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(Circulation. 1997;95:1111-1114.)
© 1997 American Heart Association, Inc.

Articles

Role of Myocyte Nitric Oxide in ß-Adrenergic Hyporesponsiveness in Heart Failure

Shimako Yamamoto, MD; Hiroyuki Tsutsui, MD; Hirofumi Tagawa, MD; Keiko Saito, MD; Masaru Takahashi, MD; Hideo Tada, MD; Mitsutaka Yamamoto, MD; Makoto Katoh, BS; Kensuke Egashira, MD; Akira Takeshita, MD

the Research Institute of Angiocardiology and Cardiovascular Clinic, Faculty of Medicine, Kyushu University, Fukuoka, Japan.

Correspondence to Hiroyuki Tsutsui, MD, PhD, Research Institute of Angiocardiology and Cardiovascular Clinic, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-82, Japan.

	Abstract

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Background The positive inotropic response to ß-adrenergic stimulation is attenuated at the isolated myocyte level in heart failure. Nitric oxide (NO) has a negative inotropic effect and attenuates the response to isoproterenol. It has been suggested that NO synthesis is increased in failing myocytes. However, the pathophysiological consequences after induction of NO in myocyte contractility are less clear in the setting of heart failure.

Methods and Results We examined the effects of an NO synthase (NOS) inhibitor on contractile function in myocytes isolated from 11 dogs with rapid pacing–induced heart failure (ejection fraction, 29±2%) and 8 control dogs (ejection fraction, 74±3%). Sarcomere shortening velocity was measured as an index of contractility under four experimental conditions: at baseline, after adding isoproterenol (ISO; 1 nmol/L), after an NOS inhibitor (N-nitro-L-arginine methyl ester [L-NAME], 0.1 nmol/L), and after L-NAME plus ISO. L-NAME alone had no effects on basal sarcomere shortening velocity in either control or heart failure myocytes. However, L-NAME significantly augmented the inotropic response to isoproterenol in heart failure myocytes (107.1±7.3% [ISO alone] versus 140.6±10.7% [ISO plus L-NAME] increase from baseline; P<.05) but not in control myocytes (135.5±9.9% [ISO alone] versus 137.1±11.4% [ISO plus L-NAME]; P=NS). Myocardial NOS activity measured by the conversion of arginine to citrulline was significantly increased in dogs with heart failure compared with that in control dogs.

Conclusions The increased NO induction in failing myocytes does not alter baseline sarcomere mechanics but attenuates the positive inotropic response to isoproterenol. Thus, myocyte NO plays an important role in the autocrine regulation of the contractile function of myocytes in congestive heart failure.

Key Words: heart failure • endothelium-derived factors • cells • contractility • receptors, adrenergic, beta

	Introduction

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Contractile function is commonly impaired in HF at the cellular (myocyte) level.¹ Positive inotropic responses to ß-adrenergic stimulation are also attenuated in failing myocytes.² Even though the attenuation of ß-adrenergic responsiveness is due in part to the downregulation of its receptor, abnormalities in postreceptor pathways may also be involved.²

NO is now recognized to be present in many tissues, acting as a ubiquitous intracellular signaling molecule in diverse mammalian cells. Recent in vitro studies in cardiac myocytes^{3 4} and in vivo studies in the experimental animal⁵ suggested that NO can decrease myocardial contractility and also attenuate the positive inotropic responses to ß-adrenergic stimulation. Furthermore, NO expression is enhanced in the myocardium, especially in myocytes, from patients with end-stage HF.⁶ In addition, HF is commonly associated with an increased level of inflammatory cytokines, which could induce NOS expression in myocytes.⁵ Therefore, it is conceivable that NO might be responsible for contractile abnormalities in failing myocytes. However, the functional consequences of NO induction in the failing heart remain poorly understood. Recent in vivo studies by Hare et al⁷ provided convincing evidence that NO plays a crucial role in ß-adrenergic hyporesponsiveness in HF patients. There are several limitations of in vivo studies in defining the functional role of myocyte NO in contractile abnormalities. First, NOS inhibitors may affect systemic hemodynamics. Second, the contribution of sustained sympathetic neuronal activation cannot be excluded. Third, the relative contribution of NO synthesized within myocytes themselves and NO derived from neighboring cells to produce the functional effects could not be distinguished in in vivo studies because the myocardium is composed of myocardial, neural, vascular, and interstitial cells.³

In the present study, we used isolated cardiac myocyte preparations to avoid the confounding effects of an NOS inhibitor on systemic hemodynamics and to examine the direct effects of NO generated within myocytes on contractile function. Pacing-induced HF is a useful animal model to examine the pathophysiological role of NO in contractile dysfunction and ß-adrenergic hyporesponsiveness because such abnormalities have been previously demonstrated at the myocyte level.² To determine whether NO generated in myocytes could directly modulate ß-adrenergic responsiveness, we examined the effects of NOS inhibitors on myocyte contractile responses to isoproterenol.

	Methods

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Preparation of Animal Models
Nineteen adult mongrel dogs (15 to 25 kg body weight) were used in the present study. Eleven underwent rapid pacing (HF dogs) and eight served as control animals. Under general anesthesia, a bipolar pacing lead (1236T; Pace Setter Inc) was introduced into the external jugular vein and placed in the right ventricle under fluoroscopic guidance. All dogs were then allowed to recover from the surgery. Rapid ventricular pacing at 220 to 260 bpm was performed continuously for 4 weeks by connecting the lead to an external pulse generator (Nihon-Kohden). Cardiac auscultation was done every day during the pacing protocol to ensure that the pacemaker was operating properly and that 1:1 conduction was present. Control dogs were treated in an identical manner as HF dogs but without pacing.

In Vivo LV Function Studies
On the day of the study, all dogs underwent echocardiographic studies in the conscious condition in sinus rhythm after 15 minutes of the stabilization period. Two-dimensional and M-mode echocardiographic examinations were performed with the use of an ultrasonograph (SSH-65A; Toshiba Medical Inc). LV short-axis (cross-sectional) views were recorded at the papillary muscle level, and the internal LV dimensions were measured. LV ejection fraction (percent) was then calculated by use of the formula {[(LV End-Diastolic Dimension)³-(LV End-Systolic Dimension)³]/(LV End-Diastolic Dimension)³}x100. After echocardiographic recordings, the animals were generally anesthetized, intubated, and ventilated with a respirator. A catheter was inserted into the aortic arch via the left carotid artery for the measurement of systemic arterial pressure. After thoracotomy was performed, an externally calibrated 7F catheter-tipped pressure transducer (PC 350; Millar Instruments) was inserted into the LV through the left atrium for the measurement of LV pressure. The protocols were approved by the Committee on the Ethics of Animal Experiments, Kyushu University and were in accordance with the guiding principles for the care and use of laboratory animals of the American Physiological Society and the National Institutes of Health.

Preparation of Isolated Myocytes and Evaluation of Contractile Function
At the time of the study, animals were killed with a lethal dose of -chloralose, and the hearts were quickly excised. Cardiac myocytes were isolated from the LV free wall as described previously in detail.¹ Myocyte contractile function was evaluated by analysis of sarcomere motion during electric stimulation (0.25 Hz) with the use of laser diffraction technique in isolated myocytes.^{1 8}

Measurement of NOS Activity
Myocardial tissue specimens (200 to 300 mg) were also obtained from the LV free wall for the measurement of NOS activity. NOS activity was quantified by monitoring the conversion of [³H]L-arginine to [³H]L-citrulline, the coproduct of NO formation, according to the methods described by Bredt and Snyder⁹ with minor modifications. Briefly, the tissue was homogenized in ice-cold buffer containing 50 mmol/L Tris/HCl (pH 7.5), 0.1 mmol/L EDTA, 0.1 mmol/L EGTA, 1 mmol/L DL-dithiothreitol, 10 µg/mL antipain and leupeptin, and 0.1 mg/mL phenylmethylsulfonyl fluoride. After centrifugation, the supernatant was incubated in the presence of L-arginine/[³H]L-arginine, 1 mmol/L NADPH, 10 µg/mL calmodulin, 5 µmol/L tetrahydrobiopterin, and 1 mmol/L CaCl₂ in Tris/HCl buffer for 30 minutes at 37°C. The reaction was stopped with the addition of HEPES buffer (pH 5.5) containing 10 mmol/L EDTA. The reaction mixture was applied to Dowex 50W-X8 columns, and the eluted [³H]L-citrulline was measured by scintillation counting for cNOS activity. Parallel experiments in the absence of CaCl₂ and the presence of EGTA (1 mmol/L) determined iNOS activity. Protein concentration was measured by use of the bicinchoninic acid assay (Pierce) with bovine serum albumin as standard. NOS activity was expressed as picomoles of citrulline formed per milligram of protein per 30 minutes. NOS activity was also measured with the use of the isolated myocyte preparations.

Statistical Analysis
All data are presented as mean±SE. An unpaired Student's t test was used to compare values between control and HF dogs or myocytes. Changes from baseline were compared by use of a one-way ANOVA for repeated measures followed by post hoc t test using Scheffe's correction. Differences were considered statistically significant at a value of P<.05.

	Results

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Myocyte Contractile Function in Control and HF Dogs
Long-term pacing-induced tachycardia caused a decrease in LV ejection fraction and an increase in LV volumes (data not shown) as previously reported by others.² The yield of rod-shaped, quiescent myocytes obtained from each harvest was comparable between control and HF dogs (83±1% versus 79±3%; P=NS). At baseline, the extent and velocity of sarcomere shortening were depressed significantly in HF myocytes (Fig 1A and B). The preliminary study examining the dose-response relationship showed that isoproterenol at a concentration of 1 nmol/L caused a nearly half-maximal effect. In the control group, isoproterenol increased significantly the extent and velocity of sarcomere shortening from baseline values (Fig 1A). In contrast, in HF myocytes, isoproterenol did not produce significant positive inotropic effects (Fig 1B).

View larger version (15K): [in this window] [in a new window]   Figure 1. Sequential samples of sarcomere mechanics in control and failing (HF) myocytes are shown at baseline, after the addition of isoproterenol (ISO; A and B), and after the addition of L-NAME and ISO (C and D). The positive inotropic response to ISO was attenuated in HF myocytes (B). Pretreatment of HF myocytes with L-NAME augmented the response to ISO (D). Resting sarcomere length was comparable between control (2.04±0.02 µm) and HF myocytes (1.98±0.03 µm).

Effects of NOS Inhibitors on Myocyte Contractile Function
Myocardial tissue iNOS activity in HF dogs was significantly increased compared with that in control dogs (17.1±2.1 versus 10.1±1.8 pmol citrulline/mg protein/30 min; P<.05). cNOS activity was also increased in HF dogs (10.8±1.8 versus 1.8±0.6 pmol citrulline/mg protein/30 min; P<.05). Similar increases in both iNOS and cNOS activities were also noted with isolated myocyte preparations (data not shown). To determine whether NO generated in myocytes could directly modulate contractile function, we examined the effects of NOS inhibitors on sarcomere mechanics. L-NAME (0.1 mmol/L, 10 minutes) alone had no effect on sarcomere shortening and its velocity in either control or HF myocytes (Fig 1C and D). After pretreatment with L-NAME, isoproterenol significantly increased the extent and velocity of sarcomere shortening from baseline values not only in control (Fig 1C) but also in HF (Fig 1D) myocytes. Thus, L-NAME significantly augmented the positive inotropic response to isoproterenol in HF cells, whereas it did not alter it in control myocytes (Fig 2). The pretreatment of HF myocytes with aminoguanidine (0.1 mmol/L, 10 minutes), a specific inhibitor for iNOS, similarly enhanced the positive inotropic effects of isoproterenol (data not shown). The amplifying effect of L-NAME on the response to isoproterenol in HF myocytes was reversed by adding excess L-arginine (5 mmol/L; Fig 2B).

View larger version (26K): [in this window] [in a new window]   Figure 2. Effects of L-NAME on isoproterenol (ISO)-induced increase in sarcomere shortening velocity of control and failing (HF) myocytes. The pretreatment of HF myocytes with L-NAME significantly augmented the response to ISO compared with pretreatment with ISO only (B). This amplifying effect of L-NAME was reversed by adding excess L-arginine. *P<.05 for difference from ISO.

	Discussion

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Our results indicate that the positive inotropic response to isoproterenol was potentiated by L-NAME in HF myocytes and that an excess of L-arginine, the natural substrate of NO, reversed the effects of L-NAME. These results suggest that excessive NO produced in the myocytes themselves may be responsible for the hyporesponsiveness to ß-adrenergic stimulation in HF myocytes. Thus, NO produced in HF myocytes may modulate myocyte contractile function in an autocrine and/or paracrine manner. Our findings are consistent with a recent observation that the positive inotropic response to intracoronary infusion of dobutamine is potentiated by N-monomethyl-L-arginine in patients with LV dysfunction.⁷ However, the findings obtained in in vivo human studies have some potential limitations. Our study using isolated myocyte preparations has several distinct advantages, including (1) the exclusion of any contributory role of circulating NO and NO produced by nonmyocytes, (2) the elimination of the effects of NOS inhibitors on systemic vascular and neural systems, and (3) the direct measurement of myocyte contractile function independently of the effects of in vivo hemodynamic or neurohumoral influences and the extracellular matrix. The present study thus allowed us to overcome the limitations of in vivo human studies and examine the role of myocyte NO in contractile abnormalities in HF in a definitive way.

Myocardial NOS activity was increased in our model of pacing-induced HF. NO could be produced by myocyte iNOS in HF dogs. In addition, the activation of cNOS in cardiac myocytes by ß-adrenergic stimulation could also contribute to the total increase of NO in HF. This was supported by a preliminary report by Kanai et al¹⁰ that NO could be produced by cNOS in isolated myocytes in response to adrenergic stimulation. Furthermore, cNOS mRNA expression was elevated in HF according to Northern blot analysis (unpublished data). These findings are consistent with recent evidence that NO production is increased in the failing myocardium.⁵ Even though a direct immunohistochemical examination of the cellular localization of NO synthesis within the myocardium is required to prove it, an increase of NOS activities in isolated myocyte preparations similar to that in myocardial tissue samples of HF would suggest that NOS activation in cardiac myocytes themselves was responsible. We thus believe that NO production is increased within myocytes in our model of HF as it is in failing human myocytes.⁶

In contrast to HF myocytes, L-NAME did not affect responsiveness to ß-adrenergic stimulation in control myocytes. The difference in the effects of NOS inhibitors between control and HF myocytes might be related to the differences in the level of NO production in control and failing myocardium. If NO is also derived from iNOS, which can generate higher and more sustained levels of NO than cNOS, it is likely that high local concentrations of NO in myocytes could exert significant effects on contractility. The contributory role of myocyte NO in the attenuated contractile response to isoproterenol has already been demonstrated in myocytes exposed to immune cytokines or endotoxin-stimulated macrophages.⁵ The significance of our findings is that myocyte NO modulates contractility in the setting of HF, which is of more pathophysiological and clinical importance. Inhibition of NO had no effect on myocyte contractility in the absence of ß-adrenergic stimulation, which suggests that endogenous myocyte NO had little or no effect on the basal contractile state but acted in some way on the ß-adrenergic pathway. This is also consistent with previous studies in which NOS inhibitors had no effect on basal myocardial contractility.^{3 5} It is likely that NO exerts its effects via activation of guanylate cyclase to produce cGMP because the lipid-soluble analogue of cGMP (a downstream chemical messenger of NO-dependent signaling) can elicit a similar inhibitory effect on positive inotropic responses to ß-adrenergic stimulation.⁵ However, other non-cGMP–mediated actions of NO have also been postulated that may affect myocardial contractility.⁵ The present study could not address the intracellular mechanisms of NO responsible for ß-adrenergic hyporesponsiveness and the reversibility of this phenomenon after NOS inhibitors.

The present study is the first to demonstrate that NO produced within myocytes attenuates the positive inotropic response to ß-adrenergic stimulation in HF. The myocyte NO signaling pathway plays an important role in regulating myocardial contractile function, not only in the setting of septic shock, cardiac allograft rejection, and myocarditis but also in HF.⁵ This raises the possibility that contractile dysfunction in patients with HF could be attenuated by inhibiting the synthesis and release of NO, which could lead to new therapeutic strategies in HF. Further studies examining the time course of NO induction and its reversibility after the termination of pacing or correlating these changes of NO with neurohumoral indices and the severity of contractile dysfunction would add substantially to our knowledge of the functional significance of NO induction in the pathogenesis of HF.

	Selected Abbreviations and Acronyms

 

cNOS = constitutive nitric oxide synthase HF = heart failure iNOS = inducible nitric oxide synthase L-NAME = N-nitro-L-arginine methyl ester LV = left ventricle, left ventricular NO = nitric oxide NOS = nitric oxide synthase

	Acknowledgments

 
This study was supported in part by grants from the Ministry of Education, Science and Culture (No. 07266220 and No. 08258221).

Received October 3, 1996; revision received January 6, 1997; accepted January 9, 1997.

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