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European Journal of Heart Failure 2004 6(6):705-713; doi:10.1016/j.ejheart.2003.11.010
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© 2004 European Society of Cardiology

Nitric oxide synthase inhibition impairs myocardial efficiency and ventriculo-arterial matching in acute ischemic heart failure

Dag Nordhauga,b,*, Tor Steensruda,b, Ebrahim Aghajanib, Christian Korvaldb and Truls Myrmela,b

a Department of Cardiothoracic and Vascular Surgery, University Hospital North Norway P.O. Box 102, N-9038 Tromsø, Norway
b Laboratory of Experimental Surgical Research, Institute of Clinical Medicine, University of Tromsø N-9038 Tromsø, Norway

* Corresponding author. Tel.: +47-77-62-60-00; fax: +47-77-62-82-98.. E-mail address: dagn{at}fagmed.uit.no


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 
Background and aims: The effect of nitric oxide (NO) manipulation in acute heart failure has not been sufficiently investigated. Therefore, we assessed the impact of NO-synthase (NOS) inhibition on left ventricular (LV) function and energetics as well as overall hemodynamics, in a porcine model of acute ischemic LV failure.

Methods: Acute heart failure was induced by left coronary artery microembolization in fourteen anesthetized pigs. LV pressure–volume relationships and mechanical work (PVA) were assessed 30 min after stable heart failure, using pressure-conductance catheters. Myocardial oxygen consumption (MVO2) was determined from coronary flow and coronary arteriovenous oxygen difference. Microembolization led to a significant decrease in cardiac output, arterial pressure and LV systolic and diastolic performance. Animals were then randomized to a control group (n=7) or to receive 15 mg/kg N{omega}-Nitro-L-arginine-metyl ester (n=7), an inhibitor of NO synthase (NOS).

Results: Measurements 15 min later revealed that NOS inhibited animals had significantly reduced cardiac output (1.53±0.45 vs. 2.13±0.49 l/min, P=0.003) and stroke work (1054±461 vs. 1296±348 mmHg ml, P=0.03), and also displayed a significant increase in the slope of the MVO2–PVA relationship (2.57±0.53 vs. 1.92±0.15, P=0.008), i.e. an inefficient chemomechanical coupling. NOS inhibition did not alter contractility, diastolic function or arterial pressure, but afterload was significantly increased compared to controls (arterial elastance 6.03±1.48 vs. 2.74±0.34 mmHg/ml, P=0.009).

Conclusion: Inhibition of NOS in experimental acute heart failure increased afterload without altering left ventricular systolic and diastolic function. Consequently, cardiac output was reduced. Furthermore, mechanoenergetic efficiency was severely impaired. NOS inhibition in acute heart failure and cardiogenic shock warrants further investigations.

Key Words: Heart failure • Nitric oxide • Energy metabolism • Ventricular function • Hemodynamics

Received May 14, 2003; Revised October 7, 2003; Accepted November 25, 2003


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 References
 
Cardiogenic shock is the leading cause of death in patients hospitalized for acute coronary syndromes. In the course of a myocardial infarction, approximately 7% develop shock, with mortality rates as high as 60–80% [1–3] In recent years, thrombolysis, angioplasty or surgical revascularization has improved survival [3,4]. However, despite aggressive treatment, outcome remains poor with unacceptably high mortality [5]. Further research is clearly needed to enlighten the cellular and hemodynamic mechanisms of cardiogenic shock and to develop new treatment strategies.

Because nitric oxide (NO) is thought to impair contractility [6], increased myocardial production of NO has been proposed as a contributor to the progression of chronic cardiac failure [7]. Chronically failing hearts display increased expression of nitric oxide synthase (NOS) [8] and cardiac NO production is augmented in chronic heart failure [9]. Importantly, myocardial NO production is also increased during acute ischemia [10] and coronary NO levels increase substantially during acute cardiac decompensation [11]. Therefore, a deleterious role of endogenous NO in acute ischemic left ventricular failure and cardiogenic shock could be envisioned.

In a recent study, Cotter and associates reported a remarkable effect of NOS-inhibition in human cardiogenic shock [12]. Ten out of 11 patients in severe shock after myocardial infarction could be weaned from mechanical ventilation and intra-aortic balloon pumping after NOS-inhibition. Seven of the patients were alive at 1-month follow up. The authors did not investigate the mechanisms behind these remarkable results, but suggested that increased contractility could play a role. Other possible mechanisms could be improved diastolic function or myocardial efficiency, or secondary effects due to alterations in vascular resistance.

In order to differentiate these possibilities, the present study was designed to investigate the effect of NOS inhibition in an animal model of acute ischemic heart failure. Specifically, the impact of NOS-inhibition on left ventricular function and ventriculo-arterial interplay were assessed. Since NO is known to affect ventricular energetics [13,14], we also assessed LV oxygen consumption and mechanical work during NOS-inhibition. We hypothesized that NOS-inhibition would improve left ventricular contractility at the prize of increased myocardial oxygen demands.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 References
 
The experimental protocol was approved by the local steering committee of the Norwegian Animal Experiments Authority. All animals received care in compliance with the European Convention on Animal Care, and the investigation conformed with the Guide for Care and Use of Laboratory Animals published by the US National Institutes of Health (NIH Publication No. 85-23, revised 1996).

2.1. Dose–response study
To assure that we achieved adequate NOS inhibition, we performed a dose–response study with the NOS inhibitor N{omega}-Nitro-L-arginine-metyl-ester (L-NAME) before the protocol outlined below was started. After surgery, instrumentation and heart failure induction (see below), the dose–response study was performed by a 2-min bolus infusion of L-NAME in increasing doses up to 20 mg/kg. Each dose-step was followed by 15 min of stabilization and subsequent assessment of general hemodynamics and both systolic- and diastolic properties as outlined below. Four pigs were studied after infusion of low dose L-NAME (0.5–2.0 mg/kg) and 6 pigs (including the 4 in the low-dose group) were studied after high dose infusion (5–20 mg/kg). The dose–response data are given in Table 1. Using the lower doses (0.5–2.5 mg/kg), there were no significant alterations in any values from baseline measurements. In the high dose range (5–20 mg/kg), cardiac output, stroke volume, systemic vascular resistance and arterial elastance were altered significantly at all doses compared to both baseline and measurements in the low dose range, but without differences between the different doses. From the rather large standard deviation in measurements in the low dose range, we deduced that there was a large inter-animal variation in the dose needed to achieve NOS inhibition. Therefore, to be certain that adequate NOS inhibition was achieved in all animals, we chose a dose from the high dose range. Furthermore, at 15 mg/kg there was a tendency, although not significant in this study, towards an increased LV contractility. Therefore, we chose the dose of 15 mg/kg in the main study. This is also in the NOS inhibitor bolus dose range used in several other studies, and similar doses have been shown to inhibit NO synthase [15,16].


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  		Table 1 Dose–response study using N{omega}-Nitro-L-arginine-metyl ester (L-NAME)

 
2.2. Surgery and instrumentation
Fourteen domestic castrated male pigs (30±2 kg) were used in the main study. The animals were fasted overnight and premedicated with intramuscular ketamine (20 mg/kg, Warner Lambert Nordic, Sweden) and atropine (1 mg, Nycomed Pharma, Norway). Anesthesia was induced by intravenous pentobarbital sodium (10 mg/kg, Nycomed Pharma) and fentanyl (0.01 mg/kg, Pharmlink, Sweden) and maintained with continuous infusion of pentobarbital sodium (4.0 mg kg–1 h–1), fentanyl (0.02 mg kg–1 h–1) and midazolam (0.3 mg kg–1 h–1, Alpharma, Norway). Animals were tracheostomized, intubated and ventilated with 60% oxygen. The internal jugular veins were catheterized for infusions and measurement of central venous pressure (CVP). Mean arterial pressure (MAP) was measured in the descending thoracic aorta. After sternothomy, the left hemiazygos vein was ligated and transit time flow probes (CardioMed CM-4000, Medi-Stim AS, Norway) were placed on the three main coronary arteries and on the pulmonary trunk for determination of coronary flow and cardiac output (CO). A balloon (Sorin Biomedical, CA) was introduced in the inferior caval vein for preload reduction. A combined pressure-conductance catheter (7 Fr., 12 electrodes, Sentron, the Netherlands) was inserted into the left ventricular cavity via the left carotid artery. Myocardial venous blood was drawn from a catheter placed in the great cardiac vein. Finally, a catheter was inserted into the pulmonary trunk for measurement of pulmonary artery pressure (MPAP). After surgery, the animals received 150 mg amiodarone (Cordarone, Sanofi Winthrop, Sweden) to prevent ventricular arrhythmias. Furthermore, 20 mg/kg hexamethonium chloride (Hexamethonium, Sigma, St. Louis, MO) was administered as a bolus to avoid autonomous reflex influences on hemodynamics during measurements and interventions. Finally, 2500 IU heparin was given intravenously. Animals were stabilized for 30 min before baseline measurements.

2.3. Experimental protocol
The experimental protocol is outlined in Fig. 1. To assess contractility, pressure–volume data were recorded during transient (12–15 s) preload reduction. The slope of the stroke-work-end-diastolic volume relationship (PRSW, Preload Recruitable Stroke Work) was used as the main index of contractility [17]. Pressure–volume recordings with concomitant MVO2 determination were performed at 6 different steady state preloads in order to assess the PVA–MVO2 relationship [18]. After these baseline measurements, heart failure was induced by repeated injections of 5-mg boluses of 50 µm polystyrene microspheres (NEM-005, NEN Lifescience Products, Boston, MA) in the left coronary main stem until CO was reduced by approximately 30% and MAP was under 70 mmHg. Measurements 30 min after the last microembolization confirmed the presence of stable ischemic LV failure. Animals were then randomized to receive either a 2-min intravenous infusion of 15 mg/kg of the NOS inhibitor L-NAME (Alexis biochemicals) in 0.9% NaCl (n=7), or vehicle only (NaCl) (controls, n=7). Hemodynamic and energetic measurements were repeated 15 min after pharmacological infusion. At the end of the experiment, animals were sacrificed by intracardiac injection of KCl and infusion of high-dose pentobarbital.


Figure 1
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  		Fig. 1 Outline of the experimental protocol. After baseline assessment of hemodynamics and left ventricular systolic and diastolic function, animals underwent left coronary artery microembolization. After 30 min of stabilization, new measurements confirmed the presence of heart failure. Animals were then randomized to receive infusion of either L-NAME or NaCl. Fifteen minutes after infusions, all measurements were repeated.

 
2.4. Analyses
The conductance catheter technique has been described previously [19]. Pressure- and conductance signals were processed using a conductance conditioner (Leycom, Sigma 5DF, Cardiodynamics, the Netherlands) and displayed on a computer using the software Conduct PC, CPC V3.15 (Leycom). The slope factor {alpha} was calculated from the ratio between conductance- and transit time derived cardiac outputs. Parallel conductance was estimated by the saline dilution technique [19].

Pressure–volume area (PVA) represents total mechanical work [18]. PVA was calculated as:


Formula

where SW is Stroke Work calculated from integrated pressure–volume data; ESP and ESV are end-systolic pressure and volume, respectively. V0 is the extrapolated x-intercept of quadratic fitted end-systolic pressure–volume relationships, and EDP is end-diastolic pressure. Left ventricular coronary blood flow (LVCBF) was estimated:


Formula

Where CBF is total coronary blood flow, W is total- and LVW is left ventricular myocardial weight. Myocardial oxygen consumption (MVO2) was calculated:


Formula

where avdO2 is difference between aortic and myocardial venous oxygen saturation, Hb is hemoglobin in g/ml, 1.39 is a constant (in ml O2/g Hb) and HR is heart rate. The factor 20.2 J/ml O2 was used to convert MVO2 to units equivalent to mechanical energy units. Arterial elastance (Ea) was calculated as end-systolic pressure divided by stroke volume.

2.5. Statistics
Linear, curvilinear and exponential relationships were estimated by least squares fit regression using a spreadsheet (Excel 2000, Microsoft), and all data were further analyzed in a statistical software package (SPSS 9.0, SPSS inc., Chicago, IL). After having excluded that large deviation from normal distribution of the data existed, differences between groups at baseline were evaluated by a two-sample t-test. In order to assess the impact of microembolization, t-test for paired data was used. Effect of NOS-inhibition was evaluated by 2-way ANOVA (time and group) for data before and after infusion in the L-NAME and control groups. In the dose–response study, the response was analyzed by repeated measurements of variance with Bonferroni correction for multiple comparisons. All values are given as mean±S.D. Significance is reported at the 5% level.


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 References
 
3.1. Effects of microembolization on hemodynamic and energetic parameters
Induction of acute LV failure led to a significant decline in LV performance parameters, CO and MAP, confirming the presence of acute heart failure with both systolic and diastolic components. Details are given in Table 2. Systemic vascular resistance (SVR) and arterial elastance (Ea) were not altered by microembolization. Stroke work was reduced to a greater degree than MVO2, leading to deterioration of mechanical efficiency (SW/MVO2), another characteristic of left ventricular failure [20].


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  		Table 2 Effects of microembolization

 
3.2. Effects of NOS-inhibition
Hemodynamic variables for NOS inhibited animals and controls are given in Table 3 and Fig. 2. Compared to controls, NOS-inhibited animals had an increased afterload and decreased CO. However, there were no significant differences in indices of left ventricular systolic- and diastolic function between NOS-inhibited animals and controls (Table 3). NOS-inhibition did not affect left ventricular myocardial oxygen consumption or mechanical efficiency (SW/MVO2, 0.21±0.03 in controls vs. 0.13±0.03 in L-NAME group, P=0.07), and we found no difference between the two groups in y-axis intercept of the PVA–MVO2 relationship (unloaded MVO2). However, as shown in Fig. 3, animals in the L-NAME group had a significantly increased slope of the PVA–MVO2 relationship.


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  		Table 3 Differences between NOS-inhibited animals and controls

 


Figure 2
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  		Fig. 2 Hemodynamics in L-NAME and control groups. Average and S.D. are shown for Controls and L-NAME groups. NOS-inhibited animals displayed significantly increased systemic vascular resistance and total arterial elastance compared to controls. Stroke volume and Cardiac Output was significantly reduced in L-NAME animals. *P<0.01 compared to controls (two-way ANOVA).

 


Figure 3
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  		Fig. 3 MVO2–PVA data for all animals in Control and L-NAME groups. Lines depict average values for the MVO2–PVA relationship in controls (—) and L-NAME (–) groups. NOS inhibited animals had significantly increased slope of the relationship (P=0.008), indicating decreased mechanoenergetic efficiency in this group (two-way ANOVA).

 

   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
References
 
This is the first experimental study to examine the impact of NOS-inhibition on LV mechanics and energetics in acute ischemic heart failure. The main findings in our study were:
  1. NOS-inhibition induced a profound increase in peripheral arterial resistance and arterial elastance, with a concomitant further reduction of cardiac output in already failing hearts (Fig. 2).
  2. The mechanoenergetic relationship revealed decreased myofibrillar efficiency in NOS inhibited animals (Fig. 3).

4.1. Effect of NOS-inhibition on LV mechanical properties
Experimental studies of myocardial contractile effects of NO have yielded apparent contradictory results [6,21] This can be explained by a biphasic, dose dependent effect of NO on the myocardium. In a study using isolated cat papillary muscles, Mohan and colleagues found that administration of low concentrations of NO donors induced a positive inotropic effect, but during administration of higher doses, a negative inotropic effect was seen [22]. In the chronically failing heart, increased NOS expression have been associated with negative effects on cardiac contractility [23,24]. Whether NOS expression in the myocardium is a result of heart failure or being related to its cause, is controversial [25,26]. Furthermore, some investigations have failed to demonstrate a positive inotropic effect of NOS inhibition in cardiac failure [21]. In the present study, NOS inhibition did not alter the maximum first derivative of pressure rise (dP/dtmax) or PRSW. We conclude that very early in acute ischemic heart failure, the concentration of NO present in the myocardium is not in the range where contractility is significantly affected, and that endogenous NO plays no or little role in the contractile failure during acute ischemia.

When considering the time aspect of shock development, the emergence of different isoforms of NOS could possibly explain a dual response on contractility. A cardiodepressive effect of NO could be associated with the expression of inducible NOS (iNOS) occurring later in the development of heart failure [27]. However, the constitutive form of NOS, eNOS, has been demonstrated to mediate positive inotropic effects in certain circumstances [15]. This opens for differentiated actions of NO depending on the isoenzyme source, with iNOS derived NO being a contributor to cardiac decompensation. A significant iNOS activity in our study is unlikely, since Thielman et al. found no evidence for iNOS expression 8 hours after microembolization in dogs [28]. In the phase of heart failure investigated by us, iNOS activity was probably not present, and if a heart failure of NO is mediated thorough iNOS, this could explain the unaltered LV function after NOS inhibition found in our study.

Intracoronary infusion of a NO donor has been shown to hasten relaxation and improve LV distensibility in healthy humans [29]. Furthermore, in a dog model of pacing induced heart failure, a rise in LV end-diastolic pressure was associated with a decline in cardiac NO production [30]. In our study, NOS inhibition did not alter relaxation, diastolic stiffness or end-diastolic volume. Consequently, endogenous NO does not seem to play a role in the impairment of diastolic function in ischemia induced heart failure. However, it should be noted that assessment of both systolic and diastolic properties could have been confounded by the L-NAME induced load alterations.

While contractility and diastolic function were unchanged in NOS-inhibited animals, L-NAME led to a significant increase in SVR and Ea. The increased SVR was not accompanied by a significant incline in arterial pressure, indicating that the failing LV did not manage to handle the increased afterload. Therefore, we conclude that the reduced stroke volume, stroke work and cardiac output in the L-NAME group are exclusively due to the ventriculo-arterial mismatch caused by the peripheral vasoconstrictory effects of NOS-inhibition.

4.2. Effects of NOS-inhibition on cardiovascular efficiency
Microembolization significantly reduced left ventricular contractility while arterial elastance (Ea) was unchanged. The resulting mismatch in ventriculo-arterial coupling is known to impair mechanical efficiency (reduced ratio of SW/MVO2) [31]. Accordingly, we found a highly significant reduction of mechanical efficiency after microembolization.

A key observation in our study was that NOS-inhibition led to a significantly increased Ea, while contractility was unchanged. This implies further worsening of ventriculo-arterial coupling, and one could expect an additional impairment of mechanical efficiency. We found a tendency towards further deterioration of mechanical efficiency (SW/MVO2) in NOS-inhibited animals, but this was not statistically significant (P=0.07).

While SW/MVO2 depicts all over cardiovascular efficiency, the intrinsic myocardial efficiency is studied using the PVA–MVO2 relationship. The y-axis intercept of this relationship (unloaded MVO2) represents oxygen consumption for non-contractile processes [18]. The preserved unloaded MVO2 indicates that endogenous NO plays no role in regulation of energy expenditure for basal metabolic processes or E–C coupling in acute ischemic heart failure. This is in contrast to observations in dogs with normal cardiac function where NOS-inhibition increases MVO2, probably related to increased contractility and basal metabolism [13].

The PVA–MVO2 relationship describes efficiency in processes converting oxygen to mechanical work, i.e. oxygen-to-ATP conversion and ATP consumption in myofibrillar contraction [18]. The slope of this relationship was significantly increased in NOS-inhibited animals. Several in vitro studies indicate that NO inhibits complexes in the mitochondrial respiratory chain [32–34] Consequently, one could envision that NOS-inhibition increased oxygen utilization and impaired efficiency through attenuating the mitochondrial oxygen-to-ATP generation efficiency. However, since ATP is the energy source for basal metabolic processes and E-C-coupling, as well as for contractile processes, inefficiency in oxygen-to-ATP conversion should also be reflected by an increase in unloaded MVO2. This was not found. Therefore, the most likely explanation for our findings is that endogenous NO preserved efficiency in cross bridge cycling after microembolization, and consequently that NOS-inhibition impaired this efficiency. Previous studies have shown an impact of NOS inhibition on myocardial oxygen consumption in heart failure [35,36]. Furthermore, in an in-vivo study in pigs, Heusch et al. also found indirect evidence for an effect of NO on myofibrillar efficiency [15].

4.3. Limitations of the study
Our results do not support non-selective NOS inhibition alone as a strategy to improve myocardial function in this early phase of acute cardiogenic shock.

One reason for the apparent inconsistency between the present investigation and the study by Cotter et.al., could be the time aspect. We investigated NOS-inhibition within the first few hours of acute heart failure, while Cotter and associates included patients with cardiogenic shock that persisted for more than 24 h. Several studies have indicated that vasodilation is a common denominator in the late phases of several kinds of shock [37]. Increased peripheral production of nitric oxide has been shown to play an important role in this uncontrolled and detrimental vasodilation. It is therefore possible that the vasoconstriction of NOS-inhibition could be beneficial at a later time point in cardiogenic shock.

Another reason for the apparent disagreement between these two studies could be the additional treatment given in the clinical study. Patients in the aforementioned study received maximal treatment with coronary revascularization, aspirin, heparin, loop diuretics, intra-aortic balloon pumping and beta-adrenergic stimulation. Importantly, when considering the effect of blocking NO in these patients, NOS-inhibition has been shown to increase contractility when given simultaneously with beta-adrenergic stimulation [38]. The heart failure model employed by us is also obviously different from the clinical entity of post-infarct cardiogenic shock. Microembolisation does not necessarily give the same kind of ventricular damage as occluded coronary arteries, especially if the myocardium is revascularized. However, several important studies have implied microembolisation as a very important mechanism behind acute coronary syndromes, particularly after revascularization [39,40]. We investigated the effects of NOS-inhibition after blocking the sympathetic activity with hexamethonium. Thus, the experiments were focused on the effect of NOS inhibition, avoiding the confounding effects of sympathetic activation during heart failure. However, most heart failure patients receive beta-blockers, rendering our sympathetic inhibited model comparable to a clinical setting. The use of amiodarone in our protocol could theoretically have influenced ventricular mechanical function as well as energetics. However, the drug was also used in control animals, so the findings reported were due to NOS-inhibition alone.

A final reason for the differences between the two studies could be the degree of NOS inhibition. The dose–response study performed by us indicated that 15 mg/kg L-NAME totally inhibited NOS, as no significant alteration were seen in hemodynamics after infusion of a higher dose. However, due to a possible biphasic effect of NO on the myocardium, partial NOS inhibition could be beneficial in cardiogenic shock. In the study by Cotter et.al., a significantly lower dose (1 mg/kg) of the NOS-inhibitor L-NMMA was used. In our dose–response study, no cardiac or hemodynamic effects were seen at low doses. NOS inhibition appeared to start at a dose between 2.5 and 5 mg/kg. However, there were large inter-animal variations in both SVR and CO at these doses, indicating that some animals were inhibited while others were not. To achieve a partial NOS inhibition we would need continuous evaluation of cardiac and systemic NO production, adjusting the dose according to the individuals’ response in NO production. Unfortunately, we were not able to measure NOS activity in our study.

Our findings indicate that a high-dose NOS-inhibition alone early in acute ischemic left ventricular failure and cardiogenic shock does not increase contractility or improve the energetic profile of the myocardium. Further investigations are warranted to elucidate the effects of NOS inhibition during acute cardiogenic shock.


   Acknowledgements
 
This study was supported with a grant from the Norwegian Research Council and the Norwegian Council of Cardiovascular Diseases. We are thankful for the skilful technical assistance from Hanne Maehre, Ernst-Rolf Albrigtsen, Ellinor Hareide and Hege Hagerup.


   References
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 

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