(Circulation. 1996;94:1197-1198.)
© 1996 American Heart Association, Inc.
Articles |
Nitric Oxide and Hypertension
St. Bartholomew's and The Royal London School of Medicine and Dentistry (N.B.) and the William Harvey Institute, London, England.
Correspondence to Nigel Benjamin, DM, St. Bartholomew's and The Royal London School of Medicine and Dentistry, West Smithfield, London, UK EC1A 7BE.
Key Words: Editorials • hypertension • endothelium • vasodilation • acetylcholine
 |
Introduction |
|---|
 Top Introduction References |
|---|
In this issue, Taddei and colleagues1 present evidence that offspring of hypertensive parents show a reduced forearm dilator response to local (brachial artery) infusion of acetylcholine, with the implication that endothelial nitric oxide synthesis is impaired in these subjects. This study follows from a number of related studies in the past few years.
Acetylcholine induces vasodilation through the release of endothelium-derived relaxing factor in vitro,2 identified in endothelial cells in culture as nitric oxide, a potent vasodilator molecule.3 It is clearly of interest to ask whether human hypertension is caused by a defect in endothelial nitric oxide synthesis or by an impaired vascular response to nitric oxide. The seminal study by Vallance and colleagues4 that showed that the forearm arterial circulation continually releases nitric oxide and the observation that nitric oxide prevents platelet activation5 and modifies vascular smooth muscle proliferation6 make this question even more important, for hypertension is strongly associated with vascular hypertrophy and occlusive vascular disease.
The problem is, How do we best measure nitric oxide synthesis in human vascular endothelium? This tissue synthesizes nitric oxide from L-arginine using a distinct enzyme that is constitutively active and further activated by endothelial shear stress. After synthesis, some nitric oxide will rapidly diffuse to underlying vascular smooth muscle (nitric oxide is a lipid- and water-soluble gas), while that released into the lumen is rapidly oxidized by superoxide anions (to peroxynitrite and then nitrate) and the hem of hemoglobin (to form nitrate and methemoglobin). Although direct measurement of nitric oxide from human vessels has been achieved,7 it is unlikely that this could be performed quantitatively in vivo.
Instead, the approach that most researchers have taken is to determine whether forearm resistance vessels respond abnormally to acetylcholine and other muscarinic agonists. This is most reliably achieved by brachial artery infusion of the agonist with measurement of changes in forearm blood flow through venous occlusion plethysmography. The first two studies of this type used acetylcholine, which produced a reduced vasodilator effect in the forearms of hypertensive patients, compared with the nitric oxide donor sodium nitroprusside.8 9 This was not, however, confirmed in a larger study, which showed no difference with use of essentially the same technique.10 To complicate the issue further, another study suggests impaired vasodilator responses to muscarinic agonists and sodium nitroprusside in hypertension.11 Whereas it is clear that at least part of the vasodilator response to acetylcholine is due to endothelial nitric oxide synthesis, a large component is resistant to L-NG monomethyl arginine (Me Arg, a specific inhibitor of nitric oxide synthase). This is even more the case with other muscarinic agonists that are resistant to pseudocholinesterase such as methacholine and carbachol.12 It has been known for many years that acetylcholine is rapidly broken down by plasma pseudocholinesterase, so little of the drug infused at the brachial artery will reach the resistance vessels and influence forearm blood flow.13 Not surprisingly, there is a strong negative correlation with forearm length and a positive correlation with forearm blood flow and response to acetylcholine.14 These were not measured in the study by Taddei et al. Other factors such as age, sex, and plasma cholesterol also influence the response to muscarinic agonists in this model. Taken together, these problems that are inherent in this approach may explain some of the discordance in results between studies.
Another method uses the forearm model but considers the constrictor response to Me Arg. Calver and colleagues15 showed a reduced constrictor effect of this agent in hypertensive subjects (using noradrenaline as a control agent), suggesting an impaired basal (as opposed to stimulated) release of nitric oxide. The use of a vasoactive agent, which has a different mechanism of action, will help to avoid misinterpretation caused by altered geometry in hypertensive vessels.16 Calver et al went on to show a normalization of this response after therapy,17 a result confirmed by Lyons and colleagues.18 These studies suggest that basal nitric oxide synthesis (or vascular response to nitric oxide) is impaired in hypertension, but as a result rather than as a primary cause of the blood pressure. Clearly, this interpretation is in contrast to that arrived at by the present study by Taddei and colleagues, which suggests that stimulated endothelial nitric oxide synthesis is impaired before hypertension sets in (although, it must be said, that there is no certainty that the subjects studied whose parents have hypertension will themselves develop high blood pressure).
One conclusion we can arrive at is that there is no clear consensus as to whether nitric oxide synthesis is impaired in human hypertensive vascular endothelium and, if it is, whether the defect is primary or secondary. Although the forearm model has served us well in measuring the effects of vasoactive substances on human resistance vessels, we will probably have to use other approaches to measure more directly the activity of the nitric oxide–L-arginine system and to determine whether it truly has an important part to play in the pathogenesis of essential hypertension.
An interesting approach is to measure nitric oxide in the breath and nitrate in plasma. Jilma and colleagues19 looked at 22 male and 21 female volunteers and (surprisingly) found nitric oxide single breath concentrations of 20 ppb in men and 34 ppb in women. Plasma nitrate concentrations also were higher in women than in men. Similar techniques may prove useful in sorting out the role of endothelial nitric oxide synthesis in human hypertension.
|
Footnotes |
|---|
The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
|
References |
|---|
|
TopIntroductionReferences |
|---|
1. Taddei S, Virdis A, Mattei P, Ghiadoni L, Sudano I, Salvetti A. Defective L-arginine–nitric oxide pathway in offspring of essential hypertensive patients. Circulation.. 1996;94:1298-1303.
2. Furchgott RF, Zawadzki JV. The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine. Nature.. 1980;288:373-376.[Medline] [Order article via Infotrieve]
3. Palmer RMJ, Ashton DS, Moncada S. Vascular endothelial cells synthesize nitric oxide from L-arginine. Nature.. 1988;333:664-666.[Medline] [Order article via Infotrieve]
4. Vallance P, Collier J, Moncada S. Effects of endothelium-derived nitric oxide on peripheral arteriolar tone in man. Lancet.. 1989;2:997-1000.[Medline] [Order article via Infotrieve]
5. Radomski MW, Palmer RMJ, Moncada S. Comparative pharmacology of endothelium-derived relaxing factor, nitric oxide and prostacyclin in platelets. Br J Pharmacol.. 1987;92:181-187.[Medline] [Order article via Infotrieve]
6. Garg UC, Hassid A. Nitric oxide-generating vasodilators and 8-bromo-cyclic guanosine monophosphate inhibit mitogenesis and proliferation of cultured rat vascular smooth muscle cells. J Clin Invest.. 1989;83:1774-1777.
7. Vallance P, Patton S, Bhagat K, MacAllister R, Radomski M, Moncada S, Malinski T. Direct measurement of nitric oxide in human beings. Lancet.. 1995;346:153-154.[Medline] [Order article via Infotrieve]
8.
Linder L, Kiowski W, Buhler FR, Luscher TF. Indirect evidence for release of endothelium-derived relaxing factor in human forearm circulation in vivo: blunted response in essential hypertension. Circulation.. 1990;81:1762-1767.
9. Panza JA, Quyyumi AA, Brush JE Jr, Epstein SE. Abnormal endothelium-dependent vascular relaxation in patients with essential hypertension. N Engl J Med.. 1990;323:22-27.[Abstract]
10.
Cockcroft JR, Chowienczyk PJ, Benjamin N, Ritter JM. Preserved endothelium-dependent vasodilation in patients with essential hypertension. N Engl J Med.. 1994;330:1036-1040.
11.
Kelm M, Preik M, Hafner D, Strauer BE. Evidence for a multifactorial process involved in the impaired flow response to nitric oxide in hypertensive patients with endothelial dysfunction. Hypertension.. 1996;27:346-353.
12. Chowienczyk PJ, Cockcroft JR, Ritter JM. Differential inhibition by NG-monomethyl-L-arginine of vasodilator effects of acetylcholine and methacholine in human forearm vasculature. Br J Pharmacol.. 1993;110:736-738.[Medline] [Order article via Infotrieve]
13. Duff F, Greenfield ADM, Shepherd JT, Thompson ID. A quantitive study of the response to acetylcholine and histamine of the blood vessels of the human hand and forearm. J Physiol.. 1952;120:160-170.
14. Chowienczyk PJ, Cockcroft JR, Ritter JM. Blood flow responses to intra-arterial acetylcholine in man: effects of basal flow and conduit vessel length. Clin Sci.. 1994;87:45-51.[Medline] [Order article via Infotrieve]
15. Calver A, Collier J, Moncada S, Vallance P. Effect of local intraarterial NG-monomethyl-L-arginine in patients with hypertension: the nitric oxide dilator mechanism appears abnormal. J Hypertens.. 1992;10:1025-1031.[Medline] [Order article via Infotrieve]
16.
Benjamin N, Calver AL, Collier J, Robinson BF, Vallance P, Webb DJ. Measurement of forearm blood flow by venous occlusion plethysmography: interpreting the response. Hypertension.. 1995;25:918-923.
17.
Calver A, Collier J, Vallance P. Forearm blood flow responses to a nitric oxide synthase inhibitor in patients with treated essential hypertension. Cardiovasc Res.. 1994;28:1720-1725.
18. Lyons D, Webster J, Benjamin N. The effect of antihypertensive therapy on responsiveness to local intra-arterial NG-monomethyl-L-arginine in patients with essential hypertension. J Hypertens.. 1994;12:1047-1052.[Medline] [Order article via Infotrieve]
19. Jilma B, Kastner J, Mensik C, Vondrovec B, Hildebrandt J, Krejcy K, Eichler H-G. Sex differences in concentrations of exhaled nitric oxide and plasma nitrate. Life Sci.. 1996;58:469-476.[Medline] [Order article via Infotrieve]
This article has been cited by other articles:
 |
|
 |
|
  S. Weber, D. Bernhard, R. Lukowski, P. Weinmeister, R. Worner, J. W. Wegener, N. Valtcheva, S. Feil, J. Schlossmann, F. Hofmann, et al. Rescue of cGMP Kinase I Knockout Mice by Smooth Muscle Specific Expression of Either Isozyme Circ. Res., November 26, 2007; 101(11): 1096 - 1103. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Sausbier, R. Schubert, V. Voigt, C. Hirneiss, A. Pfeifer, M. Korth, T. Kleppisch, P. Ruth, and F. Hofmann Mechanisms of NO/cGMP-Dependent Vasorelaxation Circ. Res., October 27, 2000; 87(9): 825 - 830. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Preik, M. Kelm, P. Rosen, D. Tschope, and B. E. Strauer Additive Effect of Coexistent Type 2 Diabetes and Arterial Hypertension on Endothelial Dysfunction in Resistance Arteries of Human Forearm Vasculature Angiology, July 1, 2000; 51(7): 545 - 554. [Abstract] [PDF]
|
|
|
|
 |
|
 M. de Lorgeril Dietary arginine and the prevention of cardiovascular diseases Cardiovasc Res, March 1, 1998; 37(3): 560 - 563. [Full Text] [PDF]
|
|
|
|
 |
|
 H. I. Chen and C. T. Hu Endogenous nitric oxide on arterial hemodynamics: a comparison between normotensive and hypertensive rats Am J Physiol Heart Circ Physiol, October 1, 1997; 273(4): H1816 - H1823. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||