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Published on: December 5, 2017
Endothelial dysfunction and cardiorenal injury in experimental salt-sensitive hypertension: effects of
1Department of Medicine, Veterans Affairs Medical Center and University of Minnesota Medical School, Minneapolis 55417, USA.
Insights
Hypertension treatment with a diuretic normalized blood pressure and cardiac function but not renal protection. Combination therapy effectively treated hypertension and protected cardiac and renal systems.
Area of Science:
- Cardiovascular Research
- Nephrology
- Endothelial Function
Background:
- Hypertension control reduces cardiovascular mortality, but cardiac and renal benefits are modest.
- The endothelium regulates vascular tone, thrombogenesis, and remodeling.
- Endothelial dysfunction is linked to cardiorenal injury in hypertension.
Purpose of the Study:
- Investigate the relationship between endothelial dysfunction and cardiorenal injury in hypertensive rats.
- Evaluate the effects of a diuretic (DIU) and an ACE inhibitor (CEI) on hypertension-induced cardiorenal damage.
Main Methods:
- Dahl salt-sensitive rats were induced with hypertension via high salt diet.
- Assessed systolic blood pressure (SBP), endothelium-dependent relaxations (EDRs), nitric oxide synthase activity, left ventricular hypertrophy, glomerular injury, and urinary protein excretion.
- Treated rats with CEI (perindopril), DIU (indapamide), or combination therapy.
Main Results:
- Hypertension was associated with impaired EDRs, cardiac hypertrophy, glomerular injury, and proteinuria.
- CEI monotherapy showed modest improvement in EDRs and renal parameters but did not lower SBP.
- DIU monotherapy normalized SBP, EDRs, and cardiac hypertrophy but offered limited renal protection.
- Combination therapy normalized SBP, EDRs, cardiac hypertrophy, and significantly improved renal parameters and glomerular injury.
Conclusions:
- Antihypertensive therapy exhibits dissociation in endothelial, cardiac, and renal effects.
- This dissociation may explain variable success in preventing cardiorenal damage with different antihypertensive regimens.
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 x min(-1) x 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 x kg(-1) x 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 x kg(-1) x 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.
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