(Hypertension. 1997;29:235.)
© 1997 American Heart Association, Inc.
Arthur C. Corcoran Memorial Lecture |
The Link Among Nitric Oxide Synthase Activity, Endothelial Function, and Aortic and Ventricular Hypertrophy in Hypertension
From the Department of Medicine, Veterans Affairs Medical Center and University of Minnesota Medical School, Minneapolis, Minn.
Correspondence to Leopoldo Raij, MD, VA Medical Center, Nephrology/Hypertension Section, III j, 1 Veterans Dr, Minneapolis, MN 55417. E-mail raijx001{at}maroon.tc.umn.edu
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 depend solely on blood pressure elevation. These changes are, in fact, maladaptive since they are forerunners of cardiac failure, stroke, and renal 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 relationships among LV and aortic cNOS activity (conversion of [14C] L-arginine to [14C] L-citrulline), with LV hypertrophy (LV weight/body weight), and (2) aortic hypertrophy (aortic weight/ length) in spontaneously hypertensive rats (SHR) and Dahl salt-sensitive (DS) rats matched for blood pressure (219±12 versus 211±7 mm Hg, P=NS) and age. Compared with their normotensive counterparts, aortic cNOS activity was increased 106% in SHR but reduced by 73% in DS rats. The correlation between 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 was increased 73% in SHR compared with normotensive Wistar-Kyoto rats (P<.01). On the other hand, LV cNOS activity was not increased in hypertensive DS rats compared with normotensive DS rats. In SHR, aortic hypertrophy did not increase significantly and LV hypertrophy increased only 15%, whereas in hypertensive DS rats the aorta and LV hyper-trophied 36% and 88%, respectively (both P<.01). Moreover, in DS rats there was a negative correlation between cNOS activity and aortic hypertrophy (r=-.70, P<.01). In DS rats, antihyper-tensive therapy consisting of an 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 upregulation of vascular cNOS activity has a protective cardiovascular homeostatic role in hypertension. Clinically, the variable end-organ disease observed in individuals with similar severity of hypertension may be explained, at least in part, by genetically conditioned differences in vascular cNOS activity in response to hypertension.
Key Words: endothelium • nitric oxide synthase • rats, inbred, SHR • rats, Dahl • muscle, smooth, vascular • hypertrophy, left ventricular • hypertension
Abbreviations: ACE = angiotensin-converting enzyme • Ach = acetylcholine • cNOS = constitutive NO synthase • DR = Dahl salt-resistant • DR-0.5% = DR rats receiving 0.5% salt diet • DR-4.0% = DR rats receiving 4.0% salt diet • DS = Dahl salt-sensitive • DS-4.0% = DS rats receiving 4.0% salt • DS-0.5% = DS rats receiving 0.5% salt • DS-Rx = DS rats fed 4.0% NaCl diet + antihypertensive therapy with perindopril and indapamide • EDRelax = endothelium-dependent relaxation • iNOS = inducible NO synthase • LV = left ventricular • NO = nitric oxide • NOS = nitric oxide synthase • NOx = NO2/NO3 • SBP = systolic blood pressure • SHR = spontaneously hypertensive rat • SNP = sodium nitroprusside • WKY = Wistar-Kyoto
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