Endothelial Dysfunction and Cardiorenal Injury in Experimental Salt-Sensitive Hypertension

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Abstract
Background Pharmacological control of hypertension has contributed to a significant decrease in cardiovascular morbidity and mortality, although the beneficial effect on cardiac and renal diseases has been far more modest than the reduction in stroke. The endothelium plays a crucial homeostatic role in the regulation of vascular tone thrombogenesis and vascular remodeling. We studied the relationship between endothelial dysfunction and cardiorenal injury in hypertensive rats and evaluated the effects of two classes of antihypertensive agents commonly used in the clinical setting, a diuretic (DIU) and an ACE inhibitor (CEI). Methods and Results Dahl salt-sensitive rats (DS) given high dietary salt (4% NaCl) developed hypertension (systolic blood pressure [SBP], 218±9 versus 147±3 mm Hg in DS given 0.5% NaCl; P<.001), which was associated with impaired endothelium-dependent relaxations (EDRs) in aortic rings (ED50, 5.44±.18 versus 7.51±.10; P<.05) and mesenteric vessels (area under the curve, 299±11 versus 217±11 arbitrary units; P<.05). Hypertensive DS also demonstrated depressed nitric oxide synthase activity in the aorta (0.76±.15 versus 2.83±.17 nmol · min−1 · g protein−1; P<.05), left ventricular hypertrophy (0.43±.02 versus 0.29±.02 g ventricular weight/100 g body weight; P<.05), glomerular injury (histological injury score: 151±8 versus 11±2; P<.05), and increased urinary protein excretion (95±21 versus 25±5 mg/24 hours; P<.05). Treatment of DS rats with the CEI perindopril (4.56 mg · kg−1 · d−1) did not affect SBP (225±6 mm Hg) but modestly improved EDR (ED50: 6.07±.37; P<.05 versus hypertensive DS) as well as proteinuria and glomerular histology. Addition of the DIU indapamide (1.44 mg · kg−1 · d−1) normalized SBP (151±2 mm Hg; P<.05), EDR (ED50, 7.33±.08; P<.05), left ventricular hypertrophy (0.27±.01 g/100 g body weight; P<.05), and proteinuria (31±4 mg/24 hours; P<.05) and prevented glomerular injury (injury score: 30±2; P<.05). Monotherapy with DIU reduced SBP (175±3 mm Hg; P<.05) and normalized EDR and left ventricular hypertrophy but did not provide effective renal protection. In hypertensive DS, impaired EDR and left ventricular hypertrophy were positively correlated with SBP. In addition, we found a significant correlation between cardiac hypertrophy and endothelial dysfunction. Indeed, a hierarchical regression analysis revealed that impaired aortic EDR, and therefore decreased aortic compliance, positively contributed to left ventricular hypertrophy in addition to but independently of SBP [F(2, 37)=6.29; P=.004]. Conclusions These studies suggest a dissociation of the endothelial, cardiac, and renal effects of antihypertensive therapy in hypertension and may explain the variable success of antihypertensive regimens in treating hypertension while preventing cardiac and renal damage.