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(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.

Eduardo Nava, MD, PhD; Georg Noll, MD; Thomas F. Lüscher, MD

From Cardiovascular Research, University Hospital, Bern, Switzerland.

Correspondence to Thomas F. Lüscher, MD, Professor of Medicine, Cardiology, University Hospital, Inselspital, CH-3010 Bern, Switzerland.

	Abstract

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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 N^G-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

	Introduction

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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 cells^{8 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 beds^{10 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.

	Methods

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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, N^G-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.

	Results

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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).

View larger version (24K): [in this window] [in a new window]   Figure 1. Bar graphs showing mean arterial pressure (a) and activity of constitutive nitric oxide synthase (cNOS) (b) in hearts of normotensive Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHR) at young (3 to 4 weeks) and adult (18 to 25 weeks) ages. *P<.05, **P<.01 compared with the group of normotensive rats. 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).

View larger version (39K): [in this window] [in a new window]   Figure 2. Bar graph showing differential activity of constitutive nitric oxide synthase (cNOS) in the right (R) and left (L) heart of adult Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHR). *P<.05 compared with right side of the heart in SHR.

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).

View larger version (84K): [in this window] [in a new window]   Figure 3. Histological studies of hypertensive rat hearts (left) and the corresponding constitutive nitric oxide synthase (cNOS) activities found (right). a, Control heart. The endothelial layer of the endocardium and on the walls of the coronary capillaries is well preserved. b, Endocardial rubbing. Note the complete absence of endothelial cells over the surface of the heart and the presence of endothelium in the capillaries. c, Triton X-100–perfused heart. Most arterioles, postcapillary venules, and capillaries are without endothelium. Visible interstitial cells belong to the myocardial connective tissue. Endocardial endothelium is well preserved. In b and c, cNOS activity is markedly diminished compared with that of untreated hearts (P<.01).

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).

	Discussion

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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 contractility^{5 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.

	Acknowledgments

 
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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