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J Appl Physiol 89: 2041-2048, 2000;
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Vol. 89, Issue 5, 2041-2048, November 2000

Influence of dual ETA/ETB-receptor blockade on coronary responses to treadmill exercise in dogs

Masayuki Takamura, Robert Parent, Peter Cernacek1, and Michel Lavallée2

Departments of 1 Medicine and 2 Physiology, Institut de Cardiologie de Montréal, Faculty of Medicine, Université de Montréal, Montréal, Québec, Canada H1T 1C8


    ABSTRACT
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

We hypothesized that endothelin (ET) release during exercise may be triggered by alpha -adrenergic-receptor activation and thereby influence coronary hemodynamics and O2 metabolism in dogs. Exercise resulted in coronary blood flow increases (to 1.88 ± 0.26 from 1.10 ± 0.12 ml · min-1 · g-1) and in a fall (P < 0.01) in coronary sinus O2 saturation (17.4 ± 1.5 to 9.6 ± 0.7 vol%), whereas myocardial O2 consumption (MVO2) increased (109 ± 13% from 145 ± 16 µl O2 · min-1 · g-1). Tezosentan, a dual ETA/ETB-receptor blocker, slightly reduced mean arterial pressure (MAP) and increased heart rate throughout exercise. The relationship between coronary sinus O2 saturation and MVO2 was shifted upward (P < 0.05) after tezosentan administration; i.e., as MVO2 increased during exercise, coronary sinus O2 saturation was disproportionately higher after ET-receptor blockade. After propranolol, tezosentan resulted in significant decreases (P < 0.05) in left ventricular pressure, the first derivative of left ventricular pressure over time, and MAP during exercise. As MVO2 increased during exercise, coronary sinus O2 saturation levels after tezosentan became superimposable over those observed before ET-receptor blockade. Thus dual blockade of ETA/ETB receptors alters coronary hemodynamics and O2 metabolism during exercise, but ET activity failed to increase beyond baseline levels.

coronary blood flow; myocardial oxygen consumption; cardiac endothelin production


    INTRODUCTION
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

PLASMA IMMUNOREACTIVE endothelin-1 (irET-1) levels are augmented by exercise in rats (19) and humans (1, 18, 21, 22, 25), whereas cardiac prepro ET-1 mRNA and ET-1 peptide levels (20) are markedly higher in rats undergoing a 4-wk exercise training program. The hemodynamic consequences of these increases in ET activity in general and on the coronary circulation in particular are still unclear. ET has significant influence on the baseline caliber of large epicardial coronary arteries, which dilate after ETA-receptor blockade (30). In contrast, coronary blood flow (CBF) is little influenced by the blockade of ET receptors in conscious (30) and anesthetized dogs (28). ET has an apparently greater influence on the systemic circulation, especially after the blockade of nitric oxide (NO) formation. Blood pressure increases caused by arginine analogs are reversed by ET-receptor blockade (10, 27, 29). Conceivably, an inhibitory influence of the NO-cGMP pathway on ET production and/or action may explain this phenomenon (3, 17). In this connection, NO-dependent dilator responses of resistance and conductance coronary vessels are partially restored by ETA-receptor blockade after the administration of an arginine analog to prevent NO formation (24, 26). Together, these data indicate that ET may have significant influence on systemic and coronary vessels, in particular when NO formation is impaired.

It has been recently reported that ET-receptor blockade prevents alpha -adrenergic constriction of arteriolar vessels in vivo (7). Myocytes, which contain an abundant population of alpha -adrenergic receptors, accounted for ET production (31). Given that, during exercise, alpha 1-adrenergic-receptor activation limits CBF responses, thereby leading to a decrease in coronary sinus O2 saturation (2, 11, 14), we hypothesized that ET release during exercise may be triggered by alpha -adrenergic-receptor activation. ET may also indirectly influence coronary responses by sensitizing vascular smooth muscles to alpha -adrenergic vasoconstrictor influences (13, 34). Our first objective was to determine the effects of ET-receptor blockade on coronary hemodynamics and O2 metabolism in exercising dogs. Our second objective was to determine if exercise triggers cardiac ET-1 production, as assessed by plasma ET-1 levels in the heart.


    MATERIALS AND METHODS
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

Instrumentation. After general anesthesia with pentobarbital sodium (30 mg/kg iv) and under sterile conditions, mongrel dogs (32 ± 1 kg), under artificial ventilation, underwent a left thoracotomy at the fifth intercostal space. The pericardium was widely incised parallel to the phrenic nerve. A Tygon (Norton Plastics and Synthetic Division, Akron, OH) catheter was implanted in the thoracic aorta and connected to an external transducer (model 800, Bentley Trantec, Irvine, CA) to measure arterial pressure. Mean arterial pressure (MAP) was obtained with an active filter with a time constant of 2 s. Through an apical stab wound, a solid-state pressure transducer (model P6.5, Konigsberg Instruments, Pasadena, CA) was inserted in the left ventricular (LV) cavity to measure left ventricular pressure (LVP) and to obtain the first derivative of LVP over time (LV dP/dt). A catheter was also implanted in the LV cavity and used to repeatedly cross-calibrate the miniature pressure gauge to eliminate any drift of the instrument. A cardiotachometer (model 9857, Sensor Medics, Anaheim, CA) triggered by the LVP pulse was used to monitor heart rate (HR). An ultrasonic Doppler blood flow transducer was placed around the circumflex coronary artery, 1-2 cm from the bifurcation of the left main coronary artery. CBF was monitored using a 10 MHz-pulsed Doppler flowmeter (12). Mean CBF was obtained with an active filter with a time constant of 2 s. A Silastic (Dow Corning, Midland, MI) catheter was implanted in the coronary sinus. The tip of the catheter was at least 1 cm away from the coronary sinus ostium. The pericardium was loosely closed, the chest was closed in layers, and the catheters and wires were exteriorized on the back of the animals. Analgesia was provided postoperatively with 0.3 mg im buprenorphine (Temgesic, Reckitt, and Colman Pharmaceuticals, Hull, UK). Prophylactic procaine penicillin G (300,000 units im) and benzathine penicillin G (300,000 units im) were administered for 10 days after the surgery.

Hemodynamic variables were recorded on a VHS tape using a PCM recording adaptor (model 4000A, AR Vetter, Rebersburg, PA) and monitored on a direct ink-writing strip-chart recorder (model 2800s, Gould, Cleveland, OH).

Protocols. Experiments were initiated 2-4 wk after surgery in conscious, healthy dogs. While the dogs were standing quietly on a treadmill, hemodynamic variables were continuously monitored until a steady state was reached. At that time, blood samples were simultaneously withdrawn from the aortic and the coronary sinus catheters. Three-milliliter blood samples were immediately placed on ice into chilled tubes containing EGTA for later ET-1 determinations. Blood samples were centrifuged at 3,000 rpm and 3°C, and the plasma was collected and stored at -70°C until the day of the assay. ET-1 was measured with a sensitive and specific radioimmunoassay after extraction and purification of samples on Sep-Pak C18 cartridges (Waters, Milford, MA), as previously described (4). Measurements of Hb content and O2 saturation were made immediately after the collection of 1 ml of blood in lightly heparinized syringes, sealed after sampling. A co-oximeter (OSM-2, Radiometer, Copenhagen, Denmark) was used to perform these analyses.

Dogs ran successively at 3 miles/h (mph; 0% grade), 4 mph (5% grade), and 5 mph (5% grade) during 5 min at each step. Blood samples for Hb content and O2 saturation measurements were obtained under steady-state conditions, i.e., 3.5-4.5 min after the beginning of each exercise step. Blood samples for ET-1 determinations were obtained at baseline and at 5 mph. After the completion of the first run and after 1 h of rest, 2.0 mg/kg of tezosentan [6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-(2-1H-tetrazol-5-yl-pyridin-4-yl)-pyrimidin-4-ylamide], an ETA/ETB-receptor blocker (5), was administered intravenously over a 10-min period, followed by 0.05 mg · kg-1 · min-1 throughout the exercise period. Adequacy of ET-receptor blockade was assessed in preliminary experiments (n = 4) against an intracoronary bolus injection of 0.2 µg of ET-1 (American Peptide, Sunnyvale, CA). Ten minutes after the completion of tezosentan administration, the exercise protocol was repeated.

On a separate day, dogs were pretreated with 1.0 mg/kg iv of propranolol (Sigma Chemical, St. Louis, MO) before performing the exercise protocol. After a 1-h rest period after completion of the first run, an additional dose of propranolol (0.5 mg/kg iv) was administered, followed by tezosentan as described above, and the exercise protocol was repeated.

After completion of the experiments, animals were killed with an overdose of pentobarbital sodium and hearts were excised and placed on a pressurized dual-perfusion apparatus to determine the size (in grams) of the perfusion territory of the circumflex coronary artery. The internal circumference of the vessel under the probe was measured to obtain the vessel cross-sectional area and to calculate a calibration factor (in ml · min-1 · kHz-1). The position of the coronary sinus catheter was confirmed.

Data analysis. Data are reported as means ± SE. Data were read directly from the strip charts under baseline conditions while the dogs were standing on the treadmill and when a steady state was reached, at each step of the exercise protocol. An ANOVA for repeated measurements was used for simultaneous overall comparisons of responses before and after tezosentan (33). Blood O2 content was determined from the measurements of Hb concentration and O2 saturation with the following equation: O2 content = Hb concentration × percent O2 saturation × Hb O2 binding coefficient (1.34). Myocardial O2 consumption (MVO2) is the difference between aorta and coronary sinus O2 content multiplied by CBF (in ml · min-1 · g of tissue-1). The triple product is LV systolic pressure × peak LV dP/dt × HR. Paired t-tests were used to compare exercise and baseline irET-1 levels. Myocardial ET production/extraction was obtained from coronary sinus - aortic plasma irET-1 concentrations × CBF (in ml · min-1 · g of tissue-1). Comparisons of relationships between MVO2 and coronary sinus O2 saturation were made with analysis of covariance for repeated measurements. Statistical significance was reached at P < 0.05 in all cases.

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


    RESULTS
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

Control conditions. The graded exercise protocol caused the expected increases in CBF, HR, MAP, LVP and LV dP/dt, as reported in Table 1 and illustrated in Fig. 1. Coronary sinus O2 saturation and content fell (P < 0.01) throughout the exercise protocol, consistent with a mismatch between myocardial O2 demand and supply, as reported in Fig. 2. There was no irET-1 plasma gradient between the coronary sinus and the aorta under baseline conditions (Table 2). During exercise, coronary sinus and aortic plasma irET-1 levels failed to increase significantly. No arteriovenous irET-1 plasma gradient across the heart could be detected during exercise.

                              
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  		Table 1.   Hemodynamic responses to exercise before and after tezosentan administration



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  		Fig. 1.   Recording of left ventricular pressure (LVP) and its first derivative over time (LV dP/dt), mean arterial pressure (MAP), phasic (~) and mean (-) coronary blood flow (CBF), and mean heart rate (<OVL>HR</OVL>) before exercise and at 5 miles/h (mph). Responses before (left) and after (right) intravenous tezosentan administration are displayed.



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  		Fig. 2.   Coronary sinus O2 saturation and content, aortic O2 content, and CBF before and during exercise under control conditions and after tezosentan in 7 dogs. Overall, blockade of endothelin (ET) receptors with tezosentan significantly increased coronary sinus O2 saturation and content during exercise.


                              
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  		Table 2.   Aortic and coronary sinus plasma ET-1 concentration during exercise before and after tezosentan administration

In preliminary experiments (n = 4), adequacy of ET-receptor blockade with tezosentan was demonstrated by preventing the fall in CBF (25 ± 3% vs -2 ± 1%) caused by intracoronary ET-1 (0.2 µg).

Except for a significant decrease (P < 0.01) in MAP and an increase (P < 0.05) in HR, tezosentan had limited effects on the hemodynamic responses triggered by treadmill exercise, as reported in Table 1. CBF responses were not altered after tezosentan. The triple product, an estimate of cardiac metabolic demand, did not significantly differ during exercise performed before and after tezosentan. Overall, coronary sinus O2 saturation and content were significantly higher (P < 0.01) during exercise performed after tezosentan than under control conditions (Fig. 2). Aortic blood O2 content (Fig. 2) and Hb levels (Table 1) increased during exercise but to a similar extent before and after tezosentan. The relationship between MVO2 and coronary sinus O2 saturation was significantly (P < 0.05) shifted upward after tezosentan administration; i.e., as MVO2 increased, coronary sinus O2 saturation was disproportionately higher after ET-receptor blockade than before (Fig. 3). However, a parallel shift in these relationships would not be expected if ET activity had an increasingly greater influence during exercise. Both aortic and coronary sinus plasma irET-1 levels were dramatically increased (P < 0.01) after ETA/ETB-receptor blockade, but a net cardiac ET-1 production could not be demonstrated either under baseline conditions or during exercise (Table 2).


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  		Fig. 3.   Relationships between coronary sinus O2 saturation and myocardial O2 consumption before and during exercise under control conditions and after tezosentan administration in 7 dogs. As myocardial O2 consumption increased during exercise, coronary sinus O2 saturation was significantly higher after tezosentan.

beta -Adrenergic blockade. Propranolol resulted in substantial beta -adrenergic blockade, as indicated by the blunted LV dP/dt increases during exercise, which is reported in Table 3. As CBF increased during exercise, coronary sinus O2 saturation and content fell (Fig. 4). Baseline aortic and coronary sinus plasma irET-1 levels after beta -adrenergic blockade did not statistically differ from those observed under control conditions, and no arteriovenous irET-1 plasma gradient could be demonstrated (Table 2). A similar situation prevailed during exercise.

                              
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  		Table 3.   Hemodynamic responses to exercise before and after tezosentan in dogs treated with propranolol



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  		Fig. 4.   Coronary sinus O2 saturation and content, aortic O2 content, and CBF during exercise under beta -adrenergic-receptor blockade (propranolol) with and without tezosentan in 8 dogs. Overall, blockade of ET receptors with tezosentan significantly increased coronary sinus O2 saturation and content during exercise in dogs treated with propranolol.

Tezosentan had significant effects on hemodynamic responses triggered by exercise performed after beta -adrenergic-receptor blockade, as reported in Table 3. Overall, LVP, LV dP/dt, and MAP remained lower throughout exercise performed after tezosentan administration, but CBF was not significantly altered. As a consequence of these changes in the determinants of cardiac metabolic demand, the triple product and MVO2 were decreased during exercise performed after tezosentan (Table 3). In this situation, the coronary sinus O2 saturation and content were higher (P < 0.01) throughout exercise performed after tezosentan (Fig. 4). The relationship between coronary sinus O2 saturation and MVO2 was significantly altered after ET-receptor blockade (Fig. 5). These effects were most apparent at low MVO2 levels. As MVO2 increased during exercise, the coronary sinus O2 saturation levels before and after tezosentan were superimposable in dogs treated with propranolol. Consequently, the changes in coronary sinus O2 saturation levels observed during exercise after tezosentan were primarily related to an altered MVO2. Plasma irET-1 levels markedly increased (P < 0.01) after ETA/ETB-receptor blockade, but a net cardiac ET-1 production could not be demonstrated under baseline conditions. There was, however, a positive (P < 0.01) irET-1 plasma gradient across the heart during exercise, as reported in Table 2.


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  		Fig. 5.   Relationships between coronary sinus O2 saturation and myocardial O2 consumption during exercise under beta -adrenergic-receptor blockade (propranolol) with and without tezosentan in 8 dogs. As myocardial O2 consumption increased during exercise, coronary sinus O2 saturation levels became superimposable before and after tezosentan.


    DISCUSSION
TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

Our analyses reveal that blockade of ET receptors alters coronary vascular responses and cardiac oxygen metabolism during exercise. Under control conditions, blockade of ET receptors increased coronary sinus O2 saturation at all grades of exercise. The relationship between coronary sinus O2 saturation and MVO2 was shifted upward, but a change in slope was not apparent. If, as we hypothesized, ET-dependent activity increased during exercise, the difference in coronary sinus O2 saturation before and after ET-receptor blockade should widen as MVO2 increased. Because the amplitude of the effects of ET-receptor blockade on exercise-induced coronary responses was not augmented beyond the level displayed under baseline conditions, ET activity did not increase during exercise. Our measurements of plasma irET-1 levels agree with this conclusion. After beta -adrenergic and ET-receptor blockade, the higher coronary sinus O2 saturation levels during exercise were causally related to the fall in cardiac metabolic demand and the reduction in MVO2. Except for a baseline shift in the relationship between coronary sinus O2 saturation and MVO2, coronary sinus O2 saturation levels were superimposable before and after ET-receptor blockade, as MVO2 increased. Together, these data indicate that blockade of ET effects alters coronary responses to exercise primarily through baseline effects and through decreases in MVO2, particularly after beta -adrenergic-receptor blockade.

Recently, ET production in vivo has been demonstrated to be an essential intermediate in the constriction of canine coronary arterioles caused by alpha 1-adrenergic-receptor activation (7, 31). Blockade of ETA receptors or of the ET-converting enzyme with phosphoramidon blunted alpha -adrenergic constriction. These observations led us to hypothesize that alpha 1-adrenergic-receptor activation occurring during exercise may trigger ET production, which could in turn influence coronary hemodynamics. In this respect, the coronary response to exercise is characterized by an imbalance between CBF and cardiac metabolic demand reflected by a decrease in coronary sinus O2 saturation in the face of an elevated MVO2. Blockade of alpha 1-adrenergic receptors allows for a better match between CBF and MVO2 during exercise, thereby blunting the decreases in coronary sinus O2 saturation (2, 11, 14). If ET serves as an intermediate in alpha 1-adrenergic constriction, ET-receptor blockade would be expected to shift the relationship between MVO2 and coronary sinus O2 saturation, in particular at high MVO2 levels when coronary sinus O2 saturation is the lowest. This was clearly not the case in the present study; ET did not have an increasingly greater influence on coronary vessels during exercise. Consequently, ET-dependent effects could not have contributed to the fall in coronary sinus O2 saturation during exercise. Even after propranolol administration, to eliminate the potentially confounding influence of beta -adrenergic stimulation, an augmented ET influence of coronary vessels during exercise could not be demonstrated.

Subthreshold concentrations of ET have been shown to sensitize vascular smooth muscle cells to the action of vasoconstrictors (13, 34). In this situation, even slight changes in ET production could potentially lead to augmented alpha 1-adrenergic responses. Conceivably, this phenomenon could explain the shift in the relationship between coronary sinus O2 saturation and MVO2 observed after tezosentan, even if significant increases in plasma irET-1 levels could not be demonstrated. However, the effects of tezosentan on coronary sinus O2 saturation would be expected to be more important, as MVO2 and alpha -adrenergic influences augment during exercise. Our data after beta -adrenergic and ET-receptor blockade also rule out the possibility of an altered sensitivity of coronary vessels to alpha -adrenergic influences caused by ET during exercise.

We can only speculate as to why in the context of exercise a cross talk between alpha -adrenergic receptors and ET was not apparent, since alpha -adrenergic stimulation has been clearly shown to trigger ET formation in vivo (7). Conceivably, the involvement of ET in segmental arteriolar response to phenylephrine may not be indicative of the integrated microcirculatory response in the setting of exercise. It is also possible that an elevation of plasma ET production is a delayed phenomenon, as suggested by peak increases in ET several minutes after the termination of exercise in humans (18, 22). In that eventuality, the duration of our exercise protocol may not have allowed ET-dependent effects to fully develop. In the same connection, cardiac ET content was reported to increase in rats trained to perform a prolonged exercise protocol (20). Perhaps a more strenuous exercise protocol or chronic exercise could have allowed cardiac ET production to become apparent and thereby influence coronary hemodynamics.

Although not specifically examined during exercise in previous studies, ET metabolism is dominated by an avid pulmonary (8) and cardiac (9) extraction under baseline conditions in dogs, an ETB-receptor-coupled process. This feature of ET metabolism is highlighted in the present study by the dramatic increases in plasma ET levels observed after dual ETA/ETB-receptor blockade. Even in this situation in which the balance between production and extraction should be shifted toward production, a positive coronary sinus and/or aortic gradient could not be demonstrated after tezosentan alone. The reason why a net cardiac ET production was selectively displayed during exercise after combined beta -adrenergic and ETA/ETB-receptor blockade is not clear, given that our coronary hemodynamic data did not show significant ET-dependent influences after beta -adrenergic blockade alone.

We recognize the limitations of relying on plasma levels to assess ET activity because of its abluminal release (32) and its rapid clearance (8, 9) from the plasma. Nevertheless, our measurements of coronary hemodynamics and oxygen metabolism provide direct and supporting evidence for the conclusion that ET-dependent effects are not magnified during exercise and that ET activity does not directly contribute to the fall in coronary sinus O2 saturation.

Earlier studies have reported increases in plasma ET levels (1, 18, 19, 21, 22, 25) and in myocardial ET content (20) immediately after exercise in rats but did not investigate the hemodynamic consequences of these changes in ET activity. Aside from species differences and the fact that the sampling procedure was carried out in anesthetized rats, the influence of a training period lasting several weeks before ET measurements may have influenced ET levels (19, 20). In humans, both increases (1, 18, 21, 22, 25) and no changes (6, 16, 23) in irET-1 plasma levels have been reported during exercise. Conceivably, the site (arterial or venous) of sampling may have influenced the assessment of ET activity. In this connection, ET has been reported to be released by nonworking muscles during exercise, raising the possibility that ET may contribute to the redistribution of cardiac output during exercise (21). Although not directly addressed in the present study, this possibility could be consistent with the lower MAP throughout exercise after tezosentan despite the lack of a significant increase in arterial ET levels during exercise.

Conceivably, the failure to demonstrate augmented ET-dependent influences during exercise may reflect the involvement of counterregulatory influences, such as NO production. This hypothesis is consistent with the finding that blockade of NO formation reveals and/or magnifies baseline and stimulated ET-dependent effects in animals (10, 24, 26, 27, 29). In the same connection, in humans with coronary endothelial dysfunction, acetylcholine causes coronary vasoconstriction and triggers ET release, presumably because of an impairment of NO formation (16). On a speculative basis, elevated ET production associated with endothelial dysfunction may be causally related to the loss of the inhibitory influence of NO on ET activity. In that situation, ET production may become more important during exercise and have greater hemodynamic consequences.

In conclusion, blockade of ET receptors significantly alters myocardial O2 delivery during exercise, as indicated by the higher coronary sinus O2 saturation levels for any given level of MVO2. These data, together with our measurements of the transmyocardial irET-1 gradient, do not, however, support the possibility of augmented ET-dependent effects during exercise beyond those displayed under baseline conditions. After beta -adrenergic blockade, ET-receptor blockade leads to increases in coronary sinus O2 saturation directly related to a decrease in MVO2.


    ACKNOWLEDGEMENTS

We are grateful to Dr. Martine Clozel (Actelion, Allschwil, Switzerland) for generously providing tezosentan. We also thank Claude Mousseau and Claudy Patry for expert technical assistance.


    FOOTNOTES

This work was supported through grants from the Medical Research Council of Canada, Canadian Heart and Stroke Foundation, and Fonds de la Recherche de l'Institut de Cardiologie de Montréal.

Address for reprint requests and other correspondence: M. Lavallée, Institut de Cardiologie de Montréal, 5000 east 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.

Received 23 May 2000; accepted in final form 20 June 2000.


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ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES

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J APPL PHYSIOL 89(5):2041-2048
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