AT₁receptor antagonism attenuates target organ effects of salt excess in SHRs without affecting pressure

Abstract

Our recent studies have demonstrated that salt excess in the spontaneously hypertensive rat (SHR) produces a modestly increased arterial pressure while promoting marked myocardial fibrosis and structural damage associated with altered coronary hemodynamics and ventricular function. The present study was designed to determine the efficacy of an angiotensin II type 1 (AT 1) receptor blocker (ARB) in the prevention of pressure increase and development of target organ damage from high dietary salt intake. Eight-week-old SHRs were given an 8% salt diet for 8 wk; their ageand gender-matched controls received standard chow. Some of the salt-loaded rats were treated concomitantly with ARB (candesartan; 10 mg ⅐ kg Ϫ1 ⅐ day Ϫ1 ). The ARB failed to reduce the salt-induced rise in pressure, whereas it significantly attenuated left ventricular (LV) remodeling (mass and wall thicknesses), myocardial fibrosis (hydroxyproline concentration and collagen volume fraction), and the development of LV diastolic dysfunction, as shown by longer isovolumic relaxation time, decreased ratio of peak velocity of early to late diastolic waves, and slower LV relaxation (minimum first derivative of pressure over time/maximal LV pressure). Without affecting the increased pulse pressure by high salt intake, the ARB prevented the salt-induced deterioration of coronary and renal hemodynamics but not the arterial stiffening or hypertrophy (pulse wave velocity and aortic mass index). Additionally, candesartan prevented the saltinduced increase in kidney mass index and proteinuria. In conclusion, the ARB given concomitantly with dietary salt excess ameliorated salt-related structural and functional cardiac and renal abnormalities in SHRs without reducing arterial pressure. These data clearly demonstrated that angiotensin II (via AT 1 receptors), at least in part, participated importantly in the pressure-independent effects of salt excess on target organ damage of hypertension. left ventricular function; fibrosis; coronary circulation; angiotensi II type 1 receptor blocker

Blood Pressure Lowering and Safety Improvements With Liver Angiotensinogen Inhibition in Models of Hypertension and Kidney Injury

“…Previous work in this model demonstrated no BP reduction with ARB treatment; however, BP was only evaluated after several weeks of treatments. 16,21,22 Therefore, these data are consistent with such studies, but extend the interpretation of RAAS blockade recalcitrance to be a consequence of elicitation of compensatory pathways which can be avoided by angiotensinogen inhibition. Consistent with the BP changes, plasma aldosterone was reduced with GalNAc AGT ASO, but not captopril plus losartan treatment, which would be expected to improve natriuresis and reduce BP.…”

“…Dietary salt excess in SHRs has been shown to exacerbate their hypertension and produce antihypertensive recalcitrance to RAAS inhibitors. 16 We sought to characterize this model and determine the effectiveness of AGT ASO versus traditional RAAS blockade. SHRs were fed an 8% salt diet for 10 to 14 weeks and then implanted with radiotelemetry.…”

The Salt Conundrum

“…Furthermore, in all of these WKY and SHR rats, both left and right ventricular coronary blood flow and flow reserve became markedly impaired; and all of these salt-loaded rats (younger and older adult SHR) demonstrated impaired diastolic functions, severe fibrosis of both ventricles (increased hydroxyproline content and concentration), as well as increased aortic mass associated with impaired distensibility and pulse wave velocity. 37 Moreover (in another report), when these adult SHR rats were treated with an angiotensin II (type I) receptor blocker (ARB), arterial pressure was not reduced, even though the left ventricular diastolic functions and collagen content were normalized (Figure 1) 38,39 Furthermore, in that report, salt-loading diminished renal blood flow and produced massive proteinuria, findings that were normalized by the ARB. 38 These findings prompted our more detailed study of the kidney.…”

“…37 Moreover (in another report), when these adult SHR rats were treated with an angiotensin II (type I) receptor blocker (ARB), arterial pressure was not reduced, even though the left ventricular diastolic functions and collagen content were normalized (Figure 1) 38,39 Furthermore, in that report, salt-loading diminished renal blood flow and produced massive proteinuria, findings that were normalized by the ARB. 38 These findings prompted our more detailed study of the kidney. Several individual SHR groups were given either 4, 6, or 8% salt-loads.…”

A Translational Approach to Hypertensive Heart Disease

“…In particular, sodium loading not only further increased arterial pressure and LVM in spontaneously hypertensive rats but also impaired LV and right ventricular diastolic functions and coronary flow reserve associated with enhanced interstitial and perivascular fibrosis. 15 The observation that AT 1 receptor blockade with low-dose candesartan failed to reduce the salt-induced rise in pressure but significantly attenuated LVM, myocardial fibrosis, and the development of LV diastolic dysfunction in spontaneously hypertensive rats 40 suggests that angiotensin II contributed to the pressure-independent remodeling effect of salt excess on the hypertensive myocardium. Therefore, salt restriction, shown previously to lower pressure and prevent hypertension, may also prevent myocardial remodeling and other target organ damage associated with hypertension.…”