Endothelial dysfunction and cardiorenal injury in experimental salt- sensitive hypertension: Effects of antihypertensive therapy

Hiroshi Hayakawa, Karen Coffee, Leopoldo Raij

Research output: Contribution to journalArticle

121 Citations (Scopus)

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·k-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 hyper trophy 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.

Original languageEnglish
Pages (from-to)2407-2413
Number of pages7
JournalCirculation
Volume96
Issue number7
StatePublished - Oct 7 1997
Externally publishedYes

Fingerprint

Antihypertensive Agents
Salts
Inbred Dahl Rats
Blood Pressure
Hypertension
Wounds and Injuries
Endothelium
Left Ventricular Hypertrophy
Therapeutics
Diuretics
Kidney
Proteinuria
Body Weight
Indapamide
Perindopril
Cardiomegaly
Angiotensin-Converting Enzyme Inhibitors
Nitric Oxide Synthase
Compliance
Area Under Curve

Keywords

  • Cardiovascular diseases
  • Endothelium
  • Hypertension
  • Kidney
  • Nitric oxide

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Endothelial dysfunction and cardiorenal injury in experimental salt- sensitive hypertension : Effects of antihypertensive therapy. / Hayakawa, Hiroshi; Coffee, Karen; Raij, Leopoldo.

In: Circulation, Vol. 96, No. 7, 07.10.1997, p. 2407-2413.

Research output: Contribution to journalArticle

Hayakawa, Hiroshi ; Coffee, Karen ; Raij, Leopoldo. / Endothelial dysfunction and cardiorenal injury in experimental salt- sensitive hypertension : Effects of antihypertensive therapy. In: Circulation. 1997 ; Vol. 96, No. 7. pp. 2407-2413.
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N2 - 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·k-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 hyper trophy 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.

AB - 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·k-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 hyper trophy 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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