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Am J Physiol Heart Circ Physiol 290: H1226-H1234, 2006. First published November 4, 2005; doi:10.1152/ajpheart.00607.2005
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Nitroglycerin reduces myocardial oxygen consumption during exercise despite vascular tolerance

Robert Parent,1 Normand Leblanc,2 and Michel Lavallée1

1Department of Physiology, Faculty of Medicine, Université de Montréal, Montréal, Québec, Canada; and 2Department of Pharmacology, Center of Biomedical Research Excellence, University of Nevada School of Medicine, Reno, Nevada

Submitted 7 June 2005 ; accepted in final form 28 October 2005


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
The long-term benefits of nitroglycerin (NTG) therapy are limited by the development of vascular tolerance and endothelial dysfunction in conductance coronary arteries. We have determined whether nitrate tolerance extends to NTG effects on myocardial O2 consumption (MVO2) and the ability of endogenous nitric oxide (NO) to modulate MVO2 during exercise. In chronically instrumented dogs (n = 8), hemodynamic and MVO2 responses to treadmill exercise were measured before, during tolerance (3 and 7 days of NTG delivery), and 7 days after NTG withdrawal. Acute NTG delivery caused a parallel downward shift of the MVO2-triple product (TP) relations and reversed the disproportionate increases in MVO2 caused by the blockade of NO formation. After 7 days of continuous transdermal NTG delivery, vascular tolerance was displayed as a >75% reduction of coronary blood flow (CBF) responses to NTG boluses. Despite vascular nitrate tolerance, MVO2-TP relations were shifted downward compared with pre-NTG exercise. Seven days after NTG withdrawal, vascular responses to boluses of NTG had recovered from tolerance, and MVO2-TP relations during exercise were back to pre-NTG level. At that time, blockade of NO formation failed to alter MVO2-TP relations. Thus NTG caused a sustained reduction of cardiac MVO2, independent of metabolic demand during exercise, despite tolerance of the coronary microcirculation. NTG-induced vascular tolerance and MVO2 reductions were reversible by NTG withdrawal, but endogenous NO-dependent modulation of O2 consumption was severely impaired.

nitrates; exercise; nitric oxide

NITROGLYCERIN (NTG) has been used over a century to alleviate myocardial ischemia and anginal pain. The clinical benefits of organic nitrate therapy are the consequence of a better match between myocardial O2 supply/demand balance. The oxygen-sparing effect of NTG results from a reduced cardiac metabolic demand (decreased ventricular loading), whereas the potent and long-lasting vasodilator effects on conductance coronary vessels ensure an augmented O2 supply (1). The salutary effects of nitrate therapy are, however, limited in time by the development of vascular tolerance. Several mechanisms are currently considered important in the development of tolerance: mechanism-based processes involving impaired bioconversion of NTG into its active metabolite(s) (4, 28); neurohormonal responses (pseudotolerance) counteracting the primary dilator effects of NTG (8, 23); and production of O2-derived free radicals scavenging nitric oxide (NO), presumably the key intermediate of NTG effects (15, 20, 22). This increased oxidative stress also limits endogenous NO bioavailability and causes endothelial dysfunction displayed as impaired endothelium-dependent vascular responses (10–12, 16, 21, 26, 31).

Aside from its vascular effects, NTG may also spare O2 by directly decreasing tissue metabolism through a cGMP-independent process (30). This feature of NTG is shared by endothelium-dependent dilators (carbachol and bradykinin) and is lost in transgenic endothelial NO synthase (eNOS)–/– mice (2, 9, 17, 18, 27, 33). Thus the decrease in myocardial O2 consumption (MVO2) triggered by NTG may be causally related to the production of NO. The physiological importance of NO-dependent modulation of cardiac MVO2 is highlighted by the dramatic increase in O2 consumption during exercise performed after NO formation blockade with N{omega}-nitro-L-arginine (L-NNA) (3).

Nitrate tolerance has mainly been considered as a vascular phenomenon with little attention paid to the effects of chronic NTG exposure on cardiac MVO2. The consequences of nitrate tolerance may differ in vascular and myocardial tissues. NTG has been reported to provide sustained cardioprotective effects and not to increase myocardial oxidative stress, despite vascular tolerance (6, 7). The present study addresses the following issues: 1) Can NTG act as a surrogate of NO in influencing cardiac MVO2 after the acute blockade of endogenous NO formation? 2) In the setting of vascular tolerance, can NTG reduce cardiac MVO2? 3) Does chronic exposure to NTG alter the ability of endogenous NO to modulate cardiac MVO2?


   METHODS
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 METHODS
RESULTS
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Experimental protocols were reviewed and approved by the Institutional Animal Care and Use Committee of the Montreal Heart Institute (University of Montreal).

Instrumentation. After general anesthesia with pentobarbital sodium (30 mg/kg iv), eight mongrel dogs (31 ± 1 kg) underwent a left thoracotomy to implant an aortic catheter used to measure arterial pressure with an external transducer (model 800, Bentley Trantec). A solid-state pressure gauge (model P6.5, Konigsberg Instruments) was inserted in the left ventricular (LV) cavity to record LV pressure (LVP) and to obtain its first derivative over time (LV dP/dt). The miniature pressure gauge was cross-calibrated against LVP measured with a chronically implanted LV catheter. A pulmonary artery catheter was implanted and used for systemic drug delivery. A cardiotachometer (model 9857, Sensor Medics) triggered by LVP was used to monitor heart rate (HR). Coronary blood flow (CBF) was measured with a Doppler transducer placed around the proximal circumflex coronary artery and a 10-MHz-pulsed Doppler flowmeter (C. J. Hartley). A Silastic (Dow Corning) catheter was implanted in the coronary sinus (CS). Postoperatively, analgesia was provided with buprenorphine (0.3 mg im, Reckitt and Colman Pharmaceuticals), and procaine penicillin G (300,000 U im) and benzathine penicillin G (300,000 U im) were administered prophylactically for 10 days. Hemodynamic variables were continuously recorded on a VHS tape using a PCM recording adaptor (model 4000A, Vetter) and monitored on a direct ink-writing stripchart recorder (model 2800s, Gould). Mean arterial pressure (MAP) and mean CBF were obtained with active filters with a time constant of 2 s.

Protocols. Experiments were initiated 3–5 wk after surgery in conscious healthy dogs. In dogs lying quietly on a table, CBF responses to systemic boluses of 1.0, 3.0, and 10.0 µg/kg of nitroglycerin (Sabex) were measured. At least 2 h after the completion of NTG boluses, animals performed a standard treadmill exercise consisting of three steps lasting 4 min: 3 mph, 0% grade; 4 mph, 5% grade; and 6 mph, 10% grade. Blood samples from the aortic and CS catheters were collected in lightly heparinized syringes while the dogs were standing quietly on the treadmill and 3 min after the beginning of each step of exercise, when a steady state was reached. Samples were immediately processed to measure hemoglobin concentration ([Hb]) and Hb O2 saturation with a cooxymeter (OSM-2, Radiometer). A Stat Profile pHOx Analyzer (Nova Biomedical) was used to measure PO2.

This exercise protocol was repeated 30 min after the beginning of a systemic infusion of NTG (2.0 µg·kg–1·min–1), which was maintained throughout exercise. On a different day and after a control exercise protocol, 35 mg/kg of L-NNA (Sigma) was administered over 10 min. Exercise was performed 30 min after the completion of L-NNA delivery. NTG (2.0 µg·kg–1·min–1) was then infused for 30 min and the exercise protocol repeated. On the basis of preliminary experiments (n = 5), a 5-day recovery period after L-NNA allowed exercise-induced responses and MVO2-TP relations to return to control levels. Consequently, continuous NTG delivery to achieve NTG tolerance was initiated at least 5 days after L-NNA administration to ensure complete recovery from prior NO formation blockade.

Vascular tolerance to NTG was achieved by skin application of three 0.8-mg NTG patches (Nitro-Dur, Schering) that were replaced every 12 h over 7 days. We have determined in five dogs that the method of NTG delivery mimicked the effects of systemic administration of NTG (2.0 µg·kg–1·min–1). To confirm vascular tolerance, CBF responses to NTG boluses were assessed 3 and 7 days after the beginning of continuous NTG delivery. On these days, the exercise protocol was performed at least 2 h after boluses of NTG. NTG patches were removed after 7 days of continuous application. Seven days later, CBF responses to boluses of NTG were assessed, and the exercise protocol was performed before and after L-NNA administration.

At necropsy, the size of the circumflex artery perfusion bed was measured by using a dye perfusion method, and the cross-sectional area of the artery under the Doppler probe was determined. Therefore, data for CBF and MVO2 could be reported per gram of tissue.

Data analysis. Data are reported as means ± SE under steady-state conditions during exercise. Responses to boluses of NTG were read at peak CBF before any apparent changes in MAP or HR. Blood O2 content was calculated by the following equation: [Hb] (in g/dl) x %Hb O2 saturation x 1.34 ml O2/g. MVO2 is the difference between aorta and CS O2 content times CBF (in µl·min–1·g of tissue–1). Oxygen delivery (Del O2) is the product of aortic blood O2 content and CBF. Triple product (TP) is the result of LVP x LV dP/dt x HR. Two-way analyses of variance for repeated measurements were used to compare variables to control. Post-hoc comparisons were made with the Newman-Keuls test to isolate specific contrasts. Relations between MVO2 and TP, CS PO2, or Del O2 were established for each animal, and analysis of variance or a paired t-test were used to compare slopes or intercepts. Statistical significance was reached when P < 0.05 in all cases. All experimental procedures were performed in accordance with institutional guidelines.


   RESULTS
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Acute intravenous NTG effects. Overall hemodynamic responses to exercise during intravenous NTG were characterized by reductions of LVP, LV end-diastolic pressure (LVEDP), and mean arterial pressure (MAP), increases in HR, and maintained LV dP/dt (Table 1). CBF and MVO2 fell during NTG delivery in the face of maintained TP (Table 1). Analyses of MVO2-TP relations during NTG revealed a downward and parallel shift, i.e., at any level of TP, MVO2 was disproportionately lower during NTG, indicative of a reduced cardiac metabolic demand (Fig. 1). In contrast, CS PO2-MVO2 and Del O2-MVO2 relations were not altered by NTG (Fig. 2). Therefore, O2 supply and demand balance was maintained during NTG. NTG delivered through patches (after 4 h) also caused a shift of MVO2-TP relations, similar to that produced by intravenous NTG.


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  		Table 1. Hemodynamic effects of exercise before and during systemic NTG

 

Figure 1
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  		Fig. 1. A: myocardial O2 consumption (MVO2)-triple product (TP) relations during graded exercise before and after acute nitroglycerin (NTG, 2.0 µg·kg–1·min–1). B: MVO2-TP relations during graded exercise before, after N{omega}-nitro-L-arginine (L-NNA, 35 mg/kg), and after L-NNA + NTG. NTG alone caused a downward parallel shift of the relations. L-NNA increased the slope of the relations, which were reversed by NTG. *Intercept P < 0.01 vs. previous treatment; {dagger}slope P < 0.01 vs. previous treatment; n = 8.

 

Figure 2
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  		Fig. 2. Coronary sinus (CS) PO2-MVO2 (A) and O2 delivery-MVO2 (B) relations during graded exercise before, during acute NTG infusion, and 3 and 7 days during continuous NTG delivery. NTG had no statistically significant effect on these relations; n = 8.

 
Conceivably, the decrease in MVO2 caused by NTG involves NO, as an essential intermediate. In that eventuality, NTG should mimic the effects of endogenous NO, thereby reversing the effects of blockade of NO formation on cardiac MVO2. Therefore, NTG was administered during exercise performed after the blockade of endogenous NO formation with L-NNA. Blockade of NO formation dramatically increased the slope of the MVO2-TP relations as expected (Fig. 1 and Table 2). Despite a smaller increase in TP during exercise performed after L-NNA, MVO2 increased more. These effects of L-NNA on MVO2 were reversed by NTG (Fig. 1 and Table 2). Thus NTG acted as a surrogate of endogenous NO after its suppression by L-NNA.


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  		Table 2. Hemodynamic effects of exercise before and after L-NNA and after L-NNA + NTG

 
Chronic vascular effects of NTG. The effects of systemic boluses of NTG on CBF responses are reported in Fig. 3. Three and seven days of continuous NTG delivery dramatically reduced CBF responses to systemic boluses of NTG. When reported as percent changes from baseline, CBF responses were also substantially impaired. Seven days after NTG withdrawal, CBF responses to boluses of NTG had returned close to pretolerance levels.


Figure 3
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  		Fig. 3. Baseline and peak coronary blood flow (CBF) responses elicited by systemic boluses of NTG (A) before, 3 and 7 days during continuous NTG delivery and at recovery (7 days after NTG withdrawal). B: percent changes from baseline. CBF responses to NTG were substantially reduced by chronic exposure to NTG and restored by NTG withdrawal. {dagger}P < 0.01 vs. control; n = 8. NS, not significant.

 
Continuous NTG delivery was accompanied by reductions in LVP and MAP during exercise, whereas LVEDP, LV dP/dt, HR, and TP did not statistically differ from control responses (Table 3). When compared with control, MVO2-TP relations had similar slopes but were shifted downward by NTG at 3 and 7 days of NTG delivery (Fig. 4). These sustained effects of chronic NTG exposure on the MVO2-TP relations were quantitatively similar to those observed during acute NTG delivery. Thus chronic NTG delivery caused sustained reductions in MVO2 for any given level of TP. In contrast to vascular responses, tolerance was not apparent on the metabolic effect of NTG.


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  		Table 3. Time course of hemodynamic responses to exercise before (control), during continuous NTG delivery, and 7 days after NTG withdrawal (recovery)

 

Figure 4
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  		Fig. 4. MVO2-TP relations during graded exercise before, during acute NTG infusion, and 3 and 7 days during continuous NTG delivery. NTG caused a parallel downward shift in the relations. Acute and chronic effects of NTG did not differ. *P < 0.01 vs. control; n = 8.

 
Seven days after NTG withdrawal, MVO2-TP relations were back to pre-NTG values (Fig. 5). At that time, blockade of NO formation failed to increase the slope of the MVO2-TP relations during exercise in contrast to responses before chronic NTG exposure (Fig. 5 and Table 4). Thus recovery from vascular NTG tolerance is accompanied by a reduced NO-dependent regulation of cardiac MVO2.


Figure 5
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  		Fig. 5. MVO2-TP relations during graded exercise with and without L-NNA before NTG treatment and at recovery (7 days after NTG withdrawal). Control responses did not differ before NTG exposure and at recovery. In contrast, L-NNA increased the slope of the relations before NTG treatment but did not during the recovery period. *P < 0.01 vs. respective control; n = 8.

 

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  		Table 4. Hemodynamic responses to exercise after NTG withdrawal before and after L-NNA

 

   DISCUSSION
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 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
GRANTS
 REFERENCES
 
Our data indicate that during exercise, acute NTG delivery reduces cardiac MVO2 independently of the triple product, an index of cardiac metabolic demand. At any given level of TP, NTG reverses the disproportionate rise in cardiac MVO2 caused by the blockade of NO formation with L-NNA. Thus NTG acts as a surrogate of NO when its endogenous source is compromised. Despite vascular tolerance displayed by the coronary microcirculation, after several days of continuous NTG delivery, a downward shift of the MVO2-TP relations persists, consistent with a sustained O2-sparing effect of NTG. Therefore, vascular tolerance does not extend to metabolic effects of NTG. Seven days after NTG withdrawal, MVO2-TP relations and vascular sensitivity to NTG were restored to pre-NTG levels. At that time, L-NNA failed to increase the slope of MVO2-TP relations. Thus NTG led to an impaired NO-dependent regulation of cardiac MVO2 that extended beyond the treatment period.

Our experimental strategy relies on analyses of MVO2-TP relations to assess the match between cardiac metabolic demand and oxygen consumption. As expected, MVO2 increased linearly over the range of TP created by exercise. Although our conclusions regarding the acute effects of L-NNA and NTG on MVO2 are in general agreement with those obtained from myocardial tissue in vitro, we have to acknowledge an important limitation inherent to the use of TP for the assessment of cardiac metabolic demand. With this approach, internal work, an important determinant of MVO2, is not directly accounted for. That issue may be minimized by comparing the same intervention before and after the development of tolerance, but it cannot be ignored.

The O2-sparing effects of NTG are considered to be the primary consequence of changes in ventricular loading conditions. Simultaneous decreases in LV systolic pressure (afterload) and LV diastolic size (preload) lead to reduced LV systolic wall stress, thereby limiting energy expenditure and cardiac O2 demand. NTG also favors a greater myocardial O2 delivery by dilating stenotic conductance coronary vessels. Together, these effects of NTG are deemed to improve myocardial O2 supply and demand balance (1). In the present study, a reduction of myocardial O2 demand secondary to altered LV loading conditions cannot solely account for the O2-sparing effects of NTG. In fact, NTG reduced MVO2 independently of cardiac metabolic demand; i.e., MVO2-TP relations were shifted downward by NTG. Conceivably, this downward shift of the MVO2-TP relations may be preload dependent. A reduced MVO2 would be expected if LVEDP (and LV volume) was smaller at any given level of TP, such as during acute systemic NTG delivery. This cannot explain the sustained reductions of MVO2 after 3 and 7 days of continuous NTG delivery because LVEDP during exercise had returned to pre-NTG levels. In that situation, LV end-diastolic volume may even be augmented because NO donors have been reported to increase LV compliance, which per se is not expected to reduce MVO2 (24). The loss of NTG effects on LVEDP is consistent with the development of venous tolerance to NTG along with an increase in vascular volume (8, 19, 23). Therefore, a distinct mechanism has to be invoked to account for the shift in the MVO2-TP relations caused by NTG.

NO, presumably the key intermediate in NTG effects, most likely accounts for the reductions in MVO2 caused by NTG. In that connection, NO-dependent dilators, such as carbachol and bradykinin, caused a L-NNA-sensitive reduction in cardiac O2 consumption in vitro, lost in transgenic eNOS–/– mice (9, 17, 18, 33). Interestingly enough, S-nitroso-N-acetyl-penicillamine, a spontaneous NO donor, and NTG also decreased MVO2 (9, 17, 33). Renal and skeletal muscles O2 consumption also displays a NO-dependent sensitivity (2, 27). Conversely, blockade of NO formation in exercising dogs caused a disproportionate rise in cardiac MVO2, consistent with a modulatory influence of NO on O2 consumption (3). In the present experiments, the effects of L-NNA on cardiac MVO2 were reversed by NTG, as expected, if NTG effects involved NO production. Although functional and circumstantial evidence strongly support the concept that NTG-derived NO accounts for the O2-sparing effect of NTG, NO production in isolated vessels was only detected when doses of NTG exceeded therapeutic range (13).

The main target of NO to decrease MVO2 is probably the cytochrome-c oxidase, the terminal complex of the mitochondrial respiratory chain. NO competes with O2 for binding the heme group of the cytochrome-c oxidase, thereby inhibiting mitochondrial respiration (30).

In the present study, our method of NTG delivery was designed to trigger vascular tolerance. In agreement with this objective, CBF responses to boluses of NTG after 3 and 7 days of continuous NTG delivery were severely impaired. Given that >80% of the resistance of the coronary bed resides in vessels <200 µm, CBF responses to NTG are deemed to reflect resistance vessel dilation (5). Although vascular tolerance to organic nitrates has been mainly associated with conductance coronary vessels, the present study extends these findings to resistance coronary vessels.

Several mechanisms are currently considered pivotal to account for the time-dependent loss of sensitivity to NTG in conductance vessels. According to the mechanism-based hypothesis, tolerance is the expression of a downregulation of a key protein involved in the biotransformation of NTG to NO (4, 28). Mitochondrial aldehyde dehydrogenase, which is downregulated in NTG-tolerant tissue, could be responsible for NOFormula production from NTG that is locally converted to NO (29). The NO availability hypothesis indicates that vascular tolerance leads to the production of oxygen-derived free radicals, which scavenge NTG-derived NO (10, 15, 20, 22). A dysfunctional eNOS (21) and an augmented activity of the NAD(P)H oxidase (10, 20) account for an increased oxygen free radicals production in the setting of vascular tolerance. As a consequence of the limited bioavailability of NO, endothelium- and NO-dependent responses are compromised (10, 21, 26, 31). The prevention of NTG tolerance and the improvement of endothelial dysfunction with antioxidant agents argue for the oxygen-derived free radical hypothesis (10, 11, 20, 32). Presumably, the same mechanisms accounting for the development of tolerance in conductance vessel intervene in resistance vessels.

Recovery from tolerance was apparent 7 days after NTG withdrawal as CBF responses to boluses of NTG were restored. At that time, MVO2-TP relations were back to pre-NTG levels, but paradoxically the blockade of NO formation with L-NNA did not alter MVO2-TP relations. Thus NO-dependent modulation of MVO2 was impaired. A dysfunctional eNOS could be involved because it is the primary endogenous source of NO modulating MVO2, as demonstrated earlier (25). A limited NO bioavailability, as a consequence of increased O2 free radical production, could also account for the failure of L-NNA to increase MVO2 during the recovery period. Regardless of the mechanism, the consequences of NTG tolerance extend far beyond the recovery from vascular tolerance. Because MVO2-TP relations during the recovery period (without L-NNA) did not differ from pre-NTG, other mechanisms may intervene to regulate MVO2 in the face of impaired NO-dependent influences.

The consequences of NTG exposure differ in vascular and myocardial tissue. Metabolic effects (decreased O2 consumption) of NTG were spared from tolerance in contrast to vascular responses. A marked decrease in vascular NO bioavailability occurs in the setting of tolerance as a consequence of increased oxidative stress (21). In contrast, NTG fails to increase the O2 free-radical burden in myocardial tissue when vascular tolerance occurs (6). NTG-induced NO availability is even increased in the myocardium from animals with vascular tolerance to NTG (6). This may explain why NTG caused sustained decreases in cardiac MVO2 despite vascular tolerance. Apparently, the development of tolerance primarily targets cGMP-dependent effects of NTG, such as vascular relaxation, and do not extend to cGMP-independent responses such as O2-sparing effects.

A reduced MVO2 caused by NTG may conceivably be secondary to an altered myocardial O2 supply. If myocardial O2 supply was inadequate to the point of limiting MVO2, CS PO2 would be expected to show a disproportionate decrease as a consequence of an augmented O2 extraction. Acute or chronic NTG application did not modify MVO2/CS PO2 and MVO2/Del O2 relations. Thus NTG had little influence on resistance coronary vessels. This failure of chronic NTG treatment to cause significant dilation of the coronary microcirculation reflects the poor biotransformation of NTG by resistance vessels (14). By comparison, conductance coronary arteries are nearly 40 times more sensitive to the dilator action of NTG, making them a primary therapeutic target (34). Together with the development of tolerance, these observations argue against the involvement of resistance coronary vessels in the reduction of MVO2 caused by NTG.

In conclusion, acute NTG delivery reduces cardiac MVO2 and reverses the disproportionate rise in MVO2 caused by the blockade of endogenous NO formation during exercise. Despite vascular tolerance in the coronary microcirculation secondary to continuous NTG delivery, a sustained reduction of cardiac MVO2, independent of metabolic demand, was observed during exercise. NTG withdrawal reversed vascular tolerance and restored MVO2-TP relations during exercise. In contrast, blockade of endogenous NO formation failed to augment MVO2 during exercise, consistent with an impaired NO-dependent modulation of O2 consumption.


   GRANTS
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 GRANTS
REFERENCES
 
This work was supported through grants from Canadian Heart and Stroke Foundation, Canadian Institutes of Health Research Grants MT-10863, MOP-68968, Fonds de Recherche de l'Institut de Cardiologie de Montréal, the Center of Biomedical Research Excellence Grant NCRR 5 P20 RR15581, Western Affiliate of the American Heart Association Grant 0355060Y, and National Heart, Lung and Blood Institute Grant 1 R01 HL-075477-01.


   ACKNOWLEDGMENTS
 
The authors are grateful to C. Mousseau for expert technical assistance.


   FOOTNOTES
 

Address for reprint requests and other correspondence: M. Lavallée, Dept. of Physiology, Pavillon Paul-G Desmarais, C.P 6128, succursale Centre-ville, Montréal (Québec) H3C 3J7, Canada (e-mail: michel.lavallee{at}umontreal.ca)

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.


   REFERENCES
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