ENDOTHELIAL DYSFUNCTION AND CARDIORENAL INJURY IN EXPERIMENTAL SALT-SENSITIVE HYPERTENSION - EFFECTS OF ANTIHYPERTENSIVE THERAPY

Background Pharmacological control of hypertension has contributed to a significant decrease in cardiovascular morbidity and mortality, alth ough the beneficial effect on cardiac and renal diseases has been far more modest than the reduction in stroke. The endothelium plays a cruc ial homeostatic role in the regulation of vascular tone thrombogenesis and vascular remodeling. We studied the relationship between endothel ial dysfunction and cardiorenal injury in hypertensive rats and evalua ted the effects of two classes of antihypertensive agents commonly use d 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), wh ich was associated with impaired endothelium-dependent relaxations (ED Rs) 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 depr essed nitric oxide synthase activity in the aorta (0.76 +/- .15 versus 2.83 +/- .17 nmol.min(-1).g protein(-1); P < .05), left ventricular h ypertrophy (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 ex cretion (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 affec t 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)) norm alized SBP (151 +/- 2 mm Hg; P < .05), EDR (ED50, 7.33 +/- .08; P < .0 5), 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 protectio n. In hypertensive DS, impaired EDR and left ventricular hypertrophy w ere positively correlated with SBP. In addition, we found a significan t correlation between cardiac hypertrophy and endothelial dysfunction. Indeed, a hierarchical regression analysis revealed that impaired aor tic EDR, and therefore decreased aortic compliance, positively contrib uted to left ventricular hypertrophy in addition to but independently of SBP [F-(2,F- 37) = 6.29; P = .004]. Conclusions These studies sugge st a dissociation of the endothelial, cardiac, and renal effects of an tihypertensive therapy in hypertension and may explain the variable su ccess of antihypertensive regimens in treating hypertension while prev enting cardiac and renal damage.