THE LINK AMONG NITRIC-OXIDE SYNTHASE ACTIVITY, ENDOTHELIAL FUNCTION, AND AORTIC AND VENTRICULAR HYPERTROPHY IN HYPERTENSION

The adaptive changes that occur in the left ventricle (LV) and vessels in response to hypertension, namely, muscle hypertrophy/hyperplasia, endothelial dysfunction, and extracellular matrix increase, do not dep end solely on blood pressure elevation. These changes are, in fact, ma ladaptive since they are forerunners of cardiac failure, stroke, and r enal failure. Nitric oxide, an endogenous vasodilator and inhibitor of vascular smooth muscle cell growth, is synthesized in the endothelium by constitutive nitric oxide synthase (cNOS). We investigated the rel ationships among LV and aortic cNOS activity (conversion of [C-14] L-a rginine to [C-14] L-citrulline), with LV hypertrophy (LV weight/body w eight), and (2) aortic hypertrophy (aortic weight/length) in spontaneo usly hypertensive rats (SHR) and Dahl salt-sensitive (DS) rats matched for blood pressure (219+/-12 versus 211+/-7 mm Hg, P=NS) and age. Com pared with their normotensive counterparts, aortic cNOS activity was i ncreased 106% in SHR but reduced by 73% in DS rats. The correlation be tween blood pressure and aortic cNOS activity was positive (r=.74, P<. 01) in SHR and negative (r=-.82, P<.01) in DS rats. LV cNOS activity w as increased 73% in SHR compared with normotensive Wistar-Kyoto rats ( P<.01). On the other hand, LV cNOS activity was not increased in hyper tensive DS rats compared with normotensive DS rats. In SHR, aortic hyp ertrophy did not increase significantly and LV hypertrophy increased o nly 15%, whereas in hypertensive DS rats the aorta and LV hypertrophie d 36% and 88%, respectively (both P<.01). Moreover, in DS rats there w as a negative correlation between cNOS activity and aortic hypertrophy (r=-.70, P<.01). Ln DS rats, antihypertensive therapy consisting of a n angiotensin-converting enzyme inhibitor, perindopril, and a diuretic , indapamide, normalized blood pressure, aortic cNOS activity, and LV hypertrophy and reduced aortic hypertrophy. Our studies imply that upr egulation of vascular cNOS activity has a protective cardiovascular ho meostatic role in hypertension. Clinically, the variable end-organ dis ease observed in individuals with similar severity of hypertension may be explained, at least in part, by genetically conditioned difference s in vascular cNOS activity in response to hypertension.