Blood pressure, endothelial dysfunction and target organ injury

The architectural changes in the kidney, heart and vessels that occur in hy pertension are often maladaptive and can eventually contribute to end-organ disease, such as renal failure, heart failure and coronary artery disease. The endogenous vasodilatory and antithrombotic agent nitric oxide (NO) is synthesized in the endothelium by a constitutive nitric oxide synthase (NOS ). NO inhibits growthrelated responses to injury in vascular cells; the eff ects of NO are antagonistic to those of angiotensin II. We studied the rela tionship between endothelial dysfunction and cardiorenal injury in hyperten sive Dahl salt-sensitive (DS) rats which are a paradigm of salt-sensitive h ypertension in humans. DS rats given high dietary salt (4% NaCl) developed hypertension, which was associated with impaired endothelium-dependent rela xations (EDRs) in aortic rings and mesenteric vessels. They also demonstrat ed left ventricular hypertrophy (LVH), glomerular injury, and increased uri nary protein excretion and depressed NOS activity in the aorta. Treatment w ith the angiotensin-converting enzyme perindopril did not affect systolic b lood pressure (SBP) but modestly improved EDR as well as proteinuria and gl omerular histology. The diuretic indapamide reduced SEP and normalized EDR and LVH but did not provide complete renal protection. The fixed combinatio n of perindopril and indapamide normalized SEP, EDR, LVH and proteinuria an d prevented glomerular injury. NOS activity in aortas was also normalized b y this fixed combination. These studies suggest that the specific fixed combination of these two anti hypertensive agents not only increased effectiveness in reducing blood pres sure, but also maximized end-organ protection.