(Circulation. 1995;91:2310-2313.)
© 1995 American Heart Association, Inc.
Articles |
Increased Activity of Constitutive Nitric Oxide Synthase in Cardiac Endothelium in Spontaneous Hypertension
Presented in part at the 67th Scientific Sessions of the American Heart Association, Dallas, Tex, 1994.
From Cardiovascular Research, University Hospital, Bern, Switzerland.
Correspondence to Thomas F. Lüscher, MD, Professor of Medicine, Cardiology, University Hospital, Inselspital, CH-3010 Bern, Switzerland.
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Abstract |
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 Top Abstract IntroductionMethods Results Discussion References |
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Background We analyzed the activity of nitric oxide synthase in the rat heart to study whether this activity is affected by high blood pressure. Hearts from young (3 to 4 weeks old) and adult (15 to 25 weeks old) Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHR) were excised and frozen in liquid nitrogen. The activities of Ca2+-dependent (cNOS) and Ca2+-independent (iNOS) were determined in homogenized tissues by measuring the conversion of [14C]-L-arginine to [14C]-L-citrulline in the presence or absence of either EGTA (1 mmol/L) or EGTA plus NG-nitro-L-arginine methyl ester (L-NAME, 1 mmol/L each).
Methods and Results Arterial pressure was higher in adult SHR than in young SHR and WKY rats of both ages (P<.01). The cNOS activity was two to three times higher in hypertensive than in normotensive hearts (P=.01 to P=.04). No significant activity of iNOS was detected in any tissue. Studies of the right and left ventricles demonstrated a higher cNOS activity in the left sides of the hearts of adult SHR (P<.05). No differences were found in hearts from WKY rats. Selective removal of endocardial or coronary endothelial cells in hearts of SHR and WKY rats substantially reduced cNOS activity (P<.01).
Conclusions The cNOS activity is upregulated in cardiac endothelial cells of genetically hypertensive rats. The high activity of cardiac cNOS is related to increased arterial pressure of these animals. We propose that in the heart, endothelial cells respond with a higher production of nitric oxide as a compensatory mechanism against high blood pressure and its damaging effects in this organ.
Key Words: blood pressure • rat • heart rate
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Introduction |
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TopAbstractIntroductionMethods Results Discussion References |
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Endothelial cells are an important source of factors that affect vascular tone.1 Among these factors, nitric oxide (NO) plays a crucial role in the regulation of many physiological processes.2 NO is synthesized by a family of enzymes called NO synthases.2 One of these enzymes is Ca2+-dependent and is constitutively present in various types of cells, including endothelial cells.2 NO synthesized by this enzyme, the constitutive NO synthase (cNOS), plays a primary part in the regulation of blood pressure.3 Another type of NO synthase (iNOS) is Ca2+-independent, is inducible by immunological stimuli, and is implicated in immunopathological situations.4
In the heart, endothelium-derived, constitutive NO is known to modulate myocardial contraction and coronary tone.5 6 Endocardial endothelial cells express the constitutive form of NO synthase.7 Unlike vascular smooth muscle cells, myocytes can also express this enzyme.8 This particularity has raised speculations about its potential role in myocardial contractility.8 The inducible form of NO synthase is located in myocytes and endothelial cells8 9 and presumably is involved in the depression in myocardial contractility of septic shock.8
The role of the endothelium in hypertension is controversial. It was initially suggested that an impaired endothelium-dependent relaxation could underlie the pathogenesis of hypertension.10 However, endothelial function is heterogeneously affected in this condition.1 Endothelium-dependent relaxations are abnormal in certain vascular beds10 11 12 but not in others.12 13 On the other hand, the role of NO in hypertension is also controversial because diminished, unchanged, and even increased production has been reported.14 15 16
The purpose of the present work was to study the activity of NO synthase in the heart and its relation to hypertension. To do this, hearts from spontaneously hypertensive rats (SHR) and normotensive control Wistar-Kyoto (WKY) rats were analyzed at different stages of development.
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Methods |
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TopAbstractIntroductionMethods Results Discussion References |
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Male WKY rats and SHR, 3 to 4 weeks old (young) and 18 to 25 weeks old (adult) (Charles River), were anesthetized with pentothal (60 mg/kg), and arterial pressure was measured. Subsequently, a thoracotomy was performed, and the hearts were removed.
Protocols
1. Control hearts. The heart was rapidly removed,
the
cavities were cut open, and the blood residues were flushed out with
isotonic saline.
2. Separation of the right and left sides of the heart. The wall of the right ventricle was dissected from the rest of the heart with microsurgical scissors. Special care was taken to avoid any damage to the endocardial layer.
3. Endocardial endothelium removal. The inner wall of the heart cavities was rubbed mechanically.
4. Coronary endothelium removal. Triton X-100 (0.5%, 0.75 mL) was infused through the aortic root. Previous studies with biological stains (Cardiogreen, Becton-Dickinson) established the volume necessary to replenish the whole coronary vasculature.
The extracted specimens were immediately frozen in liquid nitrogen and stored at -80°C. Some hearts were perfused with glutaraldehyde (3%) for histological studies.
Determination of NO Synthase Activity
NO formation was
measured in homogenized tissues by the
conversion of radiolabeled [14C]-L-citrulline
from [14C]-L-arginine, essentially as
described by Salter et al.17 Incubations were performed
for 10 minutes at 37°C in the presence or absence of either the
Ca2+ chelant, EGTA (1 mmol/L), or EGTA plus the
inhibitor of NOS,
NG-nitro-L-arginine methyl
ester (L-NAME) (1 mmol/L each), to determine the levels of cNOS
and iNOS activities, respectively. All compounds were purchased from
Sigma Chemie except [U-14C]-L-arginine
monohydrochloride (318 mCi/mmol, Amersham Life Science), obtained as
indicated.
Statistical Analysis
Results, expressed as mean±SEM
for n experiments, were analyzed
by ANOVA with Bonferroni's correction for multiple comparisons, except
for the experiments performed with right and left ventricles, in which
a paired Student's t test was used, and the experiments in
which the endothelia were removed, for which an unpaired Student's
t test was applied. Significance was assumed at
P<.05.
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Results |
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TopAbstractIntroductionMethods Results Discussion References |
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Blood Pressure
Adult SHR exhibited significantly higher (P<.01) blood pressure compared with normotensive rats (Fig 1a
). In
both WKY rats and SHR, blood pressure increased with age
(P<.01).
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P<.01 compared with young
animals.
NO Synthase Activity
The cNOS activity was significantly
higher (P=.01
to P=.04) in hearts from SHR than in the normotensive rats
(Fig 1b
). No significant activity of iNOS was found in the
hearts
studied: adult WKY, 12±11
pmol · min-1 · g-1; adult SHR,
2±1
pmol · min-1 · g-1.
The
cNOS activity was similar in the right and left sides of the hearts
of WKY rats (49±10 and 29±8
pmol · min-1 · g-1,
respectively; NS). In the SHR, the left side of the heart showed higher
cNOS activity than the right side (82±9 versus 58±9
pmol · min-1 · g-1;
P<.05, Fig 2).
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In the SHR, removal of
endocardial and coronary endothelium reduced
cNOS activity to 42±11 and 32±4
pmol · min-1 · g-1,
respectively (n=6, P<.01, Fig 3).
Endothelium removal reduced NO synthase activities to a similar degree
in adult WKY rats (not shown).
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Histology
Conventional microscopy revealed no damage of the
endocardial
cells, coronary endothelium, or myocardium in control hearts. Rubbed
hearts showed approximately 70% to 80% disruption of the endothelial
layer and good preservation of the myocardium and coronary vessels.
Hearts perfused with Triton X-100 showed substantial loss, shrinkage,
or disruption of endothelium in coronary arteries and capillaries, with
no major alteration in the endocardium or myocardium (Fig 3).
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Discussion |
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TopAbstractIntroductionMethods Results Discussion References |
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This study shows that adult hypertensive SHR exhibit higher cNOS activity in the heart than normotensive WKY rats. In contrast, in young SHR, in which high blood pressure is not yet established, cNOS activity was similar to that in young and adult WKY rats. These findings indicate that increased cNOS activity in the heart is related to hypertension and not to differences in age or strain.
The left and right ventricles hold the highest differential pressure in the cardiovascular system18 ; this difference is higher in hypertension.18 19 The cNOS activity, selectively assessed in both sides of the heart, indicated that in hypertensive animals the left side has higher enzyme activity than the right side. In normotensive rats, on the other hand, the activities of the enzyme were similar in both sides of the heart. Whole hearts of adult WKY rats showed no enhanced cNOS activity compared with those of young rats, while blood pressure was significantly higher. These observations suggest that within the normotensive blood pressure range, cardiac cNOS activity remains unchanged and that there is a pressure threshold above which upregulation of the enzyme occurs.
The present results are consistent with the findings reported in coronary vessels, where NO release does not seem to be impaired13 but rather enhanced in hypertension.16 This indicates that at least in the heart, NO synthesis is higher when arterial pressure is increased. The results of this study suggest that this is related to increased cNOS activity in the heart. Although both the cNOS and iNOS might be active in the heart, we demonstrated here that cNOS activity is selectively increased, whereas iNOS activity remains very low. The observation that hypertension leads to increased cNOS activity is further supported by our previous research that showed that changes in blood pressure modulate NO release in the vasculature.20 The mechanism by which high blood pressure leads to increased production of NO is not yet clear. It is known that the release of NO by endothelial cells can be altered by changes in blood flow21 and that mRNA and protein for cNOS can be induced by mechanical forces.22 It is plausible that not only shear stress but also other mechanical factors such as blood pressure and pulsatile stretch contribute to the observed increased cNOS activity in spontaneous hypertension.
Selective removal of the endothelial layer in the heart cavities and coronary arteries showed that the increased cNOS activity in hypertension happens at the expense of both endocardial and coronary endothelial cells. The myocardium, which can also express cNOS,8 does not seem to contribute as much as the endothelium to this elevated activity. It is unlikely that NO released from endocardial endothelial cells has any major influence on myocardial contraction, considering the short half-life of NO and the thickness of the ventricular wall, particularly in the frequently hypertrophied hypertensive heart.23 24 25 In fact, it has been demonstrated that in normal, isolated hearts, sodium nitroprusside reduces myocardial contraction only when infused through the coronary vessels, not when directly applied in the left ventricle.26 It is more plausible that only NO released from coronary capillaries plays a substantial role in the hypertensive heart.
Cardiac endothelial cells regulate myocardial contractility5 27 and coronary vascular tone.6 cGMP mediates the negative inotropic effects of NO in the heart.28 Indeed, the effects of NO in cardiac muscle are indistinguishable from those of cGMP.29 Enhanced NO production in the hypertensive heart probably acts as a compensatory mechanism in hypertension by decreasing myocardial contractility and causing vascular dilatation. NO in the hypertensive heart may also protect against hypertrophy. High blood pressure causes cardiac hypertrophy and fibrosis, which often lead to left ventricular failure.19 23 24 25 30 NO, which is also a potent inhibitor of smooth muscle cell growth and migration,31 might protect the heart from these deleterious effects of hypertension, although this hypothesis has not yet been tested.
In conclusion, our present work demonstrates that hypertension leads to upregulation of cNOS activity in cardiac endothelial cells; thus, the potential to produce NO is higher in this organ than in others. These results support the concept that the endothelium responds to high blood pressure with increased NO production. In the heart, this probably represents a compensatory mechanism against hypertension and its detrimental consequences in this organ. Whether this occurs in the rest of the cardiovascular system deserves further investigation.
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Acknowledgments |
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We are very grateful to Prof T. Schaffner for his excellent help in the histological work. This work was supported by grants from the Swiss National Research Foundation (Nos. 32-32541.91 and 32-32655.91). Dr Nava was supported by a stipend from the Roche Research Foundation.
Received November 21, 1994; revision received February 28, 1995; accepted March 1, 1995.
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References |
|---|
|
TopAbstractIntroductionMethods Results Discussion References |
|---|
1. Lüscher TF. The endothelium as a target and mediator of cardiovascular disease. Eur J Clin Invest. 1993;23:670-685. [Medline] [Order article via Infotrieve]
2. Moncada S. The L-arginine:nitric oxide pathway. Acta Physiol Scand. 1992;145:201-227. [Medline] [Order article via Infotrieve]
3.
Rees DD, Palmer RMJ, Moncada S. Role of
endothelium-derived nitric oxide in the regulation of
blood pressure. Proc Natl Acad Sci U S A. 1989;86:3375-3378.
4. Nava E, Palmer RMJ, Moncada S. The role of nitric oxide in endotoxin shock: effects of NG-monomethyl-L-arginine. J Cardiovasc Pharmacol. 1992;20(suppl 12):S132-S134.
5. Balligand JL, Kelly RA, Marsden PA, Smith TW, Michel T. Control of cardiac muscle cell function by an endogenous nitric oxide signaling system. Proc Natl Acad Sci U S A. 1993;90:341-347.
6. Amezcua JL, Palmer RMJ, Souza BM, Moncada S. Nitric oxide synthesized from L-arginine regulates vascular tone in the coronary circulation of the rabbit. Br J Pharmacol. 1989;97:1119-1124. [Medline] [Order article via Infotrieve]
7. Schulz R, Smith JA, Lewis MJ, Moncada S. Nitric oxide synthase in cultured endocardial cells of the pig. Br J Pharmacol. 1991;104:21-24. [Medline] [Order article via Infotrieve]
8. Schulz R, Nava E, Moncada S. Induction and potential biological relevance of a Ca2+-independent nitric oxide synthase in the myocardium. Br J Pharmacol. 1992;105:575-580. [Medline] [Order article via Infotrieve]
9. Smith JA, Radomski MW, Schulz R, Moncada S, Lewis MJ. Porcine ventricular endocardial cells in culture express the inducible form of nitric oxide synthase. Br J Pharmacol. 1993;108:1107-1110. [Medline] [Order article via Infotrieve]
10.
Lüscher TF, Vanhoutte PM.
Endothelium-dependent contractions to acetylcholine in the aorta
of the spontaneously hypertensive rat.
Hypertension. 1986;8:344-348.
11.
Dohi Y, Thiel MA, Bühler FR, Lüscher TF.
Activation of the endothelial L-arginine pathway in
pressurized mesenteric resistance arteries: effect of age and
hypertension. Hypertension. 1990;15:170-179.
12.
Lüscher RF, Diederich D, Weber E, Vanhoutte PM,
Bühler FR. Endothelium-dependent responses in carotid and
renal arteries of normotensive and hypertensive rats.
Hypertension. 1988;11:573-578.
13. Tschudi MR, Criscione L, Lüscher TF. Effect of aging and hypertension on endothelial function of rat coronary arteries. J Hypertens. 1991;9:164-165.
14. Calver A, Collier J, Moncada S, Vallance P. Effect of local intra-arterial 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]
15.
Yamazaki J, Fujita N, Nagao T.
N-monomethyl-L-arginine-induced
pressor response at developmental and established stages in
spontaneously hypertensive rats. J Pharmacol Exp
Ther. 1991;259:52-57.
16. Kelm M, Feelisch M, Krebber T, Motz W, Strauer BE. The role of nitric oxide in the regulation of coronary vascular resistance in arterial hypertension: comparison of normotensive and spontaneously hypertensive rats. J Cardiovasc Pharmacol. 1992;20:183-186.
17. Salter M, Knowles RG, Moncada S. Widespread tissue distribution and changes in activity of Ca2+-dependent and Ca2+-independent nitric oxide synthases. FEBS Lett. 1991;291:145-149. [Medline] [Order article via Infotrieve]
18. Guyton AC. Heart muscle: the heart as a pump. In: Wonsiewicz MJ, ed. Textbook of Medical Physiology. 8th ed. New York, NY: WB Saunders Co; 1991:98-110.
19. Anversa P, Peng Li, Malhotra A, Zhang X, Herman MV, Capasso J. Effects of hypertension and coronary constriction on cardiac function, morphology, and contractile proteins in rats. Am J Physiol. 1993;265:713-725.
20. Nava E, Leone AM, Wiklund NP, Moncada S. Detection of release of nitric oxide by vasoactive substances in the anaesthesized rat. In: Feelisch M, Busse R, Moncada S, eds. The Biology of Nitric Oxide. London, England: Portland Press; 1994:179-181.
21.
Buga GM, Gold ME, Fukuto JM, Ignarro L. Shear
stress–induced release of nitric oxide from endothelial cells grown on
beads. Hypertension. 1991;17:187-193.
22.
Sessa WC, Pritchard K, Seyedi N, Wang J, Hintze TH.
Chronic exercise in dogs increases coronary vascular nitric
oxide production and endothelial cell nitric oxide synthase gene
expression. Circ Res. 1994;74:349-353.
23. Pfeffer MA, Frohlich ED. Hemodynamic and myocardial function in young and old normotensive and spontaneously hypertensive rats. Circ Res. 1973;33(suppl I):I-28-I-38.
24.
Pfeffer JM, Pfeffer MA, Fishbein MC, Frohlich ED.
Cardiac function and morphology with aging in the spontaneously
hypertensive rat. Am J Physiol. 1979;237:H461-H468.
25. Anversa P, Melissari M, Beghi C, Olivetti G. Structural compensatory mechanisms in rat in early spontaneous hypertension. Am J Physiol. 1984;246:H739-H746.
26. Fort S, Lewis MJ. Regulation of myocardial contractile performance by sodium nitroprusside in the isolated perfused heart of the ferret. Br J Pharmacol. 1991;102:351p. Abstract.
27.
Ramaciotti C, Sharkey A, McClellan G, Winegrad S.
Endothelial cells regulate cardiac contractility.
Proc Natl Acad Sci U S A. 1992;89:4033-4036.
28. Nawrath H. Does cyclic GMP mediate the negative inotropic effect of acetylcholine in the heart? Nature. 1977;267:72-74. [Medline] [Order article via Infotrieve]
29. Grocott-Mason R, Fort S, Lewis MJ, Shah AM. Myocardial relaxant effect of exogenous nitric oxide in isolated ejecting hearts. Am J Physiol. 1994;266:1699-1705.
30.
Capasso JM, Palackal T, Olivetti G, Anversa P.
Left ventricular failure induced by long-term hypertension in
rats. Circ Res. 1990;66:1400-1412.
31. Dubey RK, Lüscher TF. Nitric oxide inhibits angiotensin II–induced migration of vascular smooth muscle cells. Hypertension. 1993;22:412. Abstract.
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