dispute. The early work of Wilson and Byrom [2] suggests that if they had performed the same exhaustive studies on plaque formation and angiotensin II receptor expression in the low pressure ilio-femoral arterial system as they did on the innominate artery, they may have discovered changes that could not be attributed to high blood pressure. It may have given the results more confidence if they had differentiated the multiple effects of angiotensin II by taking a third group of animals and lowering the blood pressure with an agent without direct effects on the renin–angiotensin system, such as a dihydropyridine calcium channel blocker. Measurement of circulating angiotensin II, taken to be the final effector of the renin angiotensin system, would have been preferable to that of renin, a surrogate measure in the context of these experiments. The experimental design was contemporary, using molecular and cellular biology techniques to define pathophysiological events. These methods were probably mandated by limitations on the number of physiology experiments possible in a homozygous knockout model in a small animal such as the mouse. Nevertheless, pressor dose–response curves to infused angiotensin II would have given better confirmation of AT1R blockade than the inferential measure of elevated plasma renin, even if performed in only a small sample. There are important differences with respect to the work conducted in the 1930s and 1950s. The early workers were not studying atherogenesis but changes that they attributed to high blood pressure as a sole risk factor (i.e. reduplication of layers of the arterial wall and smooth muscle hypertrophy). Although diastolic blood pressure has been shown to constitute a continuously variable risk factor for coronary disease with no lower limit [11], we believe atherosclerosis to be a complex process in which metabolic and inflammatory changes in the subendothelial layers are of at least equal importance. The findings of Johanssen et al. [9] are consistent with the epidemiological observations. The links between high blood pressure and atheroma are still poorly understood, although shear-responsive mechanisms in the endothelium provide a credible link between haemodynamic events in the lumen and inflammatory responses in the subendothelial layers [12]. The importance of determining specific roles for the diverse pathogenic effects of the renin–angiotensin–aldosterone (RAAS) system lies in our relative failure to protect people from vascular outcomes by reducing blood pressure, with most studies showing a reduction in coronary events of approximately 30% and, for strokes, approximately 40% [13]. Agents that inhibit the renin–angiotensin system are among the most potent blood pressure-lowering agents known, which further obscures any definition of benefits that might be attributed to specific anti-inflammatory actions in the arterial wall. An angiotensin-converting enzyme (ACE) inhibitor, ramipril, reduced proteinuria in diabetic patients without hypertension, although blood pressure was observed to fall slightly in the treated groups [14]. AT1R blockers have shown superiority in preventing progression of diabetic renal disease and proteinuria in comparison with, or in addition to, parallel treatments with comparable effects on blood pressure but not on the renin–angiotensin system. These benefits were not reflected in cardiovascular outcomes [15–17]. In studies of non-diabetic cardiovascular disease, the data are also unsupportive. A study comparing cardiovascular outcomes in high-risk hypertensive patients (defined on the basis of having at least one risk factor in addition to hypertension), who were treated with different types of agents, showed no superiority in overall mortality or cardiovascular outcomes in patients receiving the ACE inhibitor lisinopril [18]. Only the Second Australian National Blood Study showed an advantage when comparing enalapril with a diuretic-based regime [19]. Although albuminuria is considered to be an important indicator of cardiovascular disease risk [20,21], it appears that its reduction by RAAS inhibitors has at best limited implications for cardiovascular disease outcomes. The undoubted vascular damaging effects of angiotensin II are a tantalizing invitation to believe in the therapeutic superiority of agents that reduce its production or block its actions. It is not surprising that so much literature on vascular, renal and diabetic disease is devoted to trying to demonstrate it. The belief appears valid in the case of diabetes and there is some evidence in the case of non-diabetic proteinuria. The grand prize of a proven therapeutically relevant role in large and medium blood vessel disease remains out of reach. The study by Johanssen et al. [9] may be flawed but offers little comfort to the true believers." @default.
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• W2077202495 title "Mechanics or mediators: arterial damage from high blood pressure" @default.
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