(Hypertension. 1995;25:1202-1211.)
© 1995 American Heart Association, Inc.
Articles |
Nitric Oxide and Its Putative Role in Hypertension
From the Department of Medicine and Therapeutics, University of Glasgow (Scotland) (A.F.D.), and the Department of Physiology, University of Michigan, Ann Arbor (D.F.B.).
Correspondence to David F. Bohr, MD, Department of Physiology, University of Michigan, Ann Arbor, MI 48109-0622.
Key Words: nitric oxide • hypertension, arterial • arginine • endothelium-derived factors • vasodilator agents • nitro compounds • blood vessels
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Introduction |
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 Top Introduction Metabolism of NOActions of NONO in Experimental HypertensionNO in Clinical HypertensionReferences |
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In the past 5 years, nitric oxide (NO) has become recognized as a major player in most physiological and pathophysiological processes. So much has been learned about the involvement of this molecule in these processes that it seems appropriate to survey the current state of this insight, with the goal of creating a solid foundation on which these studies can continue. In this review we deal first with the basic metabolism and actions of NO, emphasizing aspects of the subject that may have bearing on hypertension. We close with a review of studies that deal specifically with the involvement of NO in experimental and clinical hypertension. The involvement cannot now be clearly defined; however, this survey indicates that promising insights are within reach.
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Metabolism of NO |
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TopIntroductionMetabolism of NOActions of NONO in Experimental HypertensionNO in Clinical HypertensionReferences |
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NO Synthase
NO synthase (NOS) is the ubiquitous enzyme that generates NO. Three isoenzymes have been described1 : isoform I, present in neuronal and epithelial cells; isoform II, first described in macrophages but now known to be present in other cells including vascular smooth muscle; and isoform III, the enzyme in endothelial cells that has received the most attention in connection with hypertension. These three isoenzymes have been purified and their cDNAs cloned. Isoform I is constitutively expressed in the brain, spinal cord, sympathetic ganglia, adrenal glands, and peripheral "nitroxidergic" nerves.2 3 4 It is calcium-calmodulin regulated. The gene for NOS isoform I has been localized recently to the 12q24.2
24.31 region of chromosome 12 by fluorescent in situ
hybridization.5 NOS isoform II can be induced in
macrophages, vascular smooth muscle cells, hepatocytes,
chondrocytes, and human adenocarcinoma cell line.6 7 8 It
appears that NOS isoform II in different cells of the same species is a
product of a single gene that has been localized to the 17p1117q11
region of chromosome 17.9 Isoform III is expressed in
endothelial cells in a constitutive fashion. It is calcium-calmodulin
regulated but in contrast to isoform I, is membrane bound. Recent
studies have localized human isoform III to the 7q357q36 region of
chromosome 7.9 10 For each of the three isoenzymes there
is a very high homology of the amino acid sequence between species.
Activation of NOS
Oxygen and specific cofactors are required for the catalysis by
NOS of the guanidino nitrogen of L-arginine to NO and
citrulline.11 12 All three isoforms of the enzyme have
binding sites for calmodulin and for a series of cofactors that
transfer the electron from the guanidine moiety of
L-arginine. A critical study by Scott-Burden et
al13 demonstrated the importance of tetrahydrobiopterin as
a cofactor for the activation of inducible NOS. Both adenylyl cyclase
and protein kinase C were implicated in this activation. In vivo the
required cofactors are all available except that the constitutive forms
of the enzyme (isoforms I and III) require added calcium for their
activation. The activity of the inducible form appears to be calcium
independent. This independence may be due to calmodulin being tightly
bound to inducible NOS.14 In any case, calcium is required
for activation of the constitutive enzymes and is thereby the
physiological regulator of the activity of these enzymes. NO is
generated in neural and endothelial cells only when intracellular
ionized calcium concentration
([Ca2+]i) is elevated to levels above
10-7 mol/L.15 This increase in
[Ca2+]i in endothelial cells can be
achieved by activation of specific receptors such as those for
acetylcholine or bradykinin, or by A23187, an ionophore that forms
calcium-permeant channels in the plasma membrane. The resultant
increase in [Ca2+]i activates the NOS,
causing a release of NO by the endothelial cells. This NO diffuses into
the vascular smooth muscle cells where it stimulates soluble guanylyl
cyclase, and the resultant cGMP accounts for the vasodilator
action.
Inhibition of NO production by treatment with an arginine analogue such as NG-monomethyl-L-arginine (L-NMMA) causes a vasoconstriction16 and a pressor response.17 This observation indicates that the resistance vessels are physiologically in a state of active dilator tone, for which NO of endogenous origin is responsible. However, the agents alluded to in the preceding paragraph may not be the major physiologically important stimuli for the tonic NO release necessary to maintain arterial pressure at a normal low level.
A physiological stimulus for this NO production is the shear stress of blood flowing by the endothelial cells. Rubanyi et al18 observed that the NO concentration released from the endothelium of a perfused artery increased with perfusion rate. NO release from cultured endothelial cells has been shown to reflect the shear rate of liquid flowing by the cells.19 20 This mechanism is involved in the coronary artery dilatation that occurs in response to increased coronary flow.21 Sessa et al22 have made the interesting observation that exercise, with its prolonged increase in shear stress, led to increased NOS gene expression in the coronary artery. Coronary flow was increased in dogs by a 10-day exercise program. Acetylcholine-stimulated NO release was markedly enhanced in large coronary arteries and microvessels from hearts of the exercised dogs compared with hearts from control dogs. Steady-state mRNA levels for endothelial NOS were found to be elevated in the exercised dogs. The data appear to indicate that by increasing endothelial shear stress for a 10-day period of exercise, NOS gene expression was augmented and, as pointed out by the authors, "may contribute to the beneficial effects (ie, antihypertensive) of exercise on the cardiovascular system."
Inhibition of NOS
Early in the development of an understanding of the action of the
enzyme NOS, it was found that its production of NO could be blocked by
analogues of its substrate.23 This is a competitive
inhibition that can be reversed by excess substrate,
L-arginine.23 These analogues have been used
extensively to determine whether NO is involved in specific biological
actions. This approach has formed the cornerstone of studies that have
led to our current understanding of the many physiological and
pathophysiological actions of NO.
Vallance et al24 have made a case for the possibility that some of these analogues may themselves contribute to pathophysiological responses. The analogue asymmetrical dimethylarginine (ADMA) is produced in vivo as evidenced by their observation that the total plasma concentration of dimethylarginines in healthy men was 1.15 µmol/L, and 65 µmol of ADMA appeared in the urine in 24 hours. In end-stage chronic renal failure the plasma concentration of dimethylarginines rose to 8.7 µmol/L. This elevation paralleled the increase in serum creatinine. In vitro it was observed that this ADMA concentration was sufficient to inhibit acetylcholine relaxation of rat aortic rings. In vivo injections of ADMA caused a dose-dependent elevation of blood pressure in the guinea pig. An elevation of plasma level to 9.8 µmol/L caused a 15% increase in mean arterial pressure. It was suggested that the accumulation of endogenous ADMA, leading to impaired NO synthesis, might contribute to the hypertension and immune dysfunction in chronic renal failure. Another condition in which ADMA may contribute to the pathophysiology is preeclampsia. Plasma levels of ADMA in this condition were found to be more than twice as great as those in normotensive pregnancies.25
Another type of inhibition was revealed in experimental studies of the activity of the constitutive enzyme extracted from rat cerebellum.26 It was observed that the rate of formation of NO and citrulline was not maintained, even in the presence of excess substrate. NO, both exogenously added or enzymatically generated by NOS, caused reversible inhibition of the cytosolic constitutive NOS isoform I. Later, a similar negative feedback inhibition of NOS was found to depress the endothelium-dependent relaxation responses of vascular smooth muscle.27 NO may bind to the heme prosthetic group of NOS and thereby interfere with electron transport and substrate oxidation. In any case, this inhibition functions as any negative feedback system to protect the organism from an excess of the product, in this case NO.
Induction of NOS: Cytokines, Lipopolysaccharide, Role of
Steroids
NOS isoform II is slowly induced by cytokines such as
interleukin-1, tumor necrosis factor, interferon gamma, and
lipopolysaccharide, the active component of bacterial
endotoxin.7 28 29 30 This induction occurs over many hours
and depends on de novo protein synthesis, as the effects are absent in
cells pretreated with cycloheximide or actinomycin D, inhibitors of
protein translation and RNA transcription,
respectively.7 30 Glucocorticoids prevent expression of
inducible NOS in vivo and in vitro but do not alter the constitutive
isoforms I and III.30 31 This characterization has been
used to differentiate between NO production by these NOS
subclasses.30 32 Chen and Sanders33 showed
that pretreatment with 5 µg/d dexamethasone prevented hypotension in
rats injected with endotoxin. They observed that by administering
L-arginine and thereby increasing NO production, they
could prevent the development of hypertension in salt-sensitive
Dahl/Rapp rats fed an 8% NaCl diet. This protection was prevented when
they administered dexamethasone along with the
L-arginine, suggesting that the protection they had
observed with L-arginine required the activity of NOS
isoform II.33
Substrate for NOS
The guanidino nitrogen of L-arginine is the atom
from which NOS generates NO. Abbott and Schachter34 have
quantified the uptake and metabolism of L-arginine in rat
aorta and cultured endothelial cells. Metabolism was measured as
citrulline and cGMP production and hence reflected NOS activity. This
activity paralleled L-arginine uptake, suggesting that
under the conditions of this study the enzyme activity was substrate
limited. However, early data on vascular endothelial cells in vitro
showed that L-arginine supply was not a rate-limiting
step in NO production by NOS isoform III.35 Measured
concentrations of L-arginine in cultured and freshly
isolated endothelial cells exceed by severalfold the
Km for isoform III.36 37
However, studies in vivo suggest that endothelial NO production may be
augmented by providing an excess of circulating
L-arginine in experimental animals with
hypercholesterolemia38 and in patients with
hypercholesterolemia or hypertension.39 Relevant to
hypertension, examples of this phenomenon, which has been called by
Förstermann et al1 "the arginine paradox," are
described below.
Chen and Sanders40 carried out such a study on Dahl/Rapp salt-sensitive and salt-resistant rats. Two weeks of feeding of 8% NaCl chow caused hypertension in the salt-sensitive rats but did not alter the blood pressure of the salt-resistant rats. Intravenous administration of L-arginine to the salt-sensitive rats lowered their blood pressures to normal and increased urinary cGMP. In these rats the substrate appeared to be rate limiting, and the resultant NO deficiency was responsible for the hypertension. When salt-resistant rats were similarly treated, the high salt diet did not cause a rise in blood pressure, and the pressure was not altered by L-arginine administration. It was concluded that increasing dietary sodium increased NO production in salt-resistant but not salt-sensitive rats. This failure to produce NO appeared to be the cause of the hypertension in salt-sensitive rats. Oral L-arginine corrected the rate-limiting substrate availability and prevented the development of hypertension in these rats.
Other studies have dealt with the effect of the NOS substrate on renal function. Hayakawa et al41 evaluated the activity of the renal constitutive NOS by observing the vasodilatation and the NO released from the isolated perfused kidney in response to acetylcholine administration. The observations were made on kidneys from control rats and from rats made hypertensive by deoxycorticosterone acetate–salt treatment for 8 weeks. In the kidneys from the hypertensive rats, both vasodilatation and NO release were greatly suppressed. However, if the deoxycorticosterone acetate–salt hypertensive rats were given oral L-arginine, the suppression was largely reversed. These investigators concluded "that hypertensive vessels seem to be depleted of [L-arginine]."
In a clinical study, Hishikawa et al42 observed that L-arginine administered intravenously to patients with either essential or secondary hypertension caused a fall in arterial pressure that was accompanied by an increased NO release. This increase was evidenced by increases in plasma cGMP and citrulline and in urinary excretion of nitrite and nitrate. These investigators had previously reported43 similar changes in normotensive subjects treated with L-arginine.
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Actions of NO |
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TopIntroductionMetabolism of NOActions of NONO in Experimental HypertensionNO in Clinical HypertensionReferences |
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Action at a Molecular Level
NO is a novel physiological messenger in that it is a small molecule that diffuses freely through the cell membrane.44 Because of its rapid rate of diffusion and of reaction with intracellular target molecules, usually heme iron, NO has both autocrine and paracrine actions. The main target for NO is the heme iron of guanylyl cyclase, where it activates the production by this enzyme of cGMP, which mediates many tissue responses to NO. This increased cGMP production is so predictable that it is used as an index of NO concentration in vascular and neural tissues.
In the vascular system NO is produced in the endothelium, from which it diffuses both into the lumen and out into the wall of the vessel. In the lumen it stimulates cGMP production, reducing platelet adhesion; in the wall the cGMP relaxes vascular smooth muscle.
Recent observations suggest that another cyclic nucleotide, cyclic ADP-ribose (cADPR), may also be involved in mediating the effects of NO.45 cADPR causes calcium channels in the sarcoplasmic reticulum to open, releasing calcium into the sarcoplasm. The cADPR concentration in the cell is regulated by the activities of its synthetic enzyme, ADP-ribosylcyclase, and its degrading enzyme, cADPR hydrolase. The two actions appear to be carried out by a single bifunctional enzyme. This enzyme can either increase or decrease [Ca2+]i and is regulated by cGMP and possibly by NO directly.
NO may also act independently of cGMP. The ADP ribosylation of GAPDH is stimulated by NO.46 47 Since this ribosylation inhibits the action of GAPDH, NO could inhibit glycolysis and contribute to reperfusion injury and neurotoxicity. Stimulation by NO of ribosylation of G proteins may inhibit their function and thereby alter signal transduction in the plasma membrane.48 Inhibition by NO of mitochondrial iron-sulfur enzymes may be responsible for the cytotoxicity of macrophages for tumor cells.49
NO in Vascular Tissue
NOS isoforms are expressed in three cell types within arterial
wall. Under physiological conditions, constitutive isoform III in
endothelial cells appears to be a major regulator of arterial tone.
This is supported by the observation that NOS inactivation with
L-arginine analogues has a potent vasoconstrictor effect
and that removal of endothelial cells almost abolishes basal NO
production.50 Studies of NO levels with a sensitive
porphyrinic microsensor demonstrated NO production by endothelial cells
in response to bradykinin, followed by elevation of NO levels in the
underlying vascular smooth muscle.51
The inducible isoform II is less likely to be involved in physiological regulation of vessel tone, but it plays a role in impaired vessel reactivity during septic shock.27 50 NOS isoform I has been shown to influence vascular tone because of its presence in perivascular nerves.52 53 In large vessels NOS has been shown in autonomic nerve fibers of the adventitial layer.54 Neuronal (isoform I) NOS is also expressed in sphenopalatine ganglia. Projections from these ganglia to large cerebral arteries provide perivascular nitroxidergic innervation.55 Activation of these nerves causes release of NO and relaxation of arterial smooth muscle cells, demonstrating that neuronal NOS may play the role of an inhibitory neurotransmitter in cerebral arteries.54
The calcium- and calmodulin-dependent NOS isoform III releases picomoles of NO in response to stimulation of endothelial cells with agonists such as bradykinin, acetylcholine, calcium ionophore A23187, and ATP, among others.50 56 The resultant endothelium-dependent vascular relaxation has been shown in rings of animal and human arteries and veins.57 58 59 The relaxation appears to be greater in arteries than in veins, and this difference may be explained by a more efficient L-arginine/NO pathway in the arteries.59 Our recent data60 present evidence for major differences in the vascular smooth muscle L-arginine/NO pathway of human internal thoracic artery and saphenous vein. The induction of NOS isoform II in vascular smooth muscle of the human internal thoracic artery results in a significant attenuation of contraction. In vascular smooth muscle of human saphenous vein, lipopolysaccharide inhibits contraction by a different and as yet unidentified mechanism that is not dependent on NOS induction.
The inducible and calcium- and calmodulin-independent NOS isoform II plays a role in pathological vasorelaxation that occurs in endotoxic shock in animals and humans. The induction of this isoform occurs in vascular smooth muscle and endothelial cells and results in excessive NO generation, vascular relaxation, and resistance to vasoconstrictors.61 62 It has been shown that the degree of hypotension during septic shock in animals is directly related to NO levels.63 Several strategies have been applied to the treatment of septic shock that focus on the reduction of NO production.62 63 64 These strategies include the use of L-arginine analogues62 and more recently the use of methylene blue, a known inhibitor of soluble guanylyl cyclase that recently has also been shown to have a direct NOS inhibitory activity.64 65
Several studies describe a deleterious effect of angiotensin II (Ang II) on endothelial function.66 67 68 69 Recent studies in experimental and human hypertension demonstrate that angiotensin-converting enzyme (ACE) inhibitors can reverse endothelial dysfunction as measured by normalization of acetylcholine-induced relaxation of aortic rings from spontaneously hypertensive rats (SHR)70 or correction of impaired acetylcholine-induced relaxation in the forearm.69 The mechanism responsible is not fully understood, but there is some evidence that ACE inhibition may increase NO production, most likely at the level of NOS isoform III in the endothelial cells.70
Recently we have studied a different type of cellular abnormality in genetically hypertensive rats and observed similar protection with an ACE inhibitor. Using flow cytometry, we studied the incidence of tetraploidy in vascular smooth muscle cells freshly isolated from aortas of normotensive Wistar-Kyoto rats (WKY) and from genetically hypertensive stroke-prone SHR (SHRSP). The incidence of tetraploidy was much greater in cells from the hypertensive rats. However, if the SHRSP had been treated for 5 weeks with perindopril, the incidence of tetraploidy was reduced to normal. Similar antihypertensive treatment with hydralazine/chlorothiazide did not correct the tetraploidy (Fig 1).68 These results suggest that ACE inhibition reduces the vascular smooth muscle cell cycle abnormality in large conduit arteries. This protection was associated with a significant reduction of Ang II and ACE activity and was not secondary to the antihypertensive action of the ACE inhibitor. This type of vascular protection may be mediated by the reduced Ang II and/or increased kinins.71 72 ACE is a dipeptidyl carboxypeptidase that not only converts Ang I to Ang II but is also an important kininase, kininase II. There is evidence that vascular tissue contains an intrinsic kallikrein-kinin system and that some of the pharmacological actions of ACE inhibitors are mediated by paracrine actions of kinins.71 Kinins are potent vasodilators, and many of their actions may be accounted for by the stimulation of NO synthesis and release.72
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Garg and Hassid73 were first to show that NO-generating vasodilators such as S-nitroso-N-acetylpenicillamine, sodium nitroprusside, and isosorbide dinitrate dose dependently inhibited mitogenesis and proliferation of vascular smooth muscle cells. The antimitogenic effect of NO-generating vasodilators was partially mimicked by 8-bromo-cGMP, suggesting that at least a portion of this effect was mediated by cGMP as the second messenger. However, as shown in the original report of Garg and Hassid,73 in a later publication from the same group,74 and in reports by others,75 only approximately half of the antimitogenic effect of NO could be accounted for by a cGMP-mediated mechanism. Sarkar et al76 have recently suggested an alternative mechanism for the action of NO that appears to be cell cycle specific but cGMP independent.
There is also evidence for the role of NO as an antimitogenic agent in vivo. Excessive vascular smooth muscle proliferation is a hallmark of atherosclerosis.77 The removal of endothelium, for example in the balloon injury model, is associated with proliferation of the underlying vascular smooth muscle.78 79 It is likely that one of the functions of the endothelial L-arginine/NO pathway is to maintain quiescence of the underlying vascular smooth muscle. It may be postulated further that in the vessel wall there is a continuous "progrowth" influence of Ang II and other growth factors and "antigrowth" influence of kinins and NO. In pathological situations such as atherosclerosis or balloon-induced arterial injury, these growth-promoting influences will act more or less unopposed, resulting in vascular smooth muscle proliferation.78 79 Furthermore, vasoprotective and antiproliferative effects of ACE inhibitors may involve removal of a growth-promoting influence of the Ang II and increase of an antigrowth influence of kinins and NO. The latter is confirmed by data of Farhy et al,72 who showed that the NOS inhibitor NG-nitro-L-arginine methyl ester (L-NAME) reversed the protective effects of ACE inhibitor on neointima formation after balloon injury in rat carotid artery.
Action of NO in the Nervous System
NOS has been found in varying amounts in all areas of the
brain.2 80 A role for NO in many functions of the nervous
system is being defined. These include memory,81
learning,82 and vision,83 and recent studies
have demonstrated that NO plays an important role in the cardiovascular
regulatory center. These observations demonstrate that NO, acting
centrally, causes a decrease in sympathetic nerve traffic and blood
pressure. El Karib et al84 observed that an infusion of an
NOS inhibitor into the lateral cerebral ventricle of rat caused an
elevation in arterial pressure. An intravenous administration of the
same small dose had no effect. They concluded that this inhibitor acts
directly in the central nervous system where NO is continuously
released. A decrease in this NO release permits an increase in the
activity of the sympathetic nervous system, causing the increase in
blood pressure. In the dog, Toda et al85 found that the
pressor response to an intravenous injection of an NOS inhibitor was
attenuated by treatment with a ganglionic blocking agent and concluded
that the hypertension caused by an NOS inhibitor is associated with an
elimination of a "nitroxidergic" neural function as well as by an
impaired release of NO by the endothelium. In the rabbit,
microinjection of an NOS inhibitor into the nucleus tractus solitarius
caused an increase in blood pressure and renal nerve
activity.86 We have recently reported that NO donors
administered intracerebroventricularly caused a fall in mean arterial
pressure, as did calcium, which stimulated the NOS to release NO in a
cardiovascular regulatory center.87
Intracerebroventricular injection of NOS inhibitors caused a pressor
response. Both the depressor response to calcium and the pressor
response to the NOS inhibitor were significantly less in SHR compared
with these responses in WKY (Fig 2A). These observations
imply that an attenuation of the NOS activity of a cardiovascular
regulatory center may contribute to arterial pressure elevation of
SHR.
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NO in Experimental Hypertension |
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TopIntroductionMetabolism of NOActions of NONO in Experimental HypertensionNO in Clinical HypertensionReferences |
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In considering the putative involvement of NO in the pathogenesis of hypertension, it is useful to recognize that there are many sites in the metabolism and action of this molecule at which an abnormality might occur. Based on our current understanding of these processes, we have identified eight relevant sites in Fig 3.24 25 26 27 33 34 35 36 37 38 39 40 89 90 91 92 93 94 95
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Attempts to evaluate a role for NO in experimental hypertension have been extensive; however, results of these studies have been highly divergent. Whereas we have reported results suggesting that the activities of all three NOS isoforms are depressed in SHRSP compared with these activities in WKY (Fig 3), other investigators have reported the enzyme to be more active than normal in experimental hypertension (Tables 1 and 2).
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Fig 2A compares blood pressure responses of WKY and SHRSP with intracerebroventricular administration of agents that alter NOS activity. L-NAME, which inhibits NO production, caused a pressor response; calcium chloride, which stimulates NO production, caused a depressor response. In both cases the blood pressure responses of the SHRSP were significantly less than those of the WKY. We interpreted these observations as indicating that NOS isoform I of the cardiovascular regulatory center of the SHRSP produced less NO than did this enzyme of WKY. Fig 2B depicts the NO concentrations at the surface of three cell types after specific treatments of the cells intended to increase NOS activities.88 A porphyrinic microsensor51 was used for these measurements. Endothelial and vascular smooth muscle cells were cultured; the macrophages were collected from the peritoneal cavity after thioglycollate stimulation. NO released at the cell surface was similarly depressed in all three cell types from the hypertensive rats.
Since neuronal NOS is isoform I, whereas the enzyme in vascular smooth muscle and macrophage is isoform II, and endothelial NOS is isoform III, these observations suggest that in SHRSP there is an abnormality in the part of the enzyme molecule that is common to the three isoenzymes. Another possibility is that there is in SHRSP an inhibitor of NOS such as ADMA24 or a substance that eliminates NO, such as superoxide.89 Whatever the mechanism responsible for the generalized deficit in NO, the deficit could contribute to the increased arterial pressure of SHRSP.
The major problem with this interpretation is that the results of the many studies on the role of NO in experimental hypertension are highly divergent. We have summarized the studies of SHR in Table 196 97 98 99 100 101 102 103 104 and of other types of experimental hypertension in Table 2.40 88 105 106 107 108 109 The data in these tables make it evident that no generalization can be made at present as to the relative roles played by NO in experimental hypertensive and normotensive animals. However, a comparison of Tables 1 and 2 suggests that, whereas the NO system may be overactive in SHR, it is depressed in SHRSP and in mineralocorticoid and renal hypertension.
These tabulated surveys depict the insecure status of the evidence bearing on the putative role of NO in experimental hypertension. Nevertheless, the following observations from these publications have bearing on specific characteristics of the endothelium in hypertension and on details of NO metabolism that may be involved in hypertension.
In addition to NO, the endothelium is the source of other vasoactive agents, the production of which may be different in hypertension. These include prostanoids97 98 99 100 101 and hyperpolarizing factor or factors.101 102 109 An observation has been made at a cellular level that could account for an altered endothelial vasorelaxant function in SHR. [Ca2+]i in cultured endothelial cells from SHR was found to be lower than that in these cells from WKY.110 The increase in [Ca2+]i in response to bradykinin was less in cells from SHR than from WKY. It has also been reported that endothelial function may be age dependent. This function is reported to be normal when the SHR is 5 weeks old but abnormal at 14 to 15 weeks of age when the rat is hypertensive.96 97
Details of the NO metabolism have also been reported that may be relevant to the pathogenesis of hypertension: The cascade of events involving angiotensin in NO metabolism is described in the section of this review dealing with NO in vascular tissue. The action of NO was found to differ in hypertension in that it stimulated the production of more cGMP in vascular smooth muscle from SHR than from WKY.103 An abnormality in the immune system in SHR has been attributed to an excess production of NO by macrophages in these rats.111 112 The endothelial abnormality in hypertension has been normalized with a high-potassium diet in both SHRSP113 and Dahl salt-sensitive rats.114 115 Recently a similar protective action of potassium has been reported in clinical essential hypertension116 in which KCl infusion into the brachial artery was found to increase the vasodilator response to acetylcholine in the forearm vascular bed. The infusion increased the potassium concentration in the plasma by 0.5 mmol/L but had no effect on the dilator action of sodium nitroprusside. No such augmentation was seen when KCl was infused into the brachial artery of normotensive control subjects.
The NO system has been firmly established as an important physiological regulator of arterial pressure. Yet notwithstanding the potent action of this system in blood pressure regulation, publications evaluating its possible role in hypertension have been highly contradictory. Reports indicating that NO production in hypertension is depressed suggest that the elevated arterial pressure reflects the deficit in this vasodilator system. Other publications describing an excessive NO production in hypertension are interpreted as indicating that NO is a compensatory vasodilator system responding to the hypertension. Obviously this basic contradiction must be resolved.
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NO in Clinical Hypertension |
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TopIntroductionMetabolism of NOActions of NONO in Experimental HypertensionNO in Clinical HypertensionReferences |
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Several studies have been reported in which the possible involvement of NO in clinical hypertension was evaluated by determining the effect of acetylcholine on vascular resistance. These studies compared the vasodilator action of acetylcholine in hypertensive patients with that in normotensive control subjects. In most of these studies the dilatation was observed in the forearm vascular bed (Table 3). The inherent variability of the method used should be recognized.126 Changes in forearm blood flow were monitored plethysmographically in response to acetylcholine infusion into the brachial artery. In six of the seven studies a significantly lesser increase in blood flow was observed in the hypertensive patients than in the normotensive control subjects.69 116 117 118 119 120 This difference was not due to a lesser sensitivity of the vascular smooth muscle to NO because the increase in flow in response to NO donors such as nitroglycerin or sodium nitroprusside was equivalent in the two groups.117 That the response to acetylcholine reflected NO release was further documented by the observation that this response was depressed after treatment of the forearm with the NO synthase inhibitor L-NMMA.123
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Most comparisons have been made by studying patients with essential hypertension and matched normotensive control subjects. However, similar deficits in vasodilator responses have been observed in patients with secondary forms of hypertension, renovascular hypertension, and primary hyperaldosteronism.119 Moreover, vasodilator responses to acetylcholine and nitroglycerin were also studied in coronary arteries of patients with essential hypertension and in normotensive control subjects.122 Similarly to the forearm vascular bed, the responses to nitroglycerin were not different, but the response to acetylcholine was reduced in the coronary arteries of the hypertensive group.
The comparative forearm blood flow study has also been carried out with an infusion of L-NMMA.123 This NOS inhibitor causes a decrease in blood flow, demonstrating that a tonic release of NO contributes to the basal vascular resistance of the forearm. The decrease in blood flow produced by L-NMMA was significantly smaller in hypertensive patients, suggesting that the basal NO-mediated dilatation is reduced in essential hypertension.123 These investigators pointed out that basal release of NO as measured in their study may be more relevant to hypertension than its stimulated release (eg, in response to acetylcholine). An interesting insight into a possible mechanism responsible for the depressed NO release in hypertension is presented in the observation that antihypertensive treatment with the ACE inhibitor captopril normalized the forearm vasodilator response to acetylcholine.69 Antihypertensive treatment with nifedipine, lowering blood pressure to the same level, did not correct the response to acetylcholine. One can speculate that some of the vasoprotective actions of ACE inhibitors are mediated via improved endothelial NO release, which in turn may be due to local stimulation of kinins within the vessel wall.
A recent study by Falloon and Heagerty124 provided new and important evidence for defective endothelium-dependent dilatation in resistance arteries of patients with essential hypertension. This study measured endothelium-dependent relaxation to acetylcholine in human subcutaneous arteries with the use of a perfusion myograph to simulate in vivo conditions. Similarly to previous studies in the forearm, they found that relaxation to acetylcholine was significantly reduced in small resistance arteries isolated from patients with essential hypertension, whereas relaxation to sodium nitroprusside did not differ between vessels from patients and from normotensive control subjects.124 This study provides further support for a role of endothelial dysfunction as an important contributor to the increased peripheral resistance of hypertension.
Two recent studies failed to support the possible contribution of attenuated NO release to the increase in vascular resistance of hypertension. Cockcroft et al121 used a standard forearm vascular resistance approach and found no difference in the vasodilator responses to acetylcholine or carbachol between patients with essential hypertension and matched normotensive control subjects. In the second study that reported no difference, brachial artery diameter was monitored in response to changes in blood flow velocity.125 Increases in flow velocity activated endothelial NO release, but no difference was found in the associated increases in brachial artery diameter between hypertensive and normotensive patients.125
In summary, most of the evidence from clinical studies indicates that there is a deficiency in the release of NO by the endothelium in hypertension. The reason for the divergent results121 125 is not clear, but it can be postulated that various subgroups of patients with essential hypertension differ with regard to endothelial NO release. This would be in keeping with a well-established heterogeneity of essential hypertension in humans.
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Acknowledgments |
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Work by the authors is supported by British Heart Foundation grants Nr 92100 and 93025 to Anna F. Dominiczak, who is a British Heart Foundation Senior Research Fellow, and by National Institutes of Health grants HL-46402 and HL-18575 (David F. Bohr). The authors thank Leslie Rolston for typing the manuscript.
Received October 17, 1994; first decision December 9, 1994; accepted February 22, 1995.
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References |
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TopIntroductionMetabolism of NOActions of NONO in Experimental HypertensionNO in Clinical HypertensionReferences |
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L. L. Kolo, T. C. Westfall, and H. Macarthur Nitric oxide decreases the biological activity of norepinephrine resulting in altered vascular tone in the rat mesenteric arterial bed Am J Physiol Heart Circ Physiol, January 1, 2004; 286(1): H296 - H303. [Abstract] [Full Text] [PDF]
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 M. Ishikawa and R. M. Quock Role of Nitric-Oxide Synthase Isoforms in Nitrous Oxide Antinociception in Mice J. Pharmacol. Exp. Ther., August 1, 2003; 306(2): 484 - 489. [Abstract] [Full Text] [PDF]
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 B. Venho, S. Voutilainen, V.-P. Valkonen, J. Virtanen, T. A Lakka, T. H Rissanen, M.-L. Ovaskainen, M. Laitinen, and J. T Salonen Arginine intake, blood pressure, and the incidence of acute coronary events in men: the Kuopio Ischaemic Heart Disease Risk Factor Study Am. J. Clinical Nutrition, August 1, 2002; 76(2): 359 - 364. [Abstract] [Full Text] [PDF]
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 B. M. Mitchell and R. C. Webb Impaired Vasodilation and Nitric Oxide Synthase Activity in Glucocorticoid-Induced Hypertension Biol Res Nurs, July 1, 2002; 4(1): 16 - 21. [Abstract] [PDF]
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B.S. Wung, J.J. Cheng, S.-K. Shyue, and D.L. Wang NO Modulates Monocyte Chemotactic Protein-1 Expression in Endothelial Cells Under Cyclic Strain Arterioscler Thromb Vasc Biol, December 1, 2001; 21(12): 1941 - 1947. [Abstract] [Full Text] [PDF]
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X.-L. Ma, F. Gao, A. H. Nelson, B. L. Lopez, T. A. Christopher, T.-L. Yue, and F. C. Barone Oxidative Inactivation of Nitric Oxide and Endothelial Dysfunction in Stroke-Prone Spontaneous Hypertensive Rats J. Pharmacol. Exp. Ther., September 1, 2001; 298(3): 879 - 885. [Abstract] [Full Text]
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F. A.W. Rabelo, E. M. Russo, M. C. O. Salgado, and E. B. Coelho Nonendothelial NO Blunts Sympathetic Response of Normotensive Rats but not of SHR Hypertension, September 1, 2001; 38(3): 565 - 568. [Abstract] [Full Text] [PDF]
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 T. V. Peterson, C. Emmeluth, and P. Bie Renal effects of nitric oxide synthase inhibition in conscious water-loaded dogs Am J Physiol Regulatory Integrative Comp Physiol, August 1, 2001; 281(2): R584 - R590. [Abstract] [Full Text] [PDF]
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 A. A. Steiner, E. C. Carnio, and L. G. S. Branco Role of neuronal nitric oxide synthase in hypoxia-induced anapyrexia in rats J Appl Physiol, September 1, 2000; 89(3): 1131 - 1136. [Abstract] [Full Text] [PDF]
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S. Klo{beta}, A. Bouloumie, and A. Mulsch Aging and Chronic Hypertension Decrease Expression of Rat Aortic Soluble Guanylyl Cyclase Hypertension, January 1, 2000; 35(1): 43 - 47. [Abstract] [Full Text] [PDF]
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 J. Zicha and J. Kunes Ontogenetic Aspects of Hypertension Development: Analysis in the Rat Physiol Rev, October 1, 1999; 79(4): 1227 - 1282. [Abstract] [Full Text] [PDF]
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M. McIntyre, D. F. Bohr, and A. F. Dominiczak Endothelial Function in Hypertension : The Role of Superoxide Anion Hypertension, October 1, 1999; 34(4): 539 - 545. [Abstract] [Full Text] [PDF]
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 H. Ruetten, U. Zabel, W. Linz, and H. H. H. W. Schmidt Downregulation of Soluble Guanylyl Cyclase in Young and Aging Spontaneously Hypertensive Rats Circ. Res., September 17, 1999; 85(6): 534 - 541. [Abstract] [Full Text] [PDF]
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 A. Broere, A. H. Van Den Meiracker, F. Boomsma, F. H. M. Derkx, A. J. Man In'T Veld, and M. A. D. H. Schalekamp Human renal and systemic hemodynamic, natriuretic, and neurohumoral responses to different doses of L-NAME Am J Physiol Renal Physiol, December 1, 1998; 275(6): F870 - F877. [Abstract] [Full Text] [PDF]
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M. Tsutsui, A. F. Y. Chen, T. O'Brien, T. B. Crotty, and Z. S. Katusic Adventitial Expression of Recombinant eNOS Gene Restores NO Production in Arteries Without Endothelium Arterioscler Thromb Vasc Biol, August 1, 1998; 18(8): 1231 - 1241. [Abstract] [Full Text] [PDF]
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 J. Bauersachs, A. Bouloumie, A. Mulsch, G. Wiemer, I. Fleming, and R. Busse Vasodilator dysfunction in aged spontaneously hypertensive rats: changes in NO synthase III and soluble guanylyl cyclase expression, and in superoxide anion production Cardiovasc Res, March 1, 1998; 37(3): 772 - 779. [Abstract] [Full Text] [PDF]
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D. H. Sigmon and W. H. Beierwaltes Influence of Nitric Oxide in the Chronic Phase of Two-Kidney, One Clip Renovascular Hypertension Hypertension, February 1, 1998; 31(2): 649 - 656. [Abstract] [Full Text] [PDF]
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H. Murakami, J.-L. Liu, H. Yoneyama, Y. Nishida, K. Okada, H. Kosaka, H. Morita, and I. H. Zucker Blockade of neuronal nitric oxide synthase alters the baroreflex control of heart rate in the rabbit Am J Physiol Regulatory Integrative Comp Physiol, January 1, 1998; 274(1): R181 - R186. [Abstract] [Full Text] [PDF]
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A. W. Haider, L. Chen, M. G. Larson, J. C. Evans, M. H. Chen, and D. Levy Antecedent Hypertension Confers Increased Risk for Adverse Outcomes After Initial Myocardial Infarction Hypertension, November 1, 1997; 30(5): 1020 - 1024. [Abstract] [Full Text]
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A. Bouloumie, J. Bauersachs, W. Linz, B. A. Scholkens, G. Wiemer, I. Fleming, and R. Busse Endothelial Dysfunction Coincides With an Enhanced Nitric Oxide Synthase Expression and Superoxide Anion Production Hypertension, October 1, 1997; 30(4): 934 - 941. [Abstract] [Full Text]
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J. Hoyer, R. Kohler, and A. Distler Mechanosensitive Cation Channels in Aortic Endothelium of Normotensive and Hypertensive Rats Hypertension, July 1, 1997; 30(1): 112 - 119. [Abstract] [Full Text]
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H. Matsuoka, S. Itoh, M. Kimoto, K. Kohno, O. Tamai, Y. Wada, H. Yasukawa, G. Iwami, S. Okuda, and T. Imaizumi Asymmetrical Dimethylarginine, an Endogenous Nitric Oxide Synthase Inhibitor, in Experimental Hypertension Hypertension, January 1, 1997; 29(1): 242 - 247. [Abstract] [Full Text] [PDF]
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M. Kelm, M. Preik, D. J. Hafner, and B. E. Strauer Evidence for a Multifactorial Process Involved in the Impaired Flow Response to Nitric Oxide in Hypertensive Patients With Endothelial Dysfunction Hypertension, March 1, 1996; 27(3): 346 - 353. [Abstract] [Full Text]
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