Cardiovascular Research

Cardiovascular Research 2004 64(3):431-436; doi:10.1016/j.cardiores.2004.07.021
© 2004 by European Society of Cardiology

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Copyright © 2004, European Society of Cardiology

Nitric oxide contributes to oxygen demand–supply balance in hypoperfused right ventricle

Srinath Setty, Johnathan D. Tune and H. Fred Downey^*

Department of Integrative Physiology, University of North Texas Health Science Center at Fort Worth, 3500 Camp Bowie Boulevard, Fort Worth, TX 76107-2699, United States

^* Corresponding author. Tel.: +1 817 735 2078; fax: +1 817 735 5084. Email address: fdowney{at}hsc.unt.edu

Received 4 May 2004; revised 15 July 2004; accepted 27 July 2004

	Abstract

Top Abstract 1. Introduction 2. Methods 3. Results 4. Discussion 5. Conclusions Acknowledgments References

 
Objective:: The present study examined the role of nitric oxide (NO) in oxygen demand–supply balance in hypoperfused canine right ventricular myocardium.

Methods:: The right coronary artery of anesthetized, open-chest dogs was perfused at pressures of 80, 60, and 40 mm Hg, and right ventricular myocardial oxygen consumption, right coronary blood flow and other hemodynamic and cardiac function variables were measured. Right ventricular mechanical function was indexed as the product of heart ratexpeak right ventricular systolic pressurexright ventricular dP/dt_max. NO synthesis blocker N-nitro-L-arginine methyl ester (L-NAME, 150 µg/min) was infused into the right coronary artery to block NO synthesis.

Results:: Neither hypoperfusion nor L-NAME altered right ventricular function. Right ventricular myocardial oxygen consumption fell with coronary perfusion pressure, but less steeply after L-NAME, and at all perfusion pressures was elevated above control. The increase in myocardial oxygen consumption in the absence of NO was met by increased oxygen extraction and by non-NO dependent vasodilation, but the relationship between flow and oxygen consumption was displaced downward after L-NAME. As right coronary perfusion pressure was reduced, the relationship between right ventricular oxygen consumption and right coronary venous PO₂ became steeper after L-NAME, and right coronary venous PO₂ was significantly reduced.

Conclusions:: During right coronary hypoperfusion, right ventricular function is well maintained, but myocardial oxygen consumption falls, reflecting an increase in oxygen utilization efficiency. NO contributes to this adaptation to hypoperfusion by restraining myocardial oxygen consumption, and by promoting coronary vasodilation with less severe reduction in myocardial PO₂. NO has an important role in right ventricular oxygen demand–supply balance when right coronary perfusion pressure is reduced.

KEYWORDS Nitric oxide; Open-chest dogs; Right coronary perfusion pressure; Right coronary blood flow; Right ventricular oxygen consumption

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This article is referred to in the Editorial by N. Westerhof (pages 379–380) in this issue.

	1. Introduction

Top Abstract 1. Introduction 2. Methods 3. Results 4. Discussion 5. Conclusions Acknowledgments References

 
Under normal physiological conditions, myocardial oxygen demand is well balanced by myocardial oxygen supply. Obstructive coronary artery disease or hypoxemia can alter this balance. As myocardial oxygen supply becomes compromised, the ratio of oxygen consumed to cardiac work, i.e. oxygen utilization efficiency, improves [1–3]. There is increasing evidence that nitric oxide (NO) blunts oxygen demand of normally and hypoperfused myocardium [4–10], possibly by reducing "excess" oxygen consumption [9,10].

Recently, Heusch et al. [9] reported beneficial effects of endogenous NO in the adaptation of left ventricular myocardium to moderate ischemia. Ischemia-induced depression of contractile function was exacerbated by blockade of NO synthesis with no change in oxygen consumption, so oxygen utilization efficiency was improved by NO. In the right ventricle, hypoperfusion (perfusion pressure >30–40 mm Hg) reduces oxygen consumption with no change in contractile function [2,3]. Since the left and right ventricles use different strategies to increase oxygen utilization efficiency during hypoperfusion, we sought to determine if NO was responsible for hypoperfusion-induced decreases in right ventricular oxygen consumption. Furthermore, we sought to delineate the role of NO in modulating right coronary flow when perfusion pressure was reduced.

Results of this investigation demonstrate that NO is an important factor in sustaining oxygen demand–supply balance in the right ventricle, both by enhancing blood flow and by increasing oxygen utilization efficiency. In absence of NO, other redundant mechanisms are activated to maintain oxygen demand–supply balance, but at the cost of more severe myocardial hypoxia.

	2. Methods

Top Abstract 1. Introduction 2. Methods 3. Results 4. Discussion 5. Conclusions Acknowledgments References

 
2.1 Surgical preparation
This investigation was approved by the Institutional Animal Care and Use Committee and was conducted in accordance with the Guide for the Care and Use of Laboratory Animals (NIH publication No. 85-23, revised 1996). Nine adult dogs of either sex, free of clinically evident disease, were used for this study. The dogs were fasted overnight, and then anesthetized with sodium pentobarbital (30 mg/kg, i.v.). Supplemental pentobarbital was administered as needed to maintain stable anesthesia. After intubation, the dogs were ventilated by a Harvard respirator with room air supplemented with oxygen to maintain normal arterial blood gases throughout the experiment. A saline-filled vinyl catheter was inserted into the thoracic aorta via a femoral artery to measure aortic pressure. In the other femoral artery, a saline-filled vinyl catheter was placed to withdraw blood to supply an extracorporeal coronary perfusion circuit. A saline-filled vinyl catheter was inserted into a femoral vein for administration of supplementary anesthetic and heparin. The right heart was exposed through a right thoracotomy in the fourth intercostal space and suspended in a pericardial cradle. A Millar catheter-tip pressure transducer was inserted through the right atrial appendage and advanced across the tricuspid valve to measure right ventricular pressure. Right ventricular developed pressure (dP/dt) was computed from the right ventricular pressure signal by an electronic differentiator. To further evaluate right ventricular mechanical performance, the "triple product" was computed from heart ratexright ventricular peak systolic pressurexright ventricular dP/dt_max.

The right coronary artery was isolated near its origin, and, after heparinization (500 U/kg, i.v.), was cannulated with a stainless steel cannula (2.1 mm o.d., 1.4 mm i.d.). The right coronary artery was perfused with arterial blood from a pressurized reservoir, which was supplied with blood from a femoral artery. The perfusion tubing was equipped with a heat exchanger to maintain coronary perfusate temperature between 37 and 38 °C. To monitor right coronary perfusion pressure, a saline-filled PE-50 catheter was advanced to the orifice of the cannula and connected to a Narco Telecare pressure transducer. The right coronary blood flow was measured with a Carolina Medical Electronics FM 501 electromagnetic flowmeter and an EP 610 in-line flow transducer. Heart rate, aortic pressure, right coronary perfusion pressure, right ventricular pressure, right ventricular dP/dt and right coronary blood flow were recorded continuously with a multichannel Grass Model 7D polygraph.

To collect right coronary venous blood samples, a 24 G i.v. catheter was inserted into a superficial vein on the RV epicardial surface. A previous study from this laboratory showed that contamination of this venous blood with blood from sources other than the right coronary artery is less than 3% for the right coronary artery perfusion pressures used in these experiments [11]. The right coronary venous blood was allowed to drain freely into a beaker and was returned to the dog periodically. Arterial and venous blood samples were collected anaerobically and stored on ice until analysis. Oxygen content of these samples was measured with an Instrumentation Laboratory model 682 CO-oximeter, and PO₂, PCO₂, and pH were measured with an Instrumentation Laboratory model Synthesis 30 blood gas analyzer, and lactate concentrations were measured with a Yellow Springs Instruments STAT model 2300 analyzer. Right ventricular myocardial oxygen consumption and lactate uptake were calculated from the product of coronary blood flow times the respective regional arteriovenous content difference. To evaluate right ventricular oxygen utilization efficiency, myocardial oxygen consumption was divided by the triple product.

When the experimental protocols (see below) were completed, the right coronary artery perfusion territory was identified by injecting Evans blue dye into the right coronary perfusion line. The dyed tissue was carefully excised and weighed, so that coronary blood flow and myocardial oxygen consumption could be normalized per gram of tissue mass.

2.2 Experimental protocols
Preliminary experiments demonstrated that inhibition of NO synthesis affected right ventricular myocardial oxygen consumption at right coronary perfusion pressures less than 80 mm Hg, so this pressure was chosen as the baseline condition for this investigation. Following observations at this baseline pressure, data were collected at right coronary perfusion pressures of 60 and 40 mm Hg. Data from nine dogs are reported for the baseline condition. Right coronary perfusion pressure was reduced to 60 mm Hg in five of the nine dogs and to 40 mm Hg in four of the nine dogs.

Following surgical preparations, right coronary perfusion pressure was maintained at 80 mm Hg for 20 min to allow stabilization. Right coronary blood flow, and other hemodynamic and cardiac function variables were recorded and right coronary arterial and venous blood samples were collected at right coronary perfusion pressure of 80 mm Hg. After baseline measurements were obtained, right coronary perfusion pressure was then reduced to 60 or to 40 mm Hg. Arterial and coronary venous blood samples were collected, and hemodynamic and cardiac function variables were recorded when hemodynamic variables were stable at each right coronary perfusion pressure.

After measurements were obtained at right coronary perfusion pressures of 80 and 60 or 40 mm Hg, right coronary perfusion pressure was returned to 80 mm Hg. For the remainder of the protocol, N-nitro-L-arginine methyl ester (L-NAME) (150 µg/min) was continuously infused into the right coronary perfusion line. This avoided the confounding effects of elevated peripheral vascular resistance and cardiac afterload produced by systemic NO synthesis blockade [12]. NO synthesis blockade was tested with 20 g intracoronary injections of acetylcholine. Relative to the untreated control condition, administration of L-NAME reduced acetylcholine-mediated right coronary vasodilation by 65%, similar to findings by others [13–15]. Fifteen minutes after initiation of the intracoronary L-NAME infusion, hemodynamic and cardiac function variables were recorded, and right coronary arterial and venous blood samples were collected with right coronary perfusion pressure at 80 mm Hg. Right coronary perfusion pressure was then reduced, and experimental data were collected. Right coronary perfusion pressure was then increased back to 80 mm Hg, and the L-NAME infusion was discontinued. After stabilization at this baseline right coronary perfusion pressure, Evans blue dye was injected into the right coronary perfusion line.

2.3 Statistics
All values are presented as mean±S.E. Effects of right coronary perfusion pressure and L-NAME on hemodynamic and right ventricular function variables were evaluated by a two-factor (Factor A: Absence or presence of L-NAME; Factor B: Right coronary perfusion pressure) repeated measures analysis of variance (ANOVA). If ANOVA detected significant (P<0.05) effects of either Factor A or Factor B, a Student–Newman–Keuls multiple comparison test was performed. Key variables of oxygen supply–demand balance were plotted as functions of right ventricular oxygen consumption, and these relationships were characterized by linear regression analysis and compared by analysis of covariance (ANCOVA). The regression analyses and ANCOVA were performed on all data, and the resulting equations and coefficients of determination (r²) are reported. However, for clarity, mean values are plotted in Figs. 1 and 2. Statistical computations were performed by GB Statistical Software (Dynamic Microsystems) and interpreted according to Zar [16].

View larger version (22K): [in this window] [in a new window] [Download PowerPoint slide]   Fig. 1 Right coronary venous PO2 is plotted as a function of right ventricular oxygen consumption in the absence and presence of L-NAME. Plotted values are mean±S.E. at right coronary perfusion pressures of 80, 60, and 40 mm Hg. Regression lines and r2 values were computed from all data values. Right coronary venous PO2 decreased with reduction in right coronary perfusion pressure from 80 to 40 mm Hg during untreated control (P<0.004) and during L-NAME (P<0.002). L-NAME significantly depressed this relationship ( slope, P=0.04), indicating that that NO is an important factor in the normal balance between right ventricular oxygen demand–supply balance during right coronary hypoperfusion.

 

View larger version (23K): [in this window] [in a new window] [Download PowerPoint slide]   Fig. 2 Right coronary blood flow is plotted as a function of right ventricular myocardial oxygen consumption and in the absence and presence and of L-NAME. Plotted values are means±S.E. at right coronary perfusion pressures of 80, 60, and 40 mm Hg. Regression lines and r2 values were computed from all data values. Right coronary blood flow fell as right ventricular myocardial oxygen consumption was decreased during untreated control (P<0.003) and during L-NAME treatment (P<0.002). L-NAME significantly depressed this relationship (ANCOVA, intercept, P=0.03), indicating that NO is an important factor that normally influences right coronary delivery of oxygen during right coronary hypoperfusion.

 

	3. Results

Top Abstract 1. Introduction 2. Methods 3. Results 4. Discussion 5. Conclusions Acknowledgments References

 
Average values for untreated baseline arterial blood gas and chemical compositions were: pH=7.37±0.01; PO₂=104±7 mm Hg; PCO₂=32±2 mm Hg; Hct=42±2%. These variables were not significantly altered by reductions in right coronary perfusion pressure or by L-NAME.

Hemodynamic, metabolic, and right ventricular function variables are summarized in Table 1. Right ventricular myocardial oxygen consumption (RVMVO₂) and lactate uptake (RVLUT) fell with right coronary perfusion pressure. Right coronary blood flow (RCBF) and right coronary venous PO₂ (RCVPO₂) also decreased as right coronary perfusion pressure was reduced with and without L-NAME, and right ventricular oxygen extraction (RVO₂ Ext) increased. Overall, mean aortic pressure fell slightly, but significantly, with right coronary hypoperfusion, however multiple comparison testing detected no specific differences among mean values. L-NAME had no significant effect on mean aortic pressure. Neither heart rate (HR), right ventricular peak systolic pressure (RVPSP), right ventricular dP/dt_max (RV dP/dt_max) nor triple product were altered by reduction in right coronary perfusion pressure. L-NAME had no significant effect on these right ventricular function variables. No differences in corresponding control and treated means for cardiac function variables were detected by multiple comparison testing, and no pressurextreatment interactions were significant.

View this table: [in this window] [in a new window]   Table 1 Hemodynamic, metabolic, and cardiac function values during right coronary hypoperfusion

 
Table 1 shows that right ventricular myocardial oxygen consumption was significantly higher after L-NAME treatment relative to the untreated control condition. Interaction of pressure and treatment was highly significant, reflecting that oxygen consumption fell less steeply with pressure after L-NAME. Right ventricular uptake of lactate (RVLUT) fell significantly with right coronary perfusion pressure, but L-NAME had no significant effect on lactate uptake at any perfusion pressure (Table 1).

Although right ventricular oxygen consumption fell as right coronary perfusion pressure was reduced, right ventricular mechanical function remained constant, as evaluated by the triple product or any of the components of the triple product (Table 1). This indicates an improvement in oxygen utilization efficiency (Efficiency), as shown in Table 1. Relative to the baseline condition with perfusion pressure at 80 mm Hg, efficiency increased significantly at perfusion pressures of 60 and 40 mm Hg in both the control and treated conditions. After NO synthesis blockade, efficiency was significantly less at 40 mm Hg than in the corresponding untreated control condition.

ANOVA detected a small but significant increase (overall 7.3%) in right coronary blood flow after L-NAME treatment. Pressurextreatment interaction was also significant, indicating that flow fell less steeply with pressure after L-NAME.

As right coronary perfusion pressure was decreased from 80 to 40 mm Hg, right coronary venous PO₂ and blood flow fell with perfusion pressure (Table 1), and so did right ventricular oxygen consumption (Table 1). Therefore it was helpful to evaluate key factors responsible for myocardial oxygen demand–supply balance as functions of oxygen consumption (5, 7, 22). Fig. 1 shows that right coronary venous PO₂ fell along with right ventricular oxygen consumption with and without L-NAME treatment. L-NAME significantly depressed this relationship (ANCOVA, slope, P=0.04), indicating that inhibition of NO synthesis altered the normal balance between right ventricular oxygen demand and right coronary delivery of oxygen. The resulting imbalance forced the right ventricle to increase oxygen extraction (Table 1) to meet right ventricular myocardial oxygen requirements.

Fig. 2 shows right coronary blood flow plotted as a function of right ventricular myocardial oxygen consumption with and without L-NAME treatment. Although as a function of perfusion pressure, right coronary flow fell slightly less steeply after L-NAME (Table 1), Fig. 2 shows that at comparable oxygen consumption, right coronary flow was depressed by L-NAME (ANCOVA, intercept, P=0.03). Together, the data in Figs. 1 and 2 further demonstrate that NO regulates factors that impact right ventricular oxygen demand–supply balance during coronary hypoperfusion.

	4. Discussion

Top Abstract 1. Introduction 2. Methods 3. Results 4. Discussion 5. Conclusions Acknowledgments References

 
Previous studies have shown that reduction of coronary blood flow stimulates release of NO [9,17,18]. Since NO is a coronary vasodilator and also may reduce myocardial oxygen consumption [4–8], NO might play a critical role in balancing myocardial oxygen demand with oxygen supply when coronary blood flow is reduced. The most important finding of this investigation is that NO reduced myocardial oxygen consumption in the right ventricle during right coronary hypoperfusion without significantly affecting mechanical performance. Thus, NO increased myocardial oxygen utilization efficiency of the right ventricle, and this beneficial effect became more evident as perfusion pressure was reduced. The present findings also demonstrate that NO is a regulator of coronary blood flow during right coronary hypoperfusion.

Studies of left coronary hypoperfusion have reported a close association between decreases in coronary flow and mechanical function [19,20]. In addition, Heusch et al. [9] described a similar close association between decreases in left ventricular oxygen consumption and mechanical function. In contrast, decreases in right coronary blood flow have remarkably little effect on right ventricular function, so long as right coronary perfusion pressure is maintained above a critical value of 30–40 mm Hg [2,3,21]. The current investigation produced findings consistent with these earlier reports; right ventricular function, as indexed by the triple product, was not significantly altered by right coronary hypoperfusion in either the control or treated condition.

Since right ventricular oxygen consumption fell with perfusion pressure, and mechanical function was unchanged, right ventricular oxygen utilization efficiency was increased in the untreated condition, as we have previously reported [2,3]. The corresponding decrease in lactate uptake at reduced perfusion pressures most likely reflected the lesser requirement for oxidative substrate, consistent with the reduction in oxygen consumption. An alternative view that reduced lactate uptake was due to ischemia seems unlikely, since we detected no deterioration of right ventricular mechanical function during right coronary hypoperfusion. Previous investigations have reported NO-induced depression of myocardial oxygen consumption in both right and left ventricular myocardium perfused at normal pressure [4–10], although this topic is controversial [4–10,14,22–26]. While the current investigation examined the function of NO in hypoperfused right ventricle, earlier investigations reported on the function of NO in hypoperfused left ventricle [9,10]. In contrast to the L-NAME-induced elevation of right ventricular oxygen consumption observed in this investigation, NO synthesis inhibition in left ventricle produced a decrease in left ventricular function, but no change in myocardial oxygen consumption [9]. The net effect of NO synthesis inhibition was the same in both ventricles, i.e. a decrease in oxygen utilization efficiency, but clearly, the left and right ventricles use different strategies to maintain oxygen demand–supply balance during hypoperfusion in absence of NO. The decrease in left ventricular function during hypoperfusion most likely reflects the already noted close association between blood flow and function in the left ventricle [19,20]. The decrease in oxygen utilization efficiency observed in both ventricles might be explained by the recent report of Martin et al. [10] that efficiency of oxidative metabolism is impaired after NO synthesis inhibition.

In the untreated condition, increased NO release during hypoperfusion should have resulted in more efficient production of ATP (10). This could have contributed to the sustained right ventricular mechanical function observed when right coronary perfusion pressure and blood flow and right ventricular oxygen consumption were reduced. On the other hand, when NO synthesis was blocked, right ventricular oxygen consumption and flow were elevated, so even if ATP were less efficiently produced, a similar amount of ATP might have been available to support mechanical function. Whether NO was entirely responsible for maintenance of contractile function when right coronary perfusion pressure was reduced cannot be ascertained from the results of this study. Previously, we have suggested that reductions in coronary perfusion pressure in the poorly autoregulating right coronary circulation result in lesser coronary blood volume, and by unloading the coronary hydraulic skeleton, reduce ventricular systolic stiffness and cardiac internal work [3]. This would allow external work to be maintained at lower oxygen cost [3,27], as observed in the current study. Further research on this issue is required.

In a related left ventricular study, NO synthesis inhibition reduced left coronary flow during hypoperfusion [9], suggesting that NO contributes to coronary vasodilation. In the current study, right coronary flow was not depressed by L-NAME. In fact, at similar reduced perfusion pressures, right coronary blood flow was greater after L-NAME than in the untreated state (Table 1). These apparently disparate results can be reconciled by noting that right ventricular oxygen consumption was also elevated by NO synthesis inhibition (Table 1). Non-NO dependent vasodilatory mechanisms were likely activated by this increase in oxygen consumption, and a concurrent reduction in myocardial PO₂, as reflected in reduced right coronary venous PO₂ (Table 1). Even so, when right coronary flow was examined as a function of right ventricular oxygen consumption (Fig. 2), a significant depression of vasodilation was evident after inhibition of NO synthesis. Thus, results of this investigation demonstrate that NO is a regulator of both oxygen consumption and coronary flow when right coronary perfusion pressure is reduced.

	5. Conclusions

Top Abstract 1. Introduction 2. Methods 3. Results 4. Discussion 5. Conclusions Acknowledgments References

 
NO reduces right ventricular myocardial oxygen consumption during coronary hypoperfusion and improves the relationship between myocardial oxygen consumption and oxygen delivery by right coronary blood flow. Since right ventricular mechanical performance was sustained during hypoperfusion, NO increases myocardial oxygen utilization efficiency. Thus, under conditions of limited myocardial oxygen supply, NO is an important factor in maintaining oxygen demand–supply balance in the right ventricle.

	Acknowledgments

Top Abstract 1. Introduction 2. Methods 3. Results 4. Discussion 5. Conclusions Acknowledgments References

 
We are grateful to X. Bian, MD, PhD, B.J. Hart, PhD, and A.G. Williams, Jr. BS, for expert technical assistance. This study was completed by Srinath Setty, PhD, in partial fulfillment of the requirements for the Doctor of Philosophy degree at University of North Texas Health Science Center. This work was supported by National Institutes of Health grants HL-35027 and HL-64785.

	Notes

 
Time for primary review 19 days

	References

Top Abstract 1. Introduction 2. Methods 3. Results 4. Discussion 5. Conclusions Acknowledgments References

 

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