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(Circulation. 1995;92:2198-2203.)
© 1995 American Heart Association, Inc.

Articles

Nitric Oxide Inhibits the Positive Inotropic Response to ß-Adrenergic Stimulation in Humans With Left Ventricular Dysfunction

Presented in part at the 67th Scientific Sessions of the American Heart Association, Dallas, Tex, November 14-17, 1994, and published in abstract form (Circulation. 1994;90[pt 2]:I-193).

Joshua M. Hare, MD; Evan Loh, MD; Mark A. Creager, MD; Wilson S. Colucci, MD

From the Cardiomyopathy Center, Cardiovascular Division, Brigham and Women's Hospital and Harvard Medical School, Boston, Mass.

Correspondence to Dr Wilson S. Colucci, Cardiomyopathy Center, Boston University School of Medicine, 80 E Concord St, Boston, MA 02118.

	Abstract

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Background Nitric oxide (NO) attenuates the contractile response to ß-adrenergic stimulation in cultured cardiac myocytes in vitro and in myocardium in vivo. We tested the hypothesis that NO synthesized in the heart inhibits the positive inotropic response to ß-adrenergic stimulation in humans with left ventricular (LV) dysfunction.

Methods and Results Patients with various degrees of LV dysfunction and free from epicardial coronary artery disease were instrumented with an infusion catheter in the left main coronary artery and a high-fidelity micromanometer-tipped catheter in the LV. Measurements included LV pressure, aortic pressure, heart rate, and LV peak +dP/dt. In eight subjects, dobutamine was infused via the left main coronary artery (25 or 50 µg/min) before and concurrent with intracoronary infusion of the NO synthase inhibitor N^G-monomethyl-L-arginine (L-NMMA, 20 µmol/min for 10 minutes). In six other subjects, dobutamine was infused (6, 10, or 15 µg · kg^-1 · min^-1) via a peripheral vein. Intracoronary (n=8) dobutamine infusions increased LV peak +dP/dt by an average of 33±3%. The intracoronary infusion of L-NMMA had no effect on baseline LV peak +dP/dt, LV systolic or end-diastolic pressures, aortic pressure, or heart rate. The intracoronary infusion of L-NMMA, concurrent with a second infusion of dobutamine, potentiated the +dP/dt response to dobutamine by 30±10% (P<.04 versus dobutamine alone). The intracoronary infusion of L-NMMA likewise potentiated the +dP/dt response to the peripheral infusion of dobutamine by 37±18%.

Conclusions Nitric oxide produced in the heart attenuates the positive inotropic response to ß-adrenergic stimulation in humans with LV dysfunction. NO may contribute to ß-adrenergic hyporesponsiveness in patients with LV dysfunction.

Key Words: nervous system • nitric oxide • L-NMMA • receptors • adrenergic • beta • contractility • heart failure

	Introduction

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Positive inotropic¹ and chronotropic² responses to ß-adrenergic receptor stimulation are commonly attenuated in patients with LV dysfunction. Although this phenomenon is associated with downregulation of ß-adrenergic receptors,³ several observations suggest that additional mechanisms may contribute in various pathological states. For example, the relation between ß-adrenergic receptor number and physiological impairment varies depending on the etiology of heart failure,⁴ and in patients with systemic sepsis, there is evidence that marked attenuation of ß-adrenergic responsiveness may be due, in part, to abnormalities in postreceptor pathways.⁵ There is further support for postreceptor dysfunction from experimental models in which cytokine and/or endotoxin-mediated attenuation of ß-adrenergic responsiveness occurs in the absence of ß-adrenergic receptor downregulation.⁶

NO is a ubiquitous signaling molecule synthesized in the conversion of L-arginine to L-citrulline by a family of NOS enzymes that includes constitutive and inducible isoforms.⁷ In vitro studies in cultured cardiac myocytes^{8 9 10 11 12 13} and in vivo studies in laboratory animals^{8 14 15} have suggested that NO can attenuate the positive inotropic and chronotropic responses to ß-adrenergic agonists. The role of NO in the modulation of human myocardial responses is unknown, but several recent observations suggest that NO may be produced in human myocardium, particularly in the setting of myocardial dysfunction. First, NOS activity^{16 17} and mRNA^{18 19} can be demonstrated in myocardial samples from patients with dilated cardiomyopathy^{16 17 19} and cardiac allograft rejection.¹⁸ Second, the levels of inflammatory cytokines, which can induce the expression of NOS and increase NO production in several tissues, including myocardium,^{20 21} are elevated systemically^{22 23} and possibly in the myocardium^{24 25} of patients with LV dysfunction.

In the present study, we tested the hypothesis that NO attenuates the positive inotropic response to ß-adrenergic stimulation in humans. We examined the LV peak +dP/dt response to the ß-adrenergic agonist dobutamine, alone and during concurrent intracoronary infusion of L-NMMA, an inhibitor of NOS.²⁶ When infused systemically, L-NMMA causes systemic hypertension and reflex sympathetic withdrawal.²⁷ To avoid this confounding effect, L-NMMA was infused via the left main coronary artery. Patients with LV dysfunction were studied because in this setting ß-adrenergic responsiveness is frequently attenuated^{1 2 3 4} and there is circumstantial evidence to suggest increased NO activity.^{16 17 18 19 20 21 22 23 24 25}

	Methods

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Study Population
The study population consisted of 14 adults (7 men, 7 women; mean age±SD 49±14 years) who were undergoing diagnostic catheterization and were found to be free from significant coronary artery disease. Patients were referred for cardiac catheterization for evaluation of new onset (symptoms less than 6 months) congestive heart failure (n=10), chronic idiopathic dilated cardiomyopathy (n=2), valvular heart disease (n=1), or a chest pain syndrome (n=1). All medications were withheld beginning the night before study. The study protocol was approved by the Committee for the Protection of Human Subjects from Research Risks at the Brigham and Women's Hospital, and written informed consent was obtained before study.

Hemodynamic Measurements
Before the experimental protocol was begun, all subjects underwent routine diagnostic left and right heart catheterization via the femoral approach. Coronary angiography was performed with nonionic contrast media, and the research protocols were begun a minimum of 20 minutes after completion of the diagnostic catheterization. A 6F L4 Judkins catheter (Cordis Laboratories) was advanced via the right femoral artery to the ostium of the left main coronary artery. The catheter was continuously flushed with 5% dextrose in water (D₅W) containing heparin infused at a rate of 2 mL/min. A 7F micromanometer-tipped pigtail catheter (Millar Instruments) was advanced from the opposite femoral artery and placed in the LV for measurement of LV pressure. LV peak +dP/dt was computed on-line, and femoral artery pressure was monitored via a 7F sidearm sheath (Cordis Laboratories). The ECG, femoral artery pressure, LV pressure, and LV peak +dP/dt were recorded on a strip-chart recorder (Electronics for Medicine, Honeywell Inc). Each measurement represents the mean of at least 10 consecutive sinus beats, except +dP/dt, which was the average of at least 45 consecutive beats.

Drug Infusion Protocols
Drugs were infused into the left main coronary artery via the Judkins catheter with use of a Harvard pump. Heparin (5000 U IV) was administered just prior to placement of the catheters. Drugs were infused for 5 minutes, and hemodynamic measurements were made during the last minute of each drug infusion. In eight subjects, the sequence of drug infusions was as follows: (1) D₅W, the vehicle for intracoronary drugs, was infused at a rate of 2 mL/min. (2) Dobutamine (Lilly Inc), diluted in D₅W, was infused at a rate of 25 or 50 µg/min. The infusion rate was selected to increase peak +dP/dt by 30% to 50% (25 µg/min in four subjects, 50 µg/min in four subjects). (3) Dobutamine was discontinued and peak +dP/dt was monitored for at least 5 minutes and until it returned to the baseline value. (4) L-NMMA (Calbiochem) was infused at a rate of 20 µmol/min for 5 minutes. This infusion rate would yield a steady state coronary artery concentration of 160 µmol/L at a left main coronary artery blood flow rate of 125 mL/min. (5) The L-NMMA infusion was continued and dobutamine was again infused for 5 minutes at the same rate as the first dobutamine infusion. The L-NMMA infusion was thus continued for a total of 10 minutes (total dose of 50 mg). At the completion of the drug infusions, radiographic contrast was injected into the infusion catheter to confirm the continued position of the catheter in the left main coronary ostium.

In six additional patients, dobutamine was delivered by a peripheral vein to ensure that the observed hemodynamic changes were independent of alterations in intracoronary dobutamine concentration that might be induced by the inhibition of NOS. Peripheral infusion of dobutamine should result in a constant concentration of dobutamine in the coronary artery independent of coronary blood flow. In these subjects, a 5F bipolar pacing catheter was advanced to the right atrial appendage and pacing was initiated 15 beats per minute above the baseline heart rate.²⁸ The sequence of infusions was as follows: (1) Baseline measurements were obtained during the intracoronary infusion of D₅W at a rate of 2 mL/min. (2) Dobutamine diluted in D₅W was infused via a systemic vein at a rate of 6, 10, or 15 µg · kg^-1 · min^-1 for 10 minutes, titrated to achieve a 30% to 50% rise in peak +dP/dt, and until peak +dP/dt achieved a stable plateau (±5%) for at least 2 minutes. (3) During the continued systemic infusion of dobutamine, L-NMMA was infused via the left main coronary artery catheter at a rate of 20 µmol/min for 5 minutes in three patients and for 15 minutes in three patients.

Statistical Analysis
All data are presented as mean±SEM. Changes from baseline and over the different infusion combinations were compared by use of paired two-way ANOVA. Post hoc testing was performed using the Student-Newman-Keuls test.

	Results

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Baseline Hemodynamics
Baseline hemodynamic measurements for all 14 subjects are shown in Table 1. LV dysfunction was reflected by a mean LV ejection fraction of 21±3% (range, 13% to 43%), a mean pulmonary artery wedge pressure of 26±3 mm Hg, and a cardiac index of 2.3±.2 (L · min^-1 · m^-2). Baseline hemodynamics were similar in the 8 patients who received intracoronary dobutamine and the 6 patients who received intravenous dobutamine.

View this table: [in this window] [in a new window]   Table 1. Baseline Characteristics of the Study Population

Effect of L-NMMA on the Positive Inotropic Response to Intracoronary Dobutamine
Intracoronary infusion of dobutamine increased LV peak +dP/dt by 33±3% from 950±90 mm Hg/s to 1252±107 mm Hg/s (P<.0001 versus baseline) (Fig 1A). Intracoronary infusion of L-NMMA alone had no effect on LV peak +dP/dt (Table 2). A second infusion of dobutamine, during coinfusion of L-NMMA, increased LV peak +dP/dt by 44±6% to 1327±117 mm Hg/s (P<.0002 versus baseline). Coinfusion of L-NMMA potentiated the response to dobutamine in seven of eight subjects and by an average of 30±10% (Fig 2A; P<.04 versus dobutamine alone).

View larger version (21K): [in this window] [in a new window]   Figure 1. A, Bar graphs show the effect of intracoronary L-NMMA infusion on the positive inotropic response to intracoronary dobutamine. Depicted is the change in LV +dP/dt in response to the intracoronary infusion of dobutamine alone (Dobutamine), L-NMMA alone (L-NMMA), or the combination of the two (Combination) in eight subjects. The intracoronary administration of L-NMMA alone had no effect on LV +dP/dt. Changes are presented relative to the initial control value (950±90 mm Hg/s). Re-control values were obtained by stopping the intracoronary dobutamine infusion. *P<.0002 vs initial control; P<.04 vs dobutamine alone. B, Bar graphs show the effect of intracoronary L-NMMA infusion on the positive inotropic response to intravenous dobutamine. Depicted is the change in LV +dP/dt in response to the intravenous infusion of dobutamine alone and dobutamine in combination with L-NMMA in six subjects. Changes are presented relative to the initial control value (864±83 mm Hg/s).

View this table: [in this window] [in a new window]   Table 2. Effect of L-NMMA Alone on LV+dP/dt and Factors That Influence LV+dP/dt

View larger version (21K): [in this window] [in a new window]   Figure 2. Plots show the potentiation of the positive inotropic response to an intracoronary (A) or intravenous (B) infusion of dobutamine by an intracoronary infusion of L-NMMA. Depicted are the individual responses for the combination of dobutamine and L-NMMA relative to dobutamine alone. *P<.04.

Effect of L-NMMA on Heart Rate and LV Pressures
Intracoronary dobutamine decreased LVEDP by 8±3 mm Hg and increased LV developed pressure by 12±6 mm Hg but had no significant effect on heart rate or LV systolic pressure (Fig 3). Intracoronary infusion of L-NMMA alone had no effect on heart rate, mean arterial pressure, LV systolic pressure, or LVEDP (Table 2). With coinfusion of L-NMMA and dobutamine, the decrease in LVEDP (-6±2 mm Hg) was not different from dobutamine alone. However, coinfusion of L-NMMA potentiated dobutamine-stimulated increases in LV systolic pressure (18±2 mm Hg) and LV developed pressure (23±2 mm Hg) (Fig 3).

View larger version (19K): [in this window] [in a new window]   Figure 3. Bar graph shows the effect of L-NMMA on the LV response to intracoronary infusion of dobutamine. The bars represent the changes in LV pressures (relative to control values) caused by the intracoronary infusion of dobutamine alone (solid bars) or by the combination of dobutamine and L-NMMA (hatched bars). *P<.05 vs control; P<.05 vs dobutamine alone.

Peripheral Dobutamine Infusion
Because L-NMMA infusion could reduce coronary blood flow, intracoronary dobutamine concentrations could be higher during L-NMMA coinfusion. To address this issue, in six additional patients dobutamine (6, 10, or 15 µg · kg^-1 · min^-1, titrated to achieve a 30% to 50% rise in peak +dP/dt) was administered via a peripheral vein before and concurrent with intracoronary L-NMMA. Intravenous dobutamine increased LV peak +dP/dt by 44±6% from 864±83 mm Hg/s to 1244±126 mm Hg/s (Fig 1B). The addition of intracoronary L-NMMA during continued intravenous dobutamine further increased LV peak +dP/dt to 1349±156 mm Hg/s (P=.07 versus dobutamine alone). Thus, L-NMMA had a qualitatively and quantitatively similar effect to that observed with the intracoronary dobutamine infusion and potentiated the increase in LV peak +dP/dt by 37±18% (P=.07, Fig 2B). Similarly, with the addition of L-NMMA to intravenous dobutamine, there was a trend toward an increase in LV systolic and developed pressure with no change in LVEDP (data not shown). Heart rate was held constant by right atrial pacing.

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
The present study was designed to test the hypothesis that NO modulates the positive inotropic response to ß-adrenergic stimulation in humans. Our finding that the positive inotropic response to dobutamine, a ß-adrenergic agonist, was potentiated by the concurrent infusion of L-NMMA, an inhibitor of NO synthesis, indicates that inhibition of cardiac NO production potentiates the positive inotropic response to ß-adrenergic stimulation in humans with LV dysfunction, and thereby supports this hypothesis.

Our hypothesis was based on several in vitro and in vivo observations. Gulick et al²⁹ observed that exposure of cultured cardiac myocytes to immune cytokines attenuated the contractile response to ß-adrenergic agonists. Other investigators subsequently implicated NO in this phenomenon by showing that inhibitors of NO reversed the ß-adrenergic attenuating effect of cytokines³⁰ or endotoxin-stimulated macrophages.¹¹ Immune cytokines induce the expression of iNOS (type II NOS) in several cell types that are or may be present in the myocardium, including endothelial cells,³¹ macrophages,³² vascular smooth muscle cells,³³ and cardiac myocytes.^{11 20 21}

There is also evidence that cardiac NO production adequate to inhibit ß-adrenergic responses may occur in normal myocardium that has not been stimulated by immune cytokines, presumably because of basal production of NO by cNOS (type III NOS).¹⁰ In isolated rat cardiac myocytes, Balligand et al⁹ found that inhibition of NOS potentiated the contractile response to ß-adrenergic stimulation with isoproterenol. Likewise, we recently found in normal dogs with autonomic blockade that the positive inotropic response to intracoronary infusion of isoproterenol is potentiated by the concurrent infusion of the NOS inhibitor N^G-nitro-L-arginine methyl ester.¹⁴ However, the role of cNOS in normal hearts is not clear, and other studies^{34 35} have not found evidence that endogenous NO inhibits the contractile response to ß-adrenergic stimulation.

A potential physiological role for NO may be to mediate muscarinic cholinergic inhibition of ß-adrenergic contractility. This inhibition, which has been described in both animals^{36 37} and humans,³⁸ has recently been shown to be due in part to muscarinic activation of myocardial NO activity.^{10 15} There are several possible cellular sources of constitutive NO production in the myocardium, including myocytes,^{9 10} neurons (neuronal NOS or type I NOS),³⁹ and microvascular endothelial cells.^{30 40}

Our findings are consistent with direct evidence that human myocardium has NOS activity. Messenger RNA for iNOS was detected in myocardium from human cardiac allografts,¹⁸ and mRNAs for both cNOS and iNOS were detected in failing human myocardium obtained from explanted hearts at the time of cardiac transplantation.¹⁹ DeBelder et al¹⁶ have reported that there is NOS activity, as assessed by the conversion of L-arginine to L-citrulline, in ventricular myocardium obtained from patients with dilated cardiomyopathy and atrial tissue obtained from patients without overt heart failure at the time of coronary artery bypass surgery. Based on the calcium dependence of the NOS activity, it was concluded that the predominant activity in failing myocardium was iNOS, whereas the predominant activity in the subjects undergoing bypass surgery was cNOS.¹⁶

We studied patients with LV dysfunction for several reasons. First, in this group of patients, the positive inotropic response to ß-adrenergic stimulation is frequently attenuated. Second, there is evidence that NO production is increased in patients with heart failure, as evidenced by elevated circulating levels of plasma nitrate, an NO metabolite.^{41 42} Third, mRNAs for cNOS and iNOS have been demonstrated in failing human myocardium.^{18 19} Fourth, heart failure is associated with elevated circulating levels of inflammatory cytokines that could cause iNOS induction.^{20 21} It is possible that the effect of NOS inhibition observed in the present study is related to the presence of LV dysfunction in our subjects. However, there was no apparent relation between the extent of potentiation with L-NMMA and any of several measures of LV dysfunction (ejection fraction, right atrial pressure, pulmonary artery wedge pressure, and cardiac index). Further study will be required to assess the extent to which our observations depend on the presence of LV dysfunction.

In the present study, L-NMMA had no effect on measures of LV function in the absence of exogenous ß-adrenergic stimulation with dobutamine. This finding suggests that the levels of endogenous NO present in the myocardium did not affect basal LV contractile state directly, but acted in some way to attenuate the responsiveness of the ß-adrenergic receptor pathway. The delivery of exogenous NO to isolated hearts⁴³ or to humans via the intracoronary infusion of nitroprusside⁴⁴ shortened the duration of systole and accelerated the onset of diastole but, in agreement with our data, did not affect indexes of LV contraction or relaxation.

Because sympathetic tone is frequently elevated in patients with congestive heart failure, it is somewhat surprising that L-NMMA did not potentiate basal +dP/dt in our study. This may reflect the fact that the patients in our study were relatively well compensated and therefore may not have had intense sympathetic activation. In future studies, it will be interesting to compare the effect of L-NMMA to indexes of myocardial sympathetic activation. It is also possible that sympathetic activity plays a relatively minor role in supporting basal systolic function, or that the contribution of endogenous sympathetic tone, vis-à-vis the pharmacological effects of a potent exogenous ß-adrenergic agonist, may be relatively minor.

Three technical issues require consideration. First, changes in heart rate and LV pressures, most notably LVEDP, can influence the measurement of LV peak dP/dt,⁴⁵ which was the major index of inotropic response in the present study. Heart rate was unchanged throughout the protocol, and the decrease in LVEDP caused by dobutamine infusion was not affected by L-NMMA. The conclusion that L-NMMA potentiated the positive inotropic response to dobutamine is further supported by the observation that the dobutamine-stimulated increases in LV systolic and developed pressures were greater with concurrent L-NMMA infusion, consistent with a greater positive inotropic response. Second, it is possible that L-NMMA may have decreased coronary blood flow, thereby causing an increase in the steady state concentration of dobutamine in the coronary artery with the intracoronary infusion protocol. This seems unlikely, because we previously found that the intracoronary dobutamine infusion rates used in the present study cause a near-maximal increase in LV peak +dP/dt in patients with a similar degree of heart failure.¹ To further exclude this possibility, we infused dobutamine peripherally in six subjects. In these subjects, L-NMMA potentiated the positive inotropic response to dobutamine by an average of 37±18%. Thus, although we cannot completely exclude the possibility that an increase in the coronary artery concentration of dobutamine contributed to the effect seen with the intracoronary infusion protocol, it appears that this effect of L-NMMA does not require a change in coronary blood flow. Finally, our study design, which relied on comparing two successive infusions of intracoronary dobutamine without and with concurrent L-NMMA, was based on our previous observation that repeated administrations of intracoronary dobutamine produce near identical rises in dP/dt.¹ Thus, the augmentation in dP/dt with L-NMMA cannot be attributed to an effect related to successive applications of a ß-agonist.

The present study demonstrates that in humans with LV dysfunction, NO produced within the heart attenuates the positive inotropic response to ß-adrenergic stimulation. It remains to be determined whether cardiac NO production is increased in pathological states such as LV dysfunction. Nevertheless, these data suggest that NO contributes to the ß-adrenergic hyporesponsiveness that is frequently found in such patients and provide the first evidence that NO can modulate myocardial function in humans. Inhibition of NO production may improve myocardial ß-adrenergic responsiveness in patients with LV dysfunction and other states associated with increased NO production, such as systemic sepsis and myocardial inflammation.

	Selected Abbreviations and Acronyms

 

cNOS = constitutive nitric oxide synthase iNOS = inducible nitric oxide synthase L-NMMA = NG-monomethyl-L-arginine LV = left ventricular LVEDP = left ventricular end-diastolic pressure NO = nitric oxide NOS = nitric oxide synthase

	Acknowledgments

 
This work was supported in part by grant T32 HL-07604 from the NIH. Dr Hare is the recipient of a Physician-Investigator Fellowship from the American Heart Association, Massachusetts Affiliate. Dr Loh is the recipient of a physician-scientist award (K11-HL02514) from the NIH. Dr Colucci was an Established Investigator of the American Heart Association. The authors wish to acknowledge the technical support and patience of Diane Gauthier, RN, and the staff of the cardiac catheterization laboratory at the Brigham and Women's Hospital, and the generous scientific input of Drs Thomas W. Smith, Thomas Michel, and Jean-Luc Balligand.

Received March 1, 1995; revision received May 10, 1995; accepted May 16, 1995.

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