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The link among nitric oxide synthase activity, endothelial function, and aortic and ventricular hypertrophy in
1Department of Medicine, Veterans Affairs Medical Center, Minneapolis, MN 55417, USA.
Insights
Hypertension damages organs, but nitric oxide synthase (cNOS) activity varies. Upregulating cNOS in blood vessels may protect against cardiovascular issues, explaining different patient outcomes.
Area of Science:
- Cardiovascular Physiology
- Hypertension Research
- Endothelial Function
Background:
- Hypertension-induced cardiac and vascular changes like hypertrophy and dysfunction are maladaptive.
- Nitric oxide (NO), synthesized by constitutive nitric oxide synthase (cNOS), is a key regulator of vascular tone and smooth muscle cell growth.
- Understanding cNOS activity in hypertension is crucial for explaining variable end-organ damage.
Purpose of the Study:
- To investigate the relationship between left ventricle (LV) and aortic cNOS activity and hypertrophy in different rat models of hypertension.
- To explore the correlation between blood pressure, cNOS activity, and organ hypertrophy in spontaneously hypertensive rats (SHR) and Dahl salt-sensitive (DS) rats.
- To assess the impact of antihypertensive therapy on cNOS activity and cardiac/vascular hypertrophy in DS rats.
Main Methods:
- Measurement of LV and aortic cNOS activity via [14C] L-arginine conversion to [14C] L-citrulline.
- Assessment of LV hypertrophy (LV weight/body weight) and aortic hypertrophy (aortic weight/length) in SHR and DS rats.
- Correlation analysis between blood pressure, cNOS activity, and hypertrophy, and evaluation of therapeutic intervention effects.
Main Results:
- Aortic cNOS activity increased in SHR but decreased significantly in DS rats, despite similar blood pressure.
- LV cNOS activity increased in SHR but not in DS rats.
- DS rats exhibited greater LV and aortic hypertrophy compared to SHR, with a negative correlation between cNOS activity and aortic hypertrophy.
- Antihypertensive therapy in DS rats normalized blood pressure, cNOS activity, and cardiac/vascular hypertrophy.
Conclusions:
- Vascular cNOS activity plays a protective role in maintaining cardiovascular homeostasis during hypertension.
- Genetic differences in vascular cNOS activity may contribute to the variable end-organ damage observed in hypertensive individuals.
- Upregulation of cNOS activity is a potential therapeutic target for managing hypertension-related complications.
Abstract:
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 hypertrophied 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, antihypertensive 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.