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Am J Physiol Heart Circ Physiol 281: H831-H837, 2001;
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Vol. 281, Issue 2, H831-H837, August 2001

Endogenous nitric oxide modulates myocardial oxygen consumption in canine right ventricle

Srinath Setty, Xiaoming Bian, Johnathan D. Tune, and H. Fred Downey

Department of Integrative Physiology, University of North Texas Health Science Center at Fort Worth, Fort Worth, Texas 76107-2699


    ABSTRACT
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

The role of endogenous nitric oxide (NO) in modulating myocardial oxygen consumption (MVO2) is unclear, in part because of systemic and coronary hemodynamic effects of blocking NO release. This study evaluated the effect of NO on right ventricular MVO2 under controlled hemodynamic conditions. In 12 open-chest dogs, Nomega -nitro-L-arginine methyl ester (L-NAME, 150 µg/min), a NO synthase (NOS) blocker, was infused into the right coronary artery. Heart rate and mean aortic pressure were constant. Right coronary blood flow and right ventricular MVO2 were measured at normal and elevated right coronary perfusion pressures (RCP) before and after L-NAME. To avoid effects of NO synthesis blockade on right coronary blood flow, which might have altered right ventricular MVO2, experiments, were conducted during adenosine-induced maximal coronary vasodilation. L-NAME did not affect right coronary blood flow (P = 0.51). However, L-NAME significantly increased right ventricular MVO2 (6% at RCP 100 mmHg, and 21% at RCP 180 mmHg). Right coronary blood flow varied with perfusion pressure (P < 0.02), and the elevation of MVO2 produced by L-NAME increased at higher flows (P < 0.04), consistent with the greater shear stress-mediated release of NO. These findings indicate that endogenous NO limits right ventricular MVO2.

open-chest dogs; Nomega -nitro-L-arginine methyl ester; maximal vasodilation; right coronary perfusion pressure; right coronary blood flow


    INTRODUCTION
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

THE VASCULAR ENDOTHELIUM modulates coronary vessel tone through synthesis and metabolism of various vasoactive agents, including nitric oxide (NO) formed from L-arginine by the action of NO synthase (NOS) via a cGMP mechanism (20). NO is continuously released from endothelial cells. In addition, hypoxia and physical stimuli, such as fluid shear stress and mechanical deformation, also enhance NO release (25, 31, 33).

There is evidence that NO reduces oxygen consumption in various in vitro preparations, including hepatocytes (41), nephrocytes (26), and myocytes (30, 36, 46). Blocking NO production by inhibiting NO synthesis increased oxygen consumption in the canine resting hindlimb and also in slices of canine triceps brachii (36). Treatment of isolated myocytes with NO donors reduced oxygen consumption (46), and NO synthesis blockade increased oxygen consumption in muscle slices from the canine left ventricle (30). However, the effect of NO on myocardial oxygen consumption (MVO2) in working, in vivo myocardium is unclear. Different laboratories have reported an increase (1, 3, 39), decrease (32), or no change (8-10, 23, 34, 44) in MVO2 after NO synthesis inhibition in the left ventricular myocardium. The confounding effects of increased peripheral vascular resistance and left ventricular afterload (1, 3, 39) caused by NO synthesis inhibition may account for the disparate conclusions about the effects of NO on MVO2.

The effect of NO on right ventricular metabolism is presently unknown. Several studies have demonstrated that the regulation of right ventricular flow and metabolism differs substantially from that of the left ventricle (19, 24, 35, 43). Furthermore, inhibition of NO synthesis decreases coronary blood flow in the right ventricle (2, 12, 40) but has little or no effect on coronary blood flow in the left ventricle (1, 3, 5, 11, 13, 29, 37, 44, 45). Therefore, the present investigation was designed to examine the effects of NO on right ventricular MVO2.

Right coronary circulation is poorly autoregulated (28, 47, 48); therefore elevations in right coronary perfusion pressure cause corresponding increases in right coronary blood flow. At elevated right coronary perfusion pressures, NO release will be augmented due to the resulting increase in shear stress (33). Thus in these experiments right coronary perfusion pressure was elevated so that effects of NO synthesis blockade on right ventricular MVO2 might be more evident.

Maximal coronary vasodilation was elicited in these experiments to eliminate the effects of NO synthesis inhibition on coronary vascular resistance. In addition, the potential confounding effects of NO synthesis inhibition on peripheral vascular resistance and cardiac afterload were eliminated by direct intracoronary administration of the NO synthesis blocking agent Nomega -nitro-L-arginine methyl ester (L-NAME).


    METHODS
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

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). Twelve adult dogs of either sex, free of clinically evident disease, were used for this study. The dogs were fasted overnight and then anesthetized with pentobarbital sodium (30 mg/kg iv). 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 and the first derivative of pressure (dP/dt).

The right coronary artery was isolated near its origin, and, after heparinization (500 U/kg iv), this artery was cannulated with a stainless steel cannula (2.1 mm outer diameter, 1.4 mm inner diameter). The right coronary artery was perfused with arterial blood from a pressurized reservoir, which was supplied with blood from a femoral artery. This 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 polyethylene-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.

To collect right coronary venous blood samples, a 24-gauge intravenous catheter was inserted into a superficial vein on the right ventricular epicardial surface. A previous study from this laboratory (28) showed that contamination of this venous blood with blood from sources other than the right coronary artery is <3% for the right coronary artery perfusion pressures used in these experiments. 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. Blood glucose and lactate were measured with a Yellow Springs Instruments model 2300 STAT analyzer. MVO2 was calculated from the product of coronary blood flow times the regional arteriovenous oxygen content difference. The right coronary artery perfusion territory was identified by injecting Evans blue dye into the right coronary perfusion line just before the termination of the experiment. The dyed tissue was carefully excised and weighed, so that coronary blood flow, as well as MVO2, could be normalized per gram of tissue mass.

Experimental protocol. Twelve dogs were used in this protocol. Right coronary blood flow was recorded after the right coronary perfusion pressure was maintained at 100 mmHg for 20 min to allow stabilization and recovery from surgical procedures. To create maximal coronary vasodilation, adenosine (5 mg/min) was infused into the right coronary artery. Maximal vasodilation of right coronary vasculature was indicated by failure of an increase in the rate of adenosine infusion to cause a further increase in right coronary blood flow. The hearts were paced by a Grass stimulator at 150 beats/min to avoid bradycardia during intracoronary adenosine infusion. Fifteen minutes after the infusion of adenosine was initiated, baseline measurements were obtained and right coronary perfusion pressure was then successively elevated from 100 to 120, 140, and to 180 mmHg. Arterial and venous blood samples were collected, and hemodynamic and cardiac functions were recorded when steady-state conditions (~5 min) were achieved at each perfusion pressure.

After the measurements were obtained at 180 mmHg, right coronary perfusion pressure was lowered to 100 mmHg. For the remainder of the protocol, L-NAME (150 µg/min) was continuously infused into the right coronary perfusion line by another infusion pump. Fifteen minutes after initiation of the intracoronary L-NAME infusion, coronary arterial and venous blood samples were collected, hemodynamic and cardiac function variables were recorded, and the elevation of right coronary perfusion pressure protocol was repeated. Right coronary perfusion pressure was then lowered to 100 mmHg, and the L-NAME and adenosine infusions were discontinued. After stabilization at this right coronary perfusion pressure, Evans blue dye was injected into the right coronary perfusion line.

The dose of L-NAME (150 µg/min ic) used to block NO synthesis had been previously found in four preliminary experiments to reduce vasodilation produced by 20 µg ic acetylcholine by ~65%. This degree of blockade is similar to findings by others (8, 10, 21). Complete blockade of acetylcholine-mediated vasodilation was not anticipated because acetylcholine causes vasodilation by additional non-NO-dependent mechanisms (14).

Statistics. All values are presented as means ± SE. Right ventricular hemodynamic and metabolic variables were evaluated with and without L-NAME by a one-way analysis of variance (ANOVA). When significance (P < 0.05) was found with ANOVA, a Student-Newman-Keuls multiple comparison test was performed. Effects of graded increases in coronary perfusion pressure on right coronary blood flow and right ventricular MVO2 in the presence and absence of L-NAME treatment, and effects of right coronary blood flow on oxygen extraction and MVO2 in the presence and absence of L-NAME treatment were examined by analysis of covariance (ANCOVA). Statistical computations were performed by GB Statistical Software version 6.5 (Dynamic Microsystems) and interpreted according to Zar (50).


    RESULTS
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

Hemodynamic and right ventricular function variables are summarized in Table 1. Aortic pressure, right ventricular peak systolic pressure, and right ventricular dP/dtmax were not significantly altered by L-NAME treatment during graded increases in right coronary perfusion pressure. Baseline arterial blood gas variables were the following: pH = 7.38 ± 0.01; PO2 = 103 ± 5 mmHg; PCO2 = 33 ± 1 mmHg; Hct = 39 ± 2%. Glucose and lactate uptakes were 0.26 ± 0.05 and 0.11 ± 0.03 µmol · min-1 · g-1, respectively. None of these variables were significantly affected by either graded increases in perfusion pressure or by treatment with L-NAME.

                              
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  		Table 1.   Hemodynamic variables during graded increases in right coronary perfusion pressure

Figure 1 shows right coronary blood flow plotted as a function of right coronary perfusion pressure in the presence and absence of L-NAME treatment. Infusion of intracoronary adenosine increased right coronary blood flow from 0.62 ± 0.01 to 3.72 ± 0.20 ml · min-1 · g-1 at a right coronary perfusion pressure of 100 mmHg. As right coronary perfusion pressure was increased from 100 to 180 mmHg, right coronary blood flow increased linearly during untreated control (P = 0.016, R2 = 0.97) and during NO synthesis blockade with L-NAME treatment (P = 0.020, R2 = 0.96). Treatment with L-NAME did not alter the relationship between right coronary perfusion pressure and right coronary blood flow (P = 0.51).


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  		Fig. 1.   Relationship between right coronary perfusion pressure and right coronary blood flow during maximal vasodilation with adenosine in presence and absence of treatment with Nomega -nitro-L-arginine methyl ester (L-NAME). Values are means ± SE. With right coronary perfusion pressure at 100 mmHg, right coronary blood flow increased 600% from baseline during intracoronary adenosine infusion. Regression analysis demonstrated linear increases in right coronary blood flow as right coronary perfusion pressure was increased during untreated control (P = 0.016) and during L-NAME (P = 0.020). Right coronary blood flow was not altered by L-NAME (P = 0.51).

Figure 2 shows right ventricular MVO2 plotted as a function of right coronary perfusion pressure in the presence and absence of L-NAME treatment. Right ventricular MVO2 increased as right coronary perfusion pressure was elevated during untreated control (P = 0.013, R2 = 0.98) and during treatment with L-NAME (P = 0.015, R2 = 0.97). However, inhibition of NO synthesis with L-NAME significantly increased right ventricular MVO2 relative to untreated control at each perfusion pressure. This increase varied from 6% at right coronary perfusion pressure of 100 mmHg to 21% at 180 mmHg. The slope of this relationship tended to be higher with L-NAME treatment (P = 0.07). Treatment with L-NAME significantly increased right ventricular MVO2 at each right coronary perfusion pressure (P < 0.05). This finding indicates that NO decreases right ventricular MVO2 during increases in right coronary perfusion pressure.


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  		Fig. 2.   Relationships between right coronary perfusion pressure and right ventricular (RV) myocardial oxygen consumption during maximal vasodilation with adenosine in presence and absence of treatment with L-NAME. Values are means ± SE. RV myocardial oxygen consumption significantly increased with right coronary perfusion pressure during untreated control (P = 0.013) and during L-NAME (P = 0.015). Slopes of this relationship tended to be higher during L-NAME treatment (P = 0.07). RV myocardial oxygen consumption was significantly increased by L-NAME at all right coronary perfusion pressures (P < 0.05), indicating that nitric oxide reduces RV myocardial oxygen consumption.

Figure 3A shows that right ventricular oxygen extraction decreased as right coronary blood flow was increased during untreated control (P = 0.04, R2 = 0.91) and during treatment with L-NAME (P = 0.04, R2 = 0.91). The slope of this relationship was not altered by L-NAME treatment (P = 0.59). Figure 3B shows that right ventricular MVO2 increased as right coronary blood flow was elevated during untreated control (P = 0.012, R2 = 0.98) and during treatment with L-NAME (P = 0.002, R2 = 0.99). The slope of this relationship was significantly increased by treatment with L-NAME (P = 0.004), indicating that NO limited the increase in oxidative metabolism in the right ventricle.


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  		Fig. 3.   Relationship between right coronary blood flow and RV oxygen extraction (A) and myocardial oxygen consumption (B) during maximal vasodilation with adenosine in presence and absence of treatment with L-NAME. Values are means ± SE. RV oxygen extraction significantly decreased with increases in right coronary blood flow during untreated control (P = 0.04) and during L-NAME treatment (P = 0.04). The slope of this relationship was not altered by L-NAME (P = 0.59). RV myocardial oxygen consumption significantly increased with right coronary blood flow during untreated control (P = 0.012) and during L-NAME treatment (P = 0.002). The slope of this relationship was significantly increased by L-NAME treatment (P = 0.004), indicating that that nitric oxide limits the increase in oxidative metabolism.


    DISCUSSION
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

This is the first reported investigation of the effect of NO on right ventricular MVO2. The most important finding of this study was that inhibition of NO synthesis increased right ventricular MVO2 relative to untreated control as coronary perfusion pressure was increased in the maximally vasodilated right coronary circulation. Furthermore, the elevation of right ventricular MVO2 during NO synthesis blockade was amplified by pressure-induced increases in right coronary blood flow. The present findings indicate that NO acts to decrease oxidative metabolism in canine right ventricular myocardium.

The right ventricle was chosen for the present investigation because the effects of NO on right ventricular metabolism are presently unknown. Furthermore, earlier studies from this laboratory (15, 28, 47) and others (19, 24, 35, 43) have shown that regulation of right ventricular flow and metabolism differs substantially from that of the left ventricle. Studies have also shown that blockade of NO synthesis significantly reduces coronary blood flow in the right ventricle (2, 12, 40) but has little or no effect on coronary blood flow in the left ventricle (1, 3, 5, 11, 13, 37, 44, 45). In addition, the right coronary circulation is poorly autoregulated (4, 28, 47, 48), therefore elevations in the right coronary perfusion pressure cause corresponding increases in right coronary blood flow, and also in right ventricular MVO2 (4, 47, 48), i.e., the Gregg phenomenon (16). In the present study, we found that in the maximally dilated right coronary circulation, graded increases in coronary perfusion pressure increased both right coronary blood flow and right ventricular MVO2. This is the first study to demonstrate the Gregg phenomenon in the maximally dilated right coronary circulation.

Effects of NO synthesis inhibition on ventricular MVO2. The effects of NO synthesis inhibition on oxidative metabolism have not been clearly defined. Earlier studies reported an increase in oxygen consumption following NO synthesis inhibition in the isolated kidney (26), skeletal muscle (22, 36, 38), cardiac muscle (30), and hepatic cells (41). Some studies have also reported an increase in oxygen consumption following NO synthesis inhibition in in situ, working myocardium. Altman et al. (1) administered an NO synthesis blocker intracoronarily to instrumented, conscious dogs. They found that NO synthesis inhibition caused an increase in MVO2 at rest and during treadmill exercise. However, this may have been secondary to a significant increase in arterial blood pressure. Apparently there was an appreciable spillover of the NO synthesis blocker to the systemic circulation, where it is known to elevate arterial pressure. Although consistent with the notion that NO acts to retard MVO2, these observations are not definitive due to the change in myocardial work secondary to hypertension following NO synthesis blockade. Bernstein et al. (3) also administered an NO synthesis blocker intravenously to chronically instrumented conscious dogs. They showed that for any given level of cardiac work, there was an increase in MVO2 following NO synthesis inhibition. Shen et al. (39) also found similar results in chronically instrumented dogs at rest and during exercise-induced increase in myocardial oxygen demand.

In contrast, other studies have shown no effect of NO synthesis inhibition on MVO2. Maekawa et al. (27) infused an NO synthesis blocker intracoronarily in anesthetized dogs and observed a modest fall in coronary blood flow, but no significant change in MVO2. Crystal et al. (8, 10) determined the effects of intracoronary administration of NO synthesis blockers on MVO2 of anesthetized dogs with coronary pressure held constant by a perfusion system. Under these conditions, intracoronary NO synthesis blockade produced no significant change in MVO2. Similar results of no change in MVO2 following NO synthesis inhibition have been shown in other left ventricular studies (18, 23, 34, 44). Reller et al. (32) reported significant reductions in both coronary flow and MVO2 following systemic administration of the NO synthesis blocker Nomega -nitro-L-arginine, in fetal lambs. However, it was unclear whether MVO2 fell due to reduced flow or vice versa.

The reason for these discrepant findings is unclear but may be related to the effects of NO synthesis blockade on coronary and systemic hemodynamics. Therefore, it is apparent that the putative effects of NO synthesis inhibition on MVO2 of the in situ working heart must be evaluated under conditions that avoid these hemodynamic changes. L-NAME-induced changes in coronary hemodynamics were avoided (Fig. 1) in the present investigation by maximally vasodilating the right coronary circulation with adenosine. Alterations in systemic hemodynamics were avoided (Table 1) by infusing L-NAME directly into the right coronary artery.

When NO synthesis inhibition-mediated changes in coronary and systemic hemodynamics were avoided in this investigation, NO synthesis inhibition produced a significant increase in right ventricular MVO2 (Figs. 2 and 3). The increase in right ventricular MVO2 following NO synthesis inhibition was even greater at higher right coronary perfusion pressures (Fig. 2) and at right coronary blood flows (Fig. 3). These findings indicate that NO mediates a progressive blunting of pressure-induced increases in MVO2 as right coronary blood flow and shear stress are elevated in right ventricular myocardium.

Relationship between MVO2 and contractile function. In this investigation we found that right ventricular MVO2 increased with elevations in right coronary perfusion pressure without changes in right ventricular dP/dtmax. We previously (4) described such dissociation in right ventricular oxygen consumption and external mechanical function. As coronary perfusion pressure was varied from 40 to 120 mmHg; percent segment shortening was constant although right ventricular MVO2 increased from 3.0 to 5.5 ml · min-1 · 100 g-1. However, right ventricular systolic stiffness, an important component of ventricular internal work, varied with right coronary perfusion pressure and likely accounted for the increases in MVO2 (4).

Mechanism by which NO reduces right ventricular MVO2. The mechanism by which NO reduces right ventricular MVO2 has not been delineated. However, in vitro studies of isolated mitochondria indicate that NO may inhibit the electron transport chain either by decreasing cytochrome-c oxidase activity (7) or indirectly by forming a peroxynitrite, which inactivates complex I and II (6). Suto et al. (42) suggested that NO may spare MVO2 by reducing oxygen required for excitation-contraction coupling. Further studies are required to determine whether these mechanisms account for the reduction in MVO2 produced by NO in the in situ canine right ventricle.

Potential limitations of the study. The possibility that adenosine used to maximally dilate the right coronary vasculature might have affected right ventricular MVO2 must be acknowledged (17). Because adenosine infusion rates and right coronary blood flow were similar at each right coronary perfusion pressure, any depression of right ventricular MVO2 by adenosine should have been similar in both the untreated control and during L-NAME treatment. It should also be appreciated that the infusion of adenosine was sufficient to cause maximal coronary vasodilation, even if the NO-dependent component of adenosine-mediated vasodilation was removed by NO synthesis inhibition.

It is possible that adenosine administered to produce maximal vasodilation augmented NO release either by directly acting on the vascular endothelium or by flow-mediated increases in shear stress (25, 49). Thus these experimental conditions accentuated the effect of NO and its inhibition on myocardial oxidative metabolism. Whether NO limits right ventricular MVO2 during normal vasomotor tone merits future investigation. However, such an investigation must be designed to account for confounding effects of NO inhibition on both metabolic and hemodynamic variables.

In conclusion, the present findings are the first to show that NO acts to limit oxidative metabolism in the in situ canine right ventricle. This inhibitory effect is augmented as coronary blood flow is elevated, most likely due to shear stress-mediated increases in NO production. The mechanism underlying this effect of NO on myocardial metabolism remains to be elucidated. This study is also the first study to demonstrate the Gregg phenomenon in the maximally dilated right coronary circulation.


    ACKNOWLEDGEMENTS

We are grateful to Dr. B. J. Hart, Min Fu, and Arthur Williams Jr., for expert technical assistance. This study was completed by Srinath Setty in partial fulfillment of the requirements for the Doctor of Philosophy degree at University of North Texas Health Science Center.


    FOOTNOTES

This work was supported by National Heart, Lung, and Blood Institute Grant HL-35027.

Address for reprint requests and other correspondence: S. Setty, Dept. of Integrative Physiology, Univ. of North Texas Health Science Center at Fort Worth, 3500 Camp Bowie Blvd., Fort Worth, TX 76107-2699 (E-mail: ssetty{at}hsc.unt.edu).

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 14 December 2000; accepted in final form 18 April 2001.


    REFERENCES
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

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Am J Physiol Heart Circ Physiol 281(2):H831-H837
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