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Am J Physiol Heart Circ Physiol 282: H508-H515, 2002. First published October 11, 2001; doi:10.1152/ajpheart.00722.2001
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Vol. 282, Issue 2, H508-H515, February 2002

Enhanced contribution of NO to exercise-induced coronary responses after alpha -adrenergic receptor blockade

Masayuki Takamura, Robert Parent, and Michel Lavallée

Department of Physiology, Faculty of Medicine, Université de Montréal, and Institut de Cardiologie de Montréal, Montréal, Québec, Canada H1T 1C8


    ABSTRACT
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

We hypothesized that nitric oxide (NO), in addition to beta -adrenergic effects, may contribute to exercise-induced coronary responses after alpha -adrenergic receptor blockade. Data were analyzed as relationships between coronary sinus (CS) O2 saturation (CS O2sat) or coronary blood flow (CBF) and myocardial O2 consumption (MVO2). As MVO2 increased, CS O2sat fell more (P < 0.05) after Nomega -nitro-L-arginine methyl ester (L-NAME; slope = -2.9 ± 0.4 × 10-2 %saturation · µl O2 · min-1 · g-1) than before (slope = -2.1 ± 0.3 × 10-2 %saturation · µl O2 · min-1 · g-1). The slope of CBF versus MVO2 was not altered. After blockade of alpha -adrenergic receptors alone (phentolamine), CS O2sat failed to decrease as MVO2 increased (slope = -0.1 ± 0.5 × 10-2 %saturation · µl O2 · min-1 · g-1). L-NAME given after phentolamine led to substantial decreases in CS O2sat (P < 0.01) as MVO2 increased (slope = -2.1 ± 0.4 × 10-2 percent saturation · µl O2-1 · min-1 · g-1). CBF responses to exercise were smaller (P < 0.01) after phentolamine + L-NAME (slope = 6.1 ± 0.1 × 10-3 ml/µl O2) than after phentolamine alone (slope = 6.9 ± 0.2 × 10-3 ml/µl O2). Thus a significant portion of exercise-induced coronary responses after alpha -adrenergic receptor blockade involves NO formation.

endothelium; metabolism; oxygen; adrenergic receptors; coronary sinus


    INTRODUCTION
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

DURING EXERCISE, THE BALANCE between coronary blood flow (CBF) and myocardial oxygen consumption (MVO2) is finely tuned through local metabolic feedback mechanisms (6), over which alpha -adrenergic constriction and feedforward beta -adrenergic dilation are superimposed (7). Together, these factors lead to a relative mismatch between myocardial perfusion and metabolic demand displayed as a decrease in coronary sinus (CS) blood O2 levels in the face of increases in MVO2 (2, 9-11, 19). Nitric oxide (NO) production, which is increased during exercise (3, 23), has been considered as a factor that contributes to maintain the equilibrium between myocardial O2 supply and demand. While NO production plays a major role in the dilation of large epicardial conductance arteries during exercise (27), its contribution to vasomotor responses of resistance coronary vessels has been reported to be minimal (1, 3, 25). In fact, arginine analogues had only a limited influence on the slope of the relationship between Cs O2 tension and MVO2, an index of the match between coronary perfusion and MVO2 (1, 3, 25). Conceivably, the loss of NO formation may trigger compensatory mechanisms, which can impair a further decrease in CS O2 tension (13, 14). The possibility that adenosine production becomes more important after the blockade of NO formation has been recently ruled out (25).

On the basis of our earlier studies (15, 20) showing that coronary beta -adrenergic dilation of resistance coronary vessels in conscious dogs involves NO formation, we hypothesized that exercise performed after alpha -adrenergic receptor blockade may involve a greater contribution of NO triggered directly through enhanced beta -adrenergic receptor activation or indirectly through hemodynamic effects of alpha -adrenergic receptor blockade. The contribution of NO formation was assessed as differences of the slopes of relationships between CS O2 saturation levels or CBF and MVO2 after alpha -adrenergic blockade alone and after the combined blockade of alpha -adrenergic receptors and NO formation in exercising dogs.


    METHODS
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

Instrumentation. After general anesthesia with pentobarbital sodium (30 mg/kg iv) and under sterile conditions and artificial ventilation, eight mongrel dogs (33 ± 1 kg) were instrumented and treated postoperatively as previously described (22). CBF was measured with an implanted flow probe around the circumflex coronary artery and a pulsed-Doppler flowmeter (22). After death, the cross-sectional area of the vessel under the probe was measured and the perfusion territory of the circumflex artery was determined by dye perfusion (CBF is reported as ml · min-1 · g-1 of tissue).

Protocols. Experiments were initiated 2-4 wk after surgery. While the dogs were standing quietly on a treadmill, blood samples were simultaneously withdrawn from the aortic and the CS catheters. Measurements of hemoglobin (Hb) content and O2 saturation were made on a cooxymeter (model OSM-2, Radiometer; Copenhagen, Denmark) immediately after 1 ml of blood was collected in lightly heparinized syringes and sealed after sampling.

Dogs ran successively for 3 min at 3 miles/h (0% grade), 4 miles/h (5% grade), and 6 miles/h (10% grade). Blood samples were obtained 2.5-3.0 min after the beginning of each step under steady-state conditions. One hour after the first run, 1.5 mg/kg of phentolamine was administered intravenously, and the dogs were immediately placed on the treadmill to perform the exercise protocol. Adequacy of alpha -adrenergic blockade was demonstrated in preliminary experiments (n = 5). Mean arterial pressure (MAP) responses (24 ± 1 from 93 ± 5 mmHg) caused by 3.0 µg/kg iv phenylephrine (Sabex; Boucherville, Quebec, Canada) were blunted (P < 0.01) after phentolamine (-2 ± 1 from 93 ± 4 mmHg).

On different days, the exercise protocol was performed after Nomega -nitro-L-arginine methyl ester (L-NAME; 10 mg/kg iv) was given over 10 min. Adequacy of NO formation blockade with this dose of L-NAME has been demonstrated earlier (21) and confirmed in preliminary experiments (n = 5) by smaller (P < 0.01) acetylcholine chloride-induced (3 µg/kg iv) CBF increases after L-NAME (67 ± 15 from 61 ± 7 ml/min) than before (121 ± 13 from 61 ± 7 ml/min).

The exercise protocol was repeated at least 48 h later after combined administration of phentolamine + L-NAME or propranolol (1.0 mg/kg iv) + phentolamine. All drugs except for phenylephrine were obtained from Sigma (St. Louis, MO). Except for one animal, in which the L-NAME alone protocol could not be completed, all other experiments were carried out in the same eight dogs.

Data analysis. Data are reported as means ± SE and statistical significance was reached when P < 0.05 in all cases. An analysis of variance for repeated measurements was used for simultaneous overall comparisons of baseline hemodynamic variables under the five experimental conditions (28). Post hoc comparisons were made with the Newman-Keuls test to isolate contrasts of interest. Overall responses to exercise before and after L-NAME were compared using a two-way analysis of variance for repeated measurements. A similar approach was used to simultaneously compare phentolamine alone versus phentolamine + L-NAME and propranolol + phentolamine. Data for CBF and CS O2 saturation were reported as relationships centered on corresponding mean MVO2 levels for each exercise level. A one-way analysis of variance was first performed to determine if the dependent variable was altered during exercise and a two-way analysis of variance was used to compare the effects of the various treatments. A linear regression analysis was then performed for each animal after each drug, followed by an analysis of variance for repeated measurements on slopes or a paired Student's t-test when only two experimental conditions were compared. Because CS O2 saturation failed to decrease as MVO2 increased after phentolamine alone (one-way analysis of variance), a relationship between CS O2 saturation and MVO2 could not be demonstrated (slope not different from 0). Therefore, control or treatments were considered statistically different from phentolamine when the slopes differed from zero.

All experimental procedures were approved by an ethical committee on animal care and performed in accordance with Guide to the Care and Use of Experimental Animals (Canadian Council on Animal Care, Publication No. 0-919087-18-3, Ottawa, Ontario, Canada, 1993).


    RESULTS
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

Baseline hemodynamics. Baseline hemodynamic variables for all experimental groups are reported in Table 1. Except for the expected increases (P < 0.01) in left ventricular pressure (LVP) and MAP and decreases (P < 0.01) in heart rate, L-NAME had no other significant effects. A similar response pattern was observed when L-NAME + phentolamine was compared with phentolamine alone. Propranolol + phentolamine caused no further hemodynamic effects compared with phentolamine alone, except for a significant decrease (P < 0.01) in the LV first derivative of pressure development over time (dP/dt), as reported in Table 1.

                              
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  		Table 1.   Baseline hemodynamic variables before and after L-NAME and after phentolamine alone or combined with L-NAME or propranolol

Blockade of NO formation. As reported in Fig. 1, LVP and MAP were higher (P < 0.01) and LV dP/dt was lower (P < 0.01) throughout exercise in dogs treated with L-NAME. Heart rate, aortic blood O2 saturation, and Hb levels did not significantly differ before and after L-NAME.


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  		Fig. 1.   Means ± SE left ventricular pressure (LVP), first derivative of LVP over time (LV dP/dt), mean arterial pressure (MAP), heart rate, aortic blood O2 saturation, and hemoglobin (Hb) before and after Nomega -nitro-L-arginine methyl ester (L-NAME). Variables are reported at control (standing) and at each step of a graded exercise protocol in the same seven dogs. dagger P < 0.01, different from control.

The graded exercise protocol led to the expected increases (P < 0.01) in CBF as MVO2 augmented (Fig. 2). Mean CBF levels achieved during exercise did not statistically differ before and after L-NAME. The slopes of the relationships between CBF and MVO2 did not differ before (5.0 ± 0.1 × 10-3 ml/µl O2) and after L-NAME (4.9 ± 0.2 × 10-3 ml/µl O2). CS O2 saturation fell significantly (P < 0.01) as MVO2 increased under control conditions and after L-NAME. Overall, mean CS O2 saturation levels did not significantly differ during exercise performed before and after L-NAME. However, the slope of the relationships between CS O2 saturation levels and MVO2 was steeper (P < 0.05) after L-NAME (-2.9 ± 0.4 × 10-2 %saturation · µl O2 · min-1 · g-1) than before (-2.1 ± 0.3 × 10-2 %saturation · µl O2 · min-1 · g-1). Thus, for any given increase in MVO2, CS O2 saturation fell more after L-NAME, consistent with a greater mismatch between myocardial O2 demand and supply.


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  		Fig. 2.   Relationships between coronary blood flow (CBF; top) or coronary sinus O2 saturation (bottom) and myocardial O2 consumption (MVO2) before and after L-NAME in the same seven dogs. *P < 0.05, slope different from control.

Blockade of alpha -adrenergic receptors. Coronary responses involving metabolic and beta -adrenergic dilation (after phentolamine) and metabolic dilation alone (after propranolol + phentolamine) were compared to demonstrate the involvement of beta -adrenergic influences after alpha -adrenergic receptor blockade.

Phentolamine prevented the fall (P < 0.01) in CS O2 saturation observed under control exercise and resulted in higher (P < 0.05) mean CBF levels, as reported in Fig. 3. Further blockade of beta -adrenergic receptors with propranolol resulted in a substantial fall (P < 0.01) in CS O2 saturation levels during exercise. As expected, increases in CBF throughout exercise were smaller (P < 0.01) after the combined blockade of alpha - and beta -adrenergic receptors than after alpha -adrenergic receptor blockade alone.


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  		Fig. 3.   Relationships between CBF (top) or coronary sinus O2 saturation (bottom) and MVO2 under control conditions, after phentolamine alone, propranolol + phentolamine, and L-NAME + phentolamine in the same eight dogs. dagger P < 0.01, slope different from phentolamine alone.

After phentolamine + propranolol, CS O2 saturation fell significantly (P < 0.01) as MVO2 increased (slope = -5.3 ± 1.0 × 10-2 %saturation · µl O2 ·min-1 · g-1). In contrast, CS O2 saturation failed to decrease throughout exercise performed after phentolamine alone (slope = -0.1 ± 0.5 × 10-2 %saturation · µl O2 · min-1 · g-1) (Fig. 3). Consistent with these findings, the slope of the relationship between CBF and MVO2 was steeper (P < 0.01) after phentolamine (6.9 ± 0.2 × 10-3 ml/µl O2) than after propranolol + phentolamine (5.0 ± 0.2 × 10-3 ml/µl O2) or under control conditions (4.9 ± 0.1 × 10-3 ml/µl O2). Thus lifting alpha -adrenergic constriction led to a better match between cardiac metabolic demand and O2 delivery as MVO2 increased during exercise. After alpha -adrenergic receptor blockade, beta -adrenergic receptor activation was an important determinant of coronary dilator responses.

Combined blockade of alpha -adrenergic receptors and NO formation. L-NAME + phentolamine lead to augmented LVP (P < 0.05) and MAP (P < 0.01) levels throughout exercise compared with phentolamine alone but did not influence other hemodynamic variables as reported in Fig. 4. After the combined administration of propranolol + phentolamine, LVP (P < 0.05), LV dP/dt (P < 0.01), and heart rate (P < 0.01) remained lower than after phentolamine alone.


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  		Fig. 4.   Means ± SE, LVP, LV dP/dt, MAP, heart rate, aortic O2 saturation, and Hb after phentolamine, phentolamine + L-NAME, and propranolol + phentolamine in the same eight dogs. Variables are reported at control (standing) and at each step of a graded exercise protocol. *P < 0.05, different from phentolamine alone; dagger P < 0.01, different from phentolamine alone.

Exercise performed after phentolamine + L-NAME resulted in substantial decreases (P < 0.01) in CS O2 saturation levels, not displayed after phentolamine alone (Fig. 3). Propranolol + phentolamine also led to significant decreases (P < 0.01) in CS O2 saturation.

A significant (P < 0.01) relationship between CS O2 saturation levels and MVO2 was found after phentolamine + L-NAME (slope= -2.1 ± 0.4 × 10-2 %saturation · µl O2 · min-1 · g-1) but not after phentolamine alone, as indicated earlier. Thus, for any given increase in MVO2, CS O2 saturation fell more (P < 0.01) after phentolamine + L-NAME than after phentolamine alone, consistent with the involvement of NO in coronary dilation displayed after alpha -adrenergic receptor blockade. NO accounted for ~45% of the differences in slopes between phentolamine alone and phentolamine + propranolol.

The slope of the relationship between CBF and MVO2 after phentolamine (6.9 ± 0.2 × 10-3 ml/µl O2) was decreased (P < 0.01) by the addition of L-NAME (6.1 ± 0.1 × 10-3 ml/µl O2). Thus, for any given increase in MVO2, CBF increased less (P < 0.01) after phentolamine + L-NAME than after phentolamine alone, consistent with the involvement of NO formation to the dilation of coronary resistance vessels after alpha -adrenergic receptor blockade.

The steeper (P < 0.01) slope of the relationship between CBF and MVO2 after phentolamine + L-NAME (6.1 ± 0.1 × 10-3 ml/µl O2) than under control conditions (4.9 ± 0.1 × 10-3 ml/µl O2) is indicative of alpha -adrenergic vasoconstriction. Changes in the slope of the relationship between CS O2 saturation and MVO2 caused by phentolamine + L-NAME (-2.1 ± 0.4 × 10-2 %sauration · µl O2 · min-1 · g-1) from control conditions (-2.9 ± 0.8 × 10-2 %saturation · µl O2 ·min-1 · g-1) were directionally consistent with alpha -adrenergic influences but statistical significance was not reached.


    DISCUSSION
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

The present study highlights the significant contribution of NO to exercise-induced coronary dilation after alpha -adrenergic receptor blockade. We have relied on a strategy allowing, by pharmacological means, to exclude alpha -adrenergic constriction and to specifically examine dilator mechanisms contributing to exercise-induced coronary responses thereafter. Our data demonstrate that NO, in addition to beta -adrenergic effects, is pivotal in causing coronary dilation during exercise performed under alpha -adrenergic receptor blockade. Together, these mechanisms help to ensure a closer match between myocardial O2 demand and supply.

One important limitation should be kept in mind when considering the present data. By lifting the inhibitory activity of alpha -adrenergic receptors on norepinephrine release, phentolamine will cause an exaggerated beta -adrenergic activation. Consequently, experiments conducted under alpha -adrenergic blockade cannot allow a direct quantitative assessment of beta -adrenergic-induced coronary dilation taking place during normal exercise although under normal conditions, interstitial norepinephrine levels are well above the threshold for causing coronary beta -adrenergic dilation (8).

During exercise, the level of CBF is determined through several mechanisms, including local vasodilator effects coupled to increases in cardiac metabolism over which are superimposed alpha -adrenergic constriction and beta -adrenergic dilation (7). Acting in concert, these factors are responsible for determining the subtle equilibrium between O2 demand and supply reflected by the relationship between CS O2 levels and MVO2. Under normal exercise conditions, a relative mismatch exists between O2 demand and supply displayed as a reduction of coronary venous O2 levels in the face of increases in MVO2 (2, 7, 9-11, 19). Local feedback mechanisms coupled to cardiac metabolism are considered to be the major determinants of CBF (6). The error signal generated through this process cannot, however, completely ensure an adequate match between myocardial perfusion and metabolic demand. Coronary venous O2 tension has been reported to fall as MVO2 was increased by pacing-induced tachycardia + paired-pace stimulation (16). A similar phenomenon occurs during exercise performed only under local metabolic control (after alpha - and beta -adrenergic blockade), i.e., CS O2 level declines as MVO2 increases (7).

Our data concerning the effects of blockade of NO formation (without prior blockade of alpha -adrenergic receptors) on the relationship between coronary venous blood O2 saturation and MVO2 during exercise slightly differed from earlier studies. Altman et al. (1) and Tune et al. (25) reported that blockade of NO formation caused a parallel shift in the relationships between CS blood PO2 and MVO2, consistent with a slight contribution of NO of similar magnitude under baseline condition and during exercise. Bernstein et al. (3) also reported a parallel shift in the relationship between CS blood PO2 and MVO2, although limited to the lower levels of MVO2 during exercise. Interestingly, none of these studies observed that blockade of NO formation caused a significant reduction of CBF as MVO2 increased during exercise. Thus NO was not essential for the coronary dilation during exercise. In that respect, our data are consistent with these earlier studies because the slopes of relationships between CBF and MVO2 were similar before and after L-NAME. In contrast, the slope of the relationship between CS O2 saturation and MVO2 was slightly steeper after L-NAME than before in our study. This suggests that NO may help to better match CBF to cardiac metabolic demand at higher levels of MVO2. In this connection, it is of interest to note that nitrite and nitrate production across the coronary bed has been reported to increase at the highest exercise intensities (3, 23). Given the limited consequences of the blockade of NO formation on the match between myocardial O2 demand and CBF reported by us and by others, we have to acknowledge that NO could only play a limited role during exercise under normal conditions. This conclusion ignores other important effects of NO, which uncouples mitochondrial oxidative phosphorylation and alters substrate utilization by the heart (24). By targeting those mechanisms, the blockade of NO formation could have conceivably modified the relationship between myocardial perfusion and cardiac metabolism.

Several earlier studies (2, 7, 9-11, 19) have demonstrated that alpha -adrenergic influences limit CBF during exercise by showing higher CS O2 levels at any given level of MVO2 after pharmacological blockade of these receptors. Therefore, alpha -adrenergic constriction competes with metabolically induced coronary dilation and limits coronary perfusion (17).

In this context, beta -adrenergic dilation during exercise may serve to add to local metabolic feedback and limit the consequences of alpha -adrenergic constriction on the match between coronary perfusion and MVO2. Miyashiro and Feigl (16) first provided evidence supporting the existence of feedforward beta -adrenergic dilation in the coronary circulation. They showed that norepinephrine administration after alpha -adrenergic blockade, which unmasks beta -adrenergic effects, caused significant coronary dilation and prevented the fall in CS O2 levels. During exercise, a similar phenomenon takes place. Feedforward beta -adrenergic dilation can be demonstrated on the basis of an altered relationship between CS O2 levels and MVO2. As MVO2 increased during exercise, CS O2 levels were disproportionately higher when beta -adrenergic effects and local metabolic feedback intervened, i.e., after phentolamine, than when local metabolic feedback alone accounted for coronary dilation, i.e., after propranolol + phentolamine (7). Our data agree with those of Gorman et al. (7), who demonstrated the contribution of feedforward beta -adrenergic dilation to coronary responses caused by exercise in dogs. On the basis of a quantitative model allowing calculations of interstitial norepinephrine concentration during exercise, they estimated the contribution of feedforward beta -adrenergic dilation to overall CBF response to exercise to be ~25% (8). This phenomenon allows for a better match between CBF and cardiac metabolism during exercise. The relative contribution of feedforward beta -adrenergic activation to coronary dilation may show substantial interspecies differences. In contrast to dogs, swine display minimal alpha -adrenergic constriction during exercise, thereby allowing the contribution of feedforward beta -adrenergic dilation to exercise-induced coronary responses to become more apparent, as demonstrated by Duncker et al. (5).

In the present study, we measured CS O2 saturation levels as an index of the match between myocardial O2 supply and demand, whereas Gorman et al. (7) used CS O2 tension as an index of tissue O2 level to achieve the same objective. In the present study, the shifts of the slopes of the relationships between CS O2 saturation and MVO2 caused by phentolamine and phentolamine + propranolol were qualitatively similar to those reported by Gorman et al. (7). In fact, absolute values of slopes in both studies were very close under the various experimental conditions. This indicates that the slope of the relationship between O2 tension and saturation was close to unity over the narrow range of O2 levels measured in CS blood. Therefore, the potential bias created by measuring O2 saturation levels in the present experiments could only have been limited.

As MVO2 increased during exercise, CS O2 saturation fell after phentolamine + L-NAME but did not after phentolamine alone. Consequently, the relationship between CS O2 saturation and MVO2 had a negative slope after phentolamine + L-NAME but not after phentolamine alone. In this situation, the slope of the relationship between CBF and MVO2 was steeper after phentolamine alone than after L-NAME + phentolamine, i.e., for any given increase in MVO2 during exercise, CBF increased more after phentolamine alone than after L-NAME + phentolamine. Thus NO formation played a significant role in exercise-induced coronary dilation after alpha -adrenergic receptor blockade. NO helped to maintain a better match between myocardial perfusion and cardiac metabolic demand. The contribution of NO became more important as exercise intensity increased because the differences in CS O2 saturation between phentolamine alone and phentolamine + L-NAME widened as MVO2 increased.

Our data indicate that after alpha -adrenergic receptor blockade, NO was an important determinant of the balance between myocardial O2 supply and demand. This raises an important question. What is the mechanism triggering NO formation after alpha -adrenergic receptor blockade? A receptor-operated process involving beta -adrenergic receptors may trigger NO formation, as suggested by our earlier studies (15, 20). It is also possible that augmented NO production may be a consequence of hemodynamic conditions created by the blockade of alpha -adrenergic receptors, in particular a flow-dependent phenomenon caused by elevated CBF after phentolamine. If beta -adrenergic activation directly triggered NO formation, L-NAME should have produced consistent shifts in the slopes of the relationship between CS O2 saturation or CBF and MVO2 with and without phentolamine. Our data do not support this hypothesis. Given that blockade of NO formation had disproportionately greater effects after phentolamine than before, NO production cannot be directly linked to beta -adrenergic receptor activation because this process should be operative in both situations. An alternate mechanism has to be involved. The hemodynamic conditions created after the blockade of alpha -adrenergic receptors most likely account for NO production after phentolamine. Consistent with this possibility, CBF increased more for any given increase in MVO2 after phentolamine than under control conditions. This relative excess in CBF may be the trigger of NO formation by augmenting shear stress levels in the microcirculation (12). This hypothesis agrees with the observation that NO formation caused by intracoronary boluses of norepinephrine was primarily a flow-dependent process (26). A further increase of CBF caused by norepinephrine given after phentolamine would be expected to magnify this phenomenon. Rate-dependent effects and changes in pulsatility have been reported to trigger NO formation in large epicardial coronary arteries (4). Within the coronary microcirculation, Morita et al. (18) showed that alpha -adrenergic blockade increased norepinephrine-induced retrograde systolic flow, thereby causing greater to-and-fro flow oscillation. These changes in the pulsatile pattern of CBF caused by phentolamine in concert with higher heart rates achieved after alpha -adrenergic receptor blockade could most likely act as the trigger for NO formation. This may explain why NO-dependent effects were more important after alpha -adrenergic receptor blockade and minimally displayed under control conditions.

Differences in slopes of CS O2 saturation levels versus MVO2 between phentolamine alone and phentolamine + propranolol have been used to demonstrate the contribution of feedforward beta -adrenergic dilation to exercise-induced coronary responses (7). The present experiments bring new insight into the interpretation of data obtained after phentolamine. beta -Adrenergic and metabolic signals were not the sole determinants of coronary perfusion in that situation, as a significant contribution of NO formation was apparent after phentolamine.

In conclusion, NO-dependent effects account for a substantial portion of exercise-induced coronary dilation after alpha -adrenergic receptor blockade. In contrast, NO played a minor role under control conditions. This apparent discrepancy may be explained by the disproportionate increases in CBF along with increases of to-and-fro flow oscillation after alpha -adrenergic blockade, which may act as the trigger for NO formation. NO formation after alpha -adrenergic receptor blockade was pivotal in maintaining a better match between cardiac metabolic demand and O2 supply.


    ACKNOWLEDGEMENTS

The authors thank Claude Mousseau, Jhésabelle Voyer, and Claudy Patry for expert technical assistance.


    FOOTNOTES

This study was supported by grants from the Medical Research Council of Canada, the Canadian Heart and Stroke Foundation, and Fonds de la Recherche de l'Institut de Cardiologie de Montréal. M. Takamura was supported by a grant from the Groupe de Recherche sur le Système Nerveux Autonome.

Address for reprint requests and other correspondence: M. Lavallée, Institut de Cardiologie de Montréal, 5000 E. Bélanger St., Montréal, Québec, Canada H1T 1C8 (E-mail: lavallem{at}icm.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.

10.1152/ajpheart.00722.2001

Received 13 August 2001; accepted in final form 10 October 2001.


    REFERENCES
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

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6.   Feigl, EO. Coronary physiology. Physiol Rev 63: 1-205, 1983.

7.   Gorman, MW, Tune JD, Richmond KN, and Feigl EO. Feedforward sympathetic coronary vasodilation in exercising dogs. J Appl Physiol 89: 1892-1902, 2000.

8.   Gorman, MW, Tune JD, Richmond KN, and Feigl EO. Quantitative analysis of feedforward sympathetic coronary vasodilation in exercising dogs. J Appl Physiol 89: 1903-1911, 2000.

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Am J Physiol Heart Circ Physiol 282(2):H508-H515
0363-6135/02 $5.00 Copyright © 2002 the American Physiological Society


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