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Cardiovascular Research 2003 59(3):745-754; doi:10.1016/S0008-6363(03)00479-6
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Copyright © 2003, European Society of Cardiology

Contribution of endothelin and its receptors to the regulation of vascular tone during exercise is different in the systemic, coronary and pulmonary circulation

Daphne Merkusa,*, Birgit Houwelinga, Amran Mirzaa, Frans Boomsmab, Anton H van den Meirackerb and Dirk J Dunckera

aExperimental Cardiology, Thoraxcenter, Erasmus MC, University Medical Center Rotterdam, P.O. Box 1738, 3000 DR Rotterdam, The Netherlands
bInternal Medicine, Cardiovascular Research Institute COEUR, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands

d.merkus{at}erasmusmc.nl

* Corresponding author. Tel.: +31-10-408-8025; fax: +31-10-408-9494.

Received 5 March 2003; revised 3 June 2003; accepted 10 June 2003


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusions and implications
 References
 
Objectives: Exercise-induced vasodilation is thought to be mediated through various vasodilator substances, but blunting the influence of vasoconstrictors such as ET may also play a role. However, the role of ET and its receptors in the regulation of systemic, pulmonary and coronary vascular resistance is incompletely understood. The aim of this study was to identify the contribution of ET-1 through the ETA and ETB receptors to the regulation of tone in the systemic, coronary and pulmonary beds at rest and during exercise. Methods: Ten chronically instrumented swine were studied while running on a treadmill before and after ETA blockade (EMD122946) or ETAB blockade (tezosentan). Results: At rest, EMD122946 resulted in vasodilation in the coronary and systemic circulation, evidenced by a decrease in coronary and systemic vascular resistance and an increase in coronary and mixed venous O2-saturation. These effects waned during exercise. The effect of tezosentan on the systemic vasculature was similar to that of EMD122946, whereas it was smaller in the coronary circulation. EMD122946 had no effect on the pulmonary vasculature, whereas tezosentan decreased pulmonary resistance but only during exercise. Conclusions: ET exerts a constrictor influence on the coronary and systemic circulation through the ETA-receptor, which decreases during exercise thereby contributing to metabolic vasodilation. ET exerts a tonic vasodilator influence on coronary resistance vessels through the ETB-receptor. Finally, ET exerts an ETB-mediated constrictor influence in the pulmonary vasculature during exercise.

KEYWORDS Metabolic vasodilation; Coronary blood flow; Peripheral resistance; Pulmonary resistance


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 5. Conclusions and implications
 References
 
Endothelin (ET)-1 is one of the most potent vasoconstrictor agents known. It is produced in endothelial cells by cleavage of its nonvasoactive precursors preproendothelin and big ET [1,2]. The ET receptors are located both on the endothelium and on vascular smooth muscle. Binding of ET to ETB receptors on the endothelium leads to production of NO and prostacyclin, which induce vasodilation, whereas binding of ET to the ETA and ETB receptors on vascular smooth muscle leads to vasoconstriction [1–3]. Administration of exogenous ET causes ETB mediated vasodilation at low doses but constriction at high doses, indicating that the ETB receptor on the endothelium is more sensitive to ET than the receptors on vascular smooth muscle [1–3]. Measurements of ET levels in blood yield concentrations in the picomolar range, while receptor sensitivities are in the nanomolar range [4]. However, reports on the role of endogenous ET have shown that, despite its low plasma concentrations and most likely due to its abluminal secretion, ET contributes to vascular tone in the systemic [5–10], coronary [6,11] and possibly in the pulmonary circulation [12] under basal physiological conditions. The role of ET in regulating resistance vessel tone during acute exercise is incompletely understood. Short term exercise does not result in changes in plasma ET-levels [6,13–15], although small increases have been reported as well [16–18]. Nevertheless, local variations in ET production may still contribute to redistribution of flow to working muscle. Thus, during one-legged exercise, the ET levels in the venous blood from the working leg did not change, whereas the ET levels in the blood from the nonworking leg increased [19]. However, because receptor sensitivity to ET can be modulated, for example by exercise training [20] and adenosine [21], changes in ET levels may not accurately reflect its role in exercise-induced changes in flow. Therefore, the aim of the present study was to investigate the role of ET and its receptors in regulation of systemic, pulmonary and coronary resistance vessel tone of swine at rest and during exercise, using a selective ETA antagonist as well as a mixed ETAB antagonist.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 5. Conclusions and implications
 References
 
2.1 Animals
The study was performed in accordance with the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health (NIH Publication No. 85-23, revised 1996), and with approval of the Animal Care Committee of the Erasmus MC. YorkshirexLandrace swine (2–3-months old, n=10, 22±1 kg at the time of surgery) of either sex entered the study. Daily adaptation of animals to laboratory conditions started 1 week before surgery.

2.2 Surgery
Swine were sedated (ketamine, 20 mg/kg, i.m.), anesthetized (thiopental, 10 mg/kg, i.v.), intubated and ventilated with O2 and N2O to which 0.2–1% (v/v) isoflurane was added [22,23]. Anesthesia was maintained with midazolam (2 mg/kg followed by 1 mg/kg per hour i.v.) and fentanyl (10 µg/kg per hour i.v.). Under sterile conditions, the chest was opened via the fourth left intercostal space and a fluid filled polyvinylchloride catheter was inserted into the aortic arch for aortic blood pressure measurement (Combitrans® pressure transducers, Braun) and blood sampling for determination of blood gases (Acid–Base Laboratory Model 505, Radiometer), O2-saturation and hemoglobin concentration (OSM2, Radiometer) and computation of O2 content, O2 supply, and O2 consumption (VO2) [22,23]. An electromagnetic flow probe (14–15 mm, Skalar) was positioned around the ascending aorta for measurement of cardiac output. A microtipped pressure-transducer (P4.5, Konigsberg Instruments) was inserted into the LV via the apex. Polyvinylchloride catheters were inserted into the LV to calibrate the Konigsberg transducer LV pressure signal, into the left atrium to measure pressure and into the pulmonary artery to measure pressure, administer drugs and collect mixed venous blood samples. An angiocatheter was inserted into the anterior interventricular vein for blood sampling, while a Transonic flow probe (2.5–3.0 mm, Transonic Systems) was placed around the proximal left anterior descending coronary artery. Catheters were tunneled to the back and animals were allowed to recover, receiving analgesia (0.3 mg buprenorphine, i.m.) for 2 days and antibiotic prophylaxis (25 mg/kg amoxicillin and 5 mg/kg gentamycin, i.v.) for 5 days [22,23].

2.3 Experimental protocols
2.3.1 Efficacy of ET receptor blockade
In six swine, we tested the efficacy of the ETA antagonist EMD122946 (a gift from Dr. P. Schelling, Merck, Darmstadt, Germany) and the mixed ETAB antagonist tezosentan (a gift from Dr. Clozel, Actelion) in blocking the arterial pressor response to ET. EMD122946 has a pA2 of 9.5 for ETA and a pA2 of 6.0 for ETB receptors, indicating a 3200-fold selectivity for ETA compared to ETB receptors [24]. Tezosentan has a pA2 of 9.5 for ETA and a pA2 of 7.7 for ETB receptors, indicating only a 63-fold selectivity for ETA compared to ETB receptors [6,25].

While swine were resting quietly, ET-1 (50 ng/kg per ml saline) was infused at rates of 25, 50 and 100 ng/kg/min i.v. (10 min consecutive infusions) and mean aortic blood pressure was measured at the end of each infusion. On another day, the same doses of ET-1 were infused after administration of 3 mg/kg i.v. of EMD122946, dissolved in 40 ml saline (at pH 8), and infused over a 10-min period. On a third day, the same doses of ET-1 were infused after administration of 3 mg/kg i.v. of tezosentan, dissolved in 15 ml saline, and infused over a 10-min period, followed by 6 mg/kg/h i.v. infused at a rate of 0.5 ml/min. These three ET-infusion protocols were performed in random order.

2.3.2 Exercise study
Systemic, pulmonary and coronary hemodynamic responses to exercise were studied 1–2 weeks after surgery. After baseline measurements (lying, 0L, and standing, 0S) were obtained, a treadmill exercise protocol was started (1–5 km/h). Hemodynamic data and blood samples were collected during the last 30 s of each 3 min exercise stage [22,23]. After completion of the exercise protocol, swine were allowed to rest for 90 min, during which the hemodynamics returned to baseline resting values that were similar (<5% different) to the baseline measurements obtained before the first exercise protocol. Then, either the ETA antagonist EMD122946 (3 mg/kg i.v., n=8) or the mixed ETAB antagonist tezosentan (3 mg/kg+6 mg/kg/h i.v., n=7) was administered as described above, and 10 min later the exercise protocol was repeated. We have previously shown excellent reproducibility of the hemodynamic responses to exercise [22,23,26,27].

2.4 Determination of plasma levels of ET
In seven swine, arterial and coronary venous blood samples (5 ml) were collected at rest (Lying) and at 1, 3 and 5 km/h and kept on ice until the end of the exercise trial. Then the blood samples were spun down and plasma was stored at –80°C. Plasma levels of ET-like immunoreactivity were determined using a radioimmunoassay from Euro-Diagnostica (Malmö, Sweden), which has a cross reactivity of 100% toward ET-1, 48% toward ET-2 and 109% toward ET-3. Since production of ET-2 and ET-3 appears to be absent in the cardiovascular system of the pig [28], the concentrations measured with the radioimmunoassay most likely represent ET-1. Importantly, there was also cross-reactivity of the radioimmunoassay with EMD122946 and tezosentan. To correct for these influences, we dissolved EMD122946 and tezosentan in naïve porcine plasma in the concentrations estimated to be present in vivo (0.04 mg/ml). The ET level of the plasma before addition of the antagonists was 2.4 pM, while it was 4.3 pM in the presence of EMD122946 and 3.8 pM in the presence of tezosentan. The artificial increases in ET levels produced by EMD122946 (1.9 pM) and by tezosentan (1.4 pM) were subtracted from the ET values obtained in the in vivo experiments with the respective antagonists to estimate true ET levels.

2.5 Data analysis
Digital recording and offline analysis of hemodynamics have been described previously [22,23]. Statistical analysis was performed using two-way (exercise and treatment) analysis of variance (ANOVA) for repeated measures, followed by Dunnett’s test (exercise effect) and paired t-test (antagonist effect). Analysis of co-variance (ANCOVA with VO2 as covariate) was used to detect statistically significant differences of relations between hemodynamic variables and body or myocardial VO2 in control versus ETA or ETAB blockade. Significance was accepted when P<0.05. Data are presented as mean±S.E.


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 5. Conclusions and implications
 References
 
3.1 Efficacy of blockade
Both ETA and ETAB blockade virtually abolished the ET-1 induced pressor response in the systemic circulation (Fig. 1).


Figure 1
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  		Fig. 1 Effect of ETA and mixed ETAB blockade on mean aortic blood pressure responses to intravenous infusion of ET-1. EMD122946: ETA receptor antagonist (3 mg/kg i.v.). Tezosentan: ETAB receptor antagonist (3 mg/kg+6 mg/kg/h i.v.). MAP, mean arterial pressure. Data are mean±S.E.; *, P<0.05 vs. baseline (0 ng/kg/min), {dagger}, P<0.05 vs. corresponding control.

 
3.2 ET levels
Exercise did not influence ET levels (Fig. 2). Furthermore, ET concentrations in arterial and coronary venous blood were not different. ETA blockade did not alter ET levels at rest, but ET levels were slightly lower during exercise. In contrast, ETAB blockade resulted in elevated ET levels both at rest and during exercise.


Figure 2
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  		Fig. 2 Arterial and coronary venous endothelin levels at rest and during exercise. Blood samples are drawn at rest (0 km/h, lying) and at 1, 3 and 5 km/h. ET, endothelin. EMD122946, ETA receptor antagonist (3 mg/kg i.v.). Tezosentan, ETAB receptor antagonist (3 mg/kg+ 6 mg/kg/h i.v.). ART, arterial. CV, coronary venous. Data are mean±S.E.; *, P<0.05 vs. 0 km/h; {dagger}, P<0.05 vs. corresponding control.

 
3.3 Systemic circulation
Exercise produced an increase in cardiac output that was principally mediated by the increase in heart rate; LVdP/dtmax almost doubled (Table 1). Mean aortic pressure decreased significantly when animals went from lying to standing, but remained essentially unchanged thereafter despite the increases in cardiac output, reflecting the decrease in systemic vascular resistance (Fig. 3).


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  		Table 1 Effect of ETA blockade on hemodynamic responses to graded treadmill exercise

 

Figure 3
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  		Fig. 3 Effect of ETA (EMD122946, upper panels) and ETAB (Tezosentan, lower panels) receptor blockade on the relation between body O2 consumption (BVO2) and systemic vascular resistance (SVR, left panels), body O2 extraction (middle panels) and mixed venous O2 saturation (right panels). ET receptor blockade resulted in systemic vasodilation at rest, that waned during exercise. Data are mean±S.E., *, P<0.05 vs. control; {dagger}, P<0.05 effect decreases during exercise.

 
Blockade of ETA or ETAB receptors resulted in a decreased mean aortic pressure (Tables 1 and 2Go), which was accompanied by a small, likely baroreceptor reflex mediated, increase in heart rate. Since cardiac output was maintained it follows that the decrease in pressure was the result of the decrease in systemic vascular resistance, which was similar for ETA and ETAB blockade (Fig. 3). Systemic vasodilation was also reflected in the decreased body O2-extraction and increased mixed venous O2 saturation (Fig. 3). These effects of ETA and ETAB blockade waned during exercise, indicating that the constrictor influence of ET was blunted during exercise.


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  		Table 2 Effect of ETAB blockade on hemodynamic responses to graded treadmill exercise

 
3.4 Coronary circulation
The increase in myocardial O2 consumption during exercise was accommodated for by an increase in coronary blood flow (Table 1), so that myocardial O2 extraction was maintained constant at approximately 80% (Fig. 4). ETA blockade resulted in a decreased coronary resistance and, as a result of this vasodilator effect, increased myocardial O2 supply allowing a decrease in myocardial O2 extraction and leading to an increased coronary venous O2 saturation (Fig. 4). The effect of ETA blockade waned during exercise.


Figure 4
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  		Fig. 4 Effect of ETA (EMD122946, upper panels) and ETAB (Tezosentan, lower panels) receptor blockade on the relation between myocardial O2 consumption (MVO2) and coronary vascular resistance (CVR, left panels), myocardial O2 extraction (middle panels) and coronary venous O2 saturation (right panels). ET receptor blockade resulted in coronary vasodilation at rest, that waned during exercise. Data are mean±S.E., *, P<0.05 vs. control; {dagger}, P<0.05 effect of receptor blockade decreases during exercise; {ddagger}, P<0.05 vs. EMD122946-induced response.

 
Combined ETAB blockade also resulted in a decrease in coronary resistance thereby increasing myocardial O2 supply and causing a decrease in myocardial O2 extraction at rest (Fig. 4). The effect of ETAB blockade disappeared during exercise. The effects of ETAB blockade were smaller than those of ETA blockade, particularly during exercise.

3.5 Pulmonary circulation
Exercise resulted in a doubling of pulmonary artery pressure and a three-fold increase in left atrial pressure. The transpulmonary pressure gradient increased almost in parallel with cardiac output so that pulmonary vascular resistance decreased by less than 10% (P=NS).

ETA blockade had no effect on pulmonary artery pressure, left atrial pressure or cardiac output (Table 1), so that pulmonary vascular resistance was unchanged (Fig. 5). In contrast, ETAB blockade reduced pulmonary artery pressure during exercise, whereas left atrial pressure and cardiac output remained unaffected (Table 2), reflecting a decrease in pulmonary vascular resistance (Fig. 5).


Figure 5
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  		Fig. 5 Effect of ETA (EMD122946, left panel) and ETAB (Tezosentan, right panel) blockade on pulmonary vascular resistance (PVR). ETB blockade resulted in pulmonary vasodilation during exercise. Data are mean±S.E., 0L: lying; 0S: standing; *, P<0.05 vs. control; {dagger}, P<0.05 vs. lying.

 

   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
5. Conclusions and implications
 References
 
The major findings in this study are that: (i) endogenous ET contributes to vascular tone in the systemic, coronary and pulmonary vasculature; (ii) the vasoconstrictor effect of ET on the systemic and coronary vasculature is mediated through the ETA receptor, whereas it is mediated through the ETB receptor in the pulmonary vasculature; (iii) in contrast, the ETB receptor exerts a vasodilator influence on the coronary circulation; (iv) although arterial ET levels do not change during exercise, its vasoconstrictor influence on the systemic and particularly the coronary resistance vessels decreases, whereas its vasoconstrictor influence on the pulmonary resistance vessels increases.

4.1 Methodological considerations
4.1.1 Efficacy and selectivity of ET receptor antagonists
Both EMD122946 and tezosentan virtually abolished the ET-1 induced pressor response in resting swine. These observations demonstrate that receptor blockade was effective during a 30-min period, which encompasses the duration of the exercise protocol and that the pressor response to exogenous ET-1 was principally mediated via ETA stimulation.

The selectivity of EMD122946 and tezosentan for the ETA and the ETB receptor has been studied in vitro. EMD122946 has a 3200-fold selectivity for ETA compared to ETB receptors [24], whereas Tezosentan has only a 63-fold selectivity for ETA compared to ETB receptors [6,25]. In accordance with these in vitro studies, we found that ET levels rose after tezosentan, but not after EMD122946. The increase in ET levels with tezosentan is due to the blockade of ETB receptors in the lungs, which are responsible for clearance of ET [29]. The absence of an increase in ET levels with EMD122946, indicates that this compound has no ETB receptor blocking properties in the dose employed in the present study in vivo.

4.1.2 Rationale for using ETA and ETAB receptor antagonists to assess the functional role of ETB receptors
ET is preferentially released on the abluminal side of the vasculature. Thus, plasma ET levels may not adequately reflect the contribution of ET in the regulation of vascular tone. Hence, the most adequate way to measure the contribution of ET to the regulation of vascular tone is the use of ET receptor antagonists. Since the ETB receptor is responsible for clearance of ET in the lungs [29], we chose to use a selective ETA and a mixed ETAB antagonist to determine the role of the ETA and ETB receptor, rather than a selective ETB antagonist. Selective ETB blockade would increase ET levels, which could then cause vasoconstriction through the ETA receptor, thereby confounding interpretation of the findings. When ET levels rise in the presence of ETAB blockade, this will not affect vascular tone. Thus, the role of the ETB receptor must be derived from the difference in response between selective ETA blockade and combined ETAB blockade.

4.2 Role of ET in the regulation of tone at rest and during exercise
4.2.1 Coronary circulation
The normal heart is characterized by a high level (80%) of myocardial O2 extraction under basal resting conditions [30,31]. Consequently, the ability of the coronary resistance vessels to dilate in response to increments in myocardial O2 demand is extremely important to maintain an adequate O2 supply. A sensitive way to study alterations in coronary vascular tone in relation to myocardial metabolism is the relationship between coronary venous O2 content and myocardial O2 demand. Thus, an increase in coronary resistance vessel tone will limit CBF and hence myocardial O2 supply at a given level of myocardial O2 consumption, forcing the myocardium to increase its myocardial O2 extraction (in order to meet myocardial O2 demand), which results in a lower coronary venous O2 content. Conversely, a decrease in resistance vessel tone increases myocardial O2 supply at a given level of myocardial O2 consumption resulting in an increased coronary venous O2 content. The coronary venous O2 content thus represents an index of myocardial tissue oxygenation (i.e. the balance between myocardial O2 supply and O2 demand) which is determined by the coronary resistance vessel tone. Using this approach, several laboratories have indicated roles for myriad vasodilator systems such as NO, adenosine, K+ATP channels and β-adrenoceptors in metabolic vasodilation [22,23,26,27,30–33].

In the present study, we extended the investigation of metabolic vasodilation to the contribution of withdrawal of endothelin-induced vasoconstriction. Using the myocardial O2 balance, we demonstrated ETA-mediated coronary constriction and simultaneous ETB-mediated coronary vasodilation in swine. This is in accordance with studies that have shown that the constrictor responses of coronary conductance and resistance arteries are predominantly ETA-mediated [34–37], whereas ETB-mediated vasodilation has been found in the large coronary arteries [38,39] and coronary arterioles [40], although an ETB-mediated constrictive component also exists in large coronary arteries [36,41]. Overall, dose response curves to ET in isolated coronary arteries [20] and arterioles [42] indicate that the sensitivity for ET increases with decreasing vessel size.

In dogs, the effect of ETAB blockade on coronary vascular tone tended to decrease during incremental levels of exercise [6]. This led us to hypothesize that there is a role for withdrawal of the vasoconstrictor effect of ET in metabolic regulation of coronary vascular tone. Indeed we recently showed that the effect of ETA blockade on the coronary circulation decreased during exercise and that the effects of ET were modified by the cardiomyocytes according to their metabolic status [11]. However, in the present study we found that only the ETA-mediated vasoconstriction waned during exercise, whereas an ETB-mediated vasodilation was tonically present. Although a decrease in local ET release, for example due to an increased NO production during exercise [2,43] could theoretically have contributed to metabolic coronary vasodilation, this is unlikely. Thus, neither coronary arterial nor coronary venous ET levels changed during exercise, which is in agreement with the study of Takamura et al. [6]. Moreover, the vasodilator influence of the ETB receptor was constant despite a decrease in the vasoconstrictor influence of the ETA receptor. There are several other mechanisms that may account for exercise-induced modulation of the effects of ET. First, interstitial adenosine levels increase during exercise, which can decrease sensitivity of the vasculature to ET [21]. Second, NO production increases during exercise, which can directly modulate the binding of ET to the ETA receptor [44,45]. NO has been shown to induce depalmitoylation of the β-adrenoceptor thereby affecting its signaling [46] and may also result in depalmitoylation of the ETA receptor, thereby decreasing its signal transduction [45,47,48]. Thus, ETA receptor sensitivity may be decreased during exercise through an increase in NO, adenosine or both, thereby facilitating metabolic vasodilation.

4.2.2 Systemic circulation
In the systemic circulation, effects of endogenous ET were predominantly exerted through the ETA receptor with no net contribution of the ETB receptor. In addition, the vasoconstriction caused by exogenously administered ET was predominantly ETA-mediated since the increase in aortic blood pressure was abolished by both the ETA and the ETAB antagonists. Hence, in the systemic vascular bed the effects of both endogenous and exogenous ET appear to be mediated exclusively through the ETA receptor. These findings are in line with other studies demonstrating that the constrictor response of systemic conductance and resistance arteries is principally ETA-mediated [34–36]. Although there was no net contribution of endogenous ET through the ETB receptor in our study, we cannot exclude that some regional vascular beds exhibit ETB mediated constriction whereas others vasodilate, as suggested by studies showing an ETB-mediated constrictive component in the renal arteries [36,41] as well as ETB-mediated vasodilation in the systemic circulation [49].

In the present study, we found that the contribution of ET to overall systemic vascular tone decreased during exercise. From our experiments, it is impossible to elucidate the mechanism behind the blunted effect of ET during exercise. The ET levels in arterial blood did not change, which is in accordance with data obtained in humans [13,15,18], dogs [6,50], and swine [14]. However, in view of the preferentially abluminal release of ET, this observation does not exclude alterations in the contribution of ET to regulation of resistance vessel tone. Thus, plasma concentrations of ET may not adequately reflect local ET levels. Furthermore, ET binds tightly to its receptors and the rate of dissociation is low [1–3], so that locally secreted ET binds to its receptors and acts, with minimal accumulation in the blood [51]. Further support for a discrepancy between local and arterial ET levels is provided by the fact that although the ET levels in blood were below the vasoactive threshold [20,42], blockade of ET receptors resulted in vasodilation at rest, an observation that is corroborated by studies in dogs [6] and humans [8–10]. However, spill-over into the blood may occur. For example, Maeda et al. reported that during one-leg exercise, ET levels increased in the venous effluent from the nonworking leg, while venous ET levels were unchanged in the exercising leg [19]. Hence, ET production may vary locally according to the metabolic status of the tissue [18,52,53]. Alternatively, local increases in NO and adenosine during exercise may have decreased ETA receptor signal transduction, and thereby modulated the constriction to ET during exercise [21,44,46–48]. Thus, local modulation of ET release and/or receptor sensitivity at sites of increased metabolism provides an additional way to increase flow to areas that need it most, while tone remains intact in other areas, thereby ensuring adequate (re)distribution of flow commensurate with metabolic needs.

4.2.3 Pulmonary circulation
ET-induced constriction is mediated by ETA receptors in the large pulmonary arteries, whereas it is mediated by ETB receptors in the smaller pulmonary resistance vessels [54]. In accordance with these findings, the density of ETA receptors in the lung decreases with decreasing vessel size, whereas the density of ETB receptors, both on the endothelium and the smooth muscle increases [55]. In swine, exogenously administered ET induces transient pulmonary hypotension (endothelial ETB receptor), followed by sustained pulmonary hypertension (ETB receptor on vascular smooth muscle) [49]. The role of endogenous ET in the regulation of pulmonary resistance is less well understood. In some studies in the porcine and human circulation, ET receptor blockade had no effect [7,56], while a small vasodilator response was reported in other studies [12,57]. In our study, blockade of neither ETA nor ETB receptors affected pulmonary vascular resistance at rest, indicating that endogenous ET does not contribute to resting tone in the pulmonary resistance vessels. During exercise however, an ETB-mediated vasoconstriction became apparent, which contrasts with the blunted ET-mediated constriction in the systemic and coronary beds. Since hypoxia-induced pulmonary vasoconstriction is in part ET-mediated [56,57], it could be speculated that the decrease in pulmonary arterial pO2 which occurred during exercise may have contributed to the ETB mediated vasoconstriction.


   5. Conclusions and implications
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusions and implications
References
 
In awake swine, free from the effects of anesthesia, endothelin contributes to basal resting tone in resistance vessels of the systemic and coronary, but not the pulmonary circulation. During treadmill exercise, the ETA-mediated constriction of both the systemic and coronary bed wanes, thereby contributing to metabolic vasodilation in these beds. A tonic ETB-mediated vasodilator influence is present in the coronary circulation. In contrast, an ETB-mediated constriction becomes apparent in the pulmonary bed during exercise, which blunts the exercise-induced decrease in pulmonary vascular resistance.

The present study provides evidence for a novel concept of metabolic dilation in the systemic and coronary circulation during exercise, which involves not only increased vasodilator influences [22,23,26,27,30,31], but also inhibition of vasoconstrictor influences. Importantly, our study predicts that loss of the capacity to inhibit ET mediated vasoconstrictor influence (e.g. in situations of endothelial dysfunction) may result in impaired vasodilation during increased O2 demand. In support of this concept, McEniery et al. [58] recently showed that whereas ET blockade had no effect on exercise responses in the forearm of normotensive subjects, ET receptor blockade normalized the exercise-induced vasodilation in hypertensive humans.

Time for primary review 37 days.


   Acknowledgements
 
Financial support from the Netherlands Heart Foundation (grants 2000T038 (DJD) and 2000T042 (DM)) is gratefully acknowledged.


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

  1. Rubanyi G.M, Polokoff M.A. Endothelins: molecular biology, biochemistry, pharmacology, physiology, and pathophysiology. Pharmacol Rev (1994) 46:325–415.[Web of Science][Medline]
  2. Schiffrin E.L, Touyz R.M. Vascular biology of endothelin. J Cardiovasc Pharmacol (1998) 32:S2–13.[Web of Science][Medline]
  3. Webb D.J, Haynes W.G. The role of endothelin-1 in cardiovascular physiology and pathophysiology. Scott Med J (1995) 40:69–71.[Web of Science][Medline]
  4. Frelin C, Guedin D. Why are circulating concentrations of endothelin-1 so low? Cardiovasc Res (1994) 28:1613–1622.[Free Full Text]
  5. Schiffrin E.L, Turgeon A, Deng L.Y. Effect of chronic ETA-selective endothelin receptor antagonism on blood pressure in experimental and genetic hypertension in rats. Br J Pharmacol (1997) 121:935–940.[CrossRef][Web of Science][Medline]
  6. Takamura M, Parent R, Cernacek P, et al. Influence of dual ETA/ETB-receptor blockade on coronary responses to treadmill exercise in dogs. J Appl Physiol (2000) 89:2041–2048.[Abstract/Free Full Text]
  7. Fleisch M, Sutsch G, Yan X.W, et al. Systemic, pulmonary, and renal hemodynamic effects of endothelin ETAB-receptor blockade in patients with maintained left ventricular function. J Cardiovasc Pharmacol (2000) 36:302–309.[CrossRef][Web of Science][Medline]
  8. Haynes W.G, Ferro C.J, O’Kane K.P, et al. Systemic endothelin receptor blockade decreases peripheral vascular resistance and blood pressure in humans. Circulation (1996) 93:1860–1870.[Abstract/Free Full Text]
  9. Haynes W.G, Ferro C.E, Webb D.J. Physiologic role of endothelin in maintenance of vascular tone in humans. J Cardiovasc Pharmacol (1995) 26:S183–185.[Web of Science][Medline]
  10. Verhaar M.C, Strachan F.E, Newby D.E, et al. Endothelin-A receptor antagonist-mediated vasodilatation is attenuated by inhibition of nitric oxide synthesis and by endothelin-B receptor blockade. Circulation (1998) 97:752–756.[Abstract/Free Full Text]
  11. Merkus D, Duncker D.J, Chilian W.M. Metabolic regulation of coronary vascular tone—role of endothelin-1. Am J Physiol (2002) 283:H1915–1921.[Web of Science]
  12. Johnson W, Nohria A, Garrett L, et al. Contribution of endothelin to pulmonary vascular tone under normoxic and hypoxic conditions. Am J Physiol (2002) 283:H568–575.[Web of Science]
  13. Cosenzi A, Sacerdote A, Bocin E, et al. Neither physical exercise nor {alpha}1-and β-adrenergic blockade affect plasma endothelin concentrations. Am J Hypertens (1996) 9:819–822.[CrossRef][Web of Science][Medline]
  14. Haitsma D.B, Bac D, Raja N, et al. Minimal impairment of myocardial blood flow responses to exercise in the remodeled left ventricle early after myocardial infarction, despite significant hemodynamic and neurohumoral alterations. Cardiovasc Res (2001) 52:417–428.[Abstract/Free Full Text]
  15. Lenz T, Nadansky M, Gossmann J, et al. Exhaustive exercise-induced tissue hypoxia does not change endothelin and big endothelin plasma levels in normal volunteers. Am J Hypertens (1998) 11:1028–1031.[CrossRef][Web of Science][Medline]
  16. Ahlborg G, Weitzberg E, Lundberg J. Metabolic and vascular effects of circulating endothelin-1 during moderately heavy prolonged exercise. J Appl Physiol (1995) 78:2294–2300.[Abstract/Free Full Text]
  17. Maeda S, Miyauchi T, Goto K, et al. Alteration of plasma endothelin-1 by exercise at intensities lower and higher than ventilatory threshold. J Appl Physiol (1994) 77:1399–1402.[Abstract/Free Full Text]
  18. Maeda S, Miyauchi T, Goto K, et al. Differences in the change in the time course of plasma endothelin-1 and endothelin-3 levels after exercise in humans. The response to exercise of endothelin-3 is more rapid than that of endothelin-1. Life Sci (1997) 61:419–425.[CrossRef][Web of Science][Medline]
  19. Maeda S, Miyauchi T, Sakane M, et al. Does endothelin-1 participate in the exercise-induced changes of blood flow distribution of muscles in humans? J Appl Physiol (1997) 82:1107–1111.[Abstract/Free Full Text]
  20. Jones A.W, Rubin L.J, Magliola L. Endothelin-1 sensitivity of porcine coronary arteries is reduced by exercise training and is gender dependent. J Appl Physiol (1999) 87:1172–1177.[Abstract/Free Full Text]
  21. Merkus D, Stepp D.W, Jones D.W, et al. Adenosine preconditions against endothelin-induced constriction of coronary arterioles. Am J Physiol (2000) 279:H2593–2597.[Web of Science]
  22. Duncker D.J, Stubenitsky R, Verdouw P.D. Autonomic control of vasomotion in the porcine coronary circulation during treadmill exercise: evidence for feed-forward β-adrenergic control. Circ Res (1998) 82:1312–1322.[Abstract/Free Full Text]
  23. Duncker D.J, Stubenitsky R, Verdouw P.D. Role of adenosine in the regulation of coronary blood flow in swine at rest and during treadmill exercise. Am J Physiol (1998) 275:H1663–1672.[Web of Science][Medline]
  24. Mederski W.W, Dorsch D, Osswald M, et al. Endothelin antagonists: discovery of EMD 122946, a highly potent and orally active ETA selective antagonist. Bioorg Med Chem Lett (1998) 8:1771–1776.[CrossRef][Medline]
  25. Clozel M, Ramuz H, Clozel J.P, et al. Pharmacology of tezosentan, new endothelin receptor antagonist designed for parenteral use. J Pharmacol Exp Ther (1999) 290:840–846.[Abstract/Free Full Text]
  26. Duncker D.J, Oei H.H, Hu F, et al. Role of K+ATP channels in regulation of systemic, pulmonary, and coronary vasomotor tone in exercising swine. Am J Physiol (2001) 280:H22–33.[Web of Science]
  27. Duncker D.J, Stubenitsky R, Tonino P.A, et al. Nitric oxide contributes to the regulation of vasomotor tone but does not modulate O2 consumption in exercising swine. Cardiovasc Res (2000) 47:738–748.[Abstract/Free Full Text]
  28. Kjekshus H, Smiseth O.A, Klinge R, et al. Regulation of ET: pulmonary release of ET. contributes to increased plasma ET levels and vasoconstriction in CHF. Am J Physiol (2000) 278:H1299–1310.[Web of Science]
  29. Luscher T.F, Barton M. Endothelins and endothelin receptor antagonists: therapeutic considerations for a novel class of cardiovascular drugs. Circulation (2000) 102:2434–2440.[Abstract/Free Full Text]
  30. Feigl E.O. Coronary physiology. Physiol Rev (1983) 63:1–205.[Abstract/Free Full Text]
  31. Laughlin M.H, Korthuis R, Duncker D.J, et al. Regulation of blood flow to cardiac and skeletal muscle during exercise. In: Handbook of physiology. Exercise: regulation and integration of multiple systems (1996) Bethesda, MD: American Physiology Society. 705–769.
  32. Ishibashi Y, Duncker D.J, Zhang J, et al. ATP-sensitive K+ channels, adenosine, and nitric oxide-mediated mechanisms account for coronary vasodilation during exercise. Circ Res (1998) 82:346–359.[Abstract/Free Full Text]
  33. Duncker D.J, Bache R.J. Regulation of coronary vasomotor tone under normal conditions and during acute myocardial hypoperfusion. Pharmacol Ther (2000) 86:87–110.[CrossRef][Web of Science][Medline]
  34. Godfraind T. Evidence for heterogeneity of endothelin receptor distribution in human coronary artery. Br J Pharmacol (1993) 110:1201–1205.[Web of Science][Medline]
  35. Deng L.Y, Li J.S, Schiffrin E.L. Endothelin receptor subtypes in resistance arteries from humans and rats. Cardiovasc Res (1995) 29:532–535.[Abstract/Free Full Text]
  36. Awane-Igata Y, Ikeda S, Watanabe T. Inhibitory effects of TAK-044 on endothelin induced vasoconstriction in various canine arteries and porcine coronary arteries: a comparison with selective ETA and ETB receptor antagonists. Br J Pharmacol (1997) 120:516–522.[CrossRef][Web of Science][Medline]
  37. MacCarthy P.A, Pegge N.C, Prendergast B.D, et al. The physiological role of endogenous endothelin in the regulation of human coronary vasomotor tone. J Am Coll Cardiol (2001) 37:137–143.[Abstract/Free Full Text]
  38. Saetrum Opgaard O, Cantera L, Adner M, et al. Endothelin-A and -B receptors in human coronary arteries and veins. Regul Pept (1996) 63:149–156.[CrossRef][Web of Science][Medline]
  39. Traverse J.H, Judd D, Bache R.J. Dose-dependent effect of endothelin-1 on blood flow to normal and collateral-dependent myocardium. Circulation (1996) 93:558–566.[Abstract/Free Full Text]
  40. Lamping K.G, Clothier J.L, Eastham C.L, et al. Coronary microvascular response to endothelin is dependent on vessel diameter and route of administration. Am J Physiol (1992) 263:H703–709.[Web of Science][Medline]
  41. Teerlink J.R, Breu V, Sprecher U, et al. Potent vasoconstriction mediated by endothelin ETB receptors in canine coronary arteries. Circ Res (1994) 74:105–114.[Abstract/Free Full Text]
  42. Laughlin M.H, Muller J.M. Vasoconstrictor responses of coronary resistance arteries in exercise-trained pigs. J Appl Physiol (1998) 84:884–889.[Abstract/Free Full Text]
  43. Spieker L.E, Noll G, Ruschitzka F.T, et al. Endothelin receptor antagonists in congestive heart failure: a new therapeutic principle for the future? J Am Coll Cardiol (2001) 37:1493–1505.[Abstract/Free Full Text]
  44. Wiley K.E, Davenport A.P. Nitric oxide-mediated modulation of the endothelin-1 signalling pathway in the human cardiovascular system. Br J Pharmacol (2001) 132:213–220.[CrossRef][Web of Science][Medline]
  45. Goligorsky M.S, Tsukahara H, Magazine H, et al. Termination of endothelin signaling: role of nitric oxide. J Cell Physiol (1994) 158:485–494.[CrossRef][Web of Science][Medline]
  46. Adam L, Bouvier M, Jones T.L. Nitric oxide modulates β2-adrenergic receptor palmitoylation and signaling. J Biol Chem (1999) 274:26337–26343.[Abstract/Free Full Text]
  47. Horstmeyer A, Cramer H, Sauer T, et al. Palmitoylation of endothelin receptor A. Differential modulation of signal transduction activity by post-translational modification. J Biol Chem (1996) 271:20811–20819.[Abstract/Free Full Text]
  48. Okamoto Y, Ninomiya H, Tanioka M, et al. Palmitoylation of human endothelinB. Its critical role in G protein coupling and a differential requirement for the cytoplasmic tail by G protein subtypes. J Biol Chem (1997) 272:21589–21596.[Abstract/Free Full Text]
  49. Clement M.G, Albertini M. Differential release of prostacyclin and nitric oxide evoked from pulmonary and systemic vascular beds of the pig by endothelin-1. Prostaglandins Leukot Essent Fatty Acids (1996) 55:279–285.[CrossRef][Web of Science][Medline]
  50. Cheng C.P, Ukai T, Onishi K, et al. The role of ANG II and endothelin-1 in exercise-induced diastolic dysfunction in heart failure. Am J Physiol (2001) 280:H1853–1860.[Web of Science]
  51. Sokolovsky M. Endothelin receptor subtypes and their role in transmembrane signaling mechanisms. Pharmacol Ther (1995) 68:435–471.[CrossRef][Web of Science][Medline]
  52. Maeda S, Miyauchi T, Sakai S, et al. Prolonged exercise causes an increase in endothelin-1 production in the heart in rats. Am J Physiol (1998) 275:H2105–2112.[Web of Science][Medline]
  53. Maeda S, Miyauchi T, Kobayashi T, et al. Exercise causes tissue-specific enhancement of endothelin-1 mRNA expression in internal organs. J Appl Physiol (1998) 85:425–431.[Abstract/Free Full Text]
  54. MacLean M.R, McCulloch K.M, Baird M. Endothelin ETA- and ETB-receptor-mediated vasoconstriction in rat pulmonary arteries and arterioles. J Cardiovasc Pharmacol (1994) 23:838–845.[Web of Science][Medline]
  55. Soma S, Takahashi H, Muramatsu M, et al. Localization and distribution of endothelin receptor subtypes in pulmonary vasculature of normal and hypoxia-exposed rats. Am J Respir Cell Mol Biol (1999) 20:620–630.[Abstract/Free Full Text]
  56. Holm P, Liska J, Franco-Cereceda A. The ETA receptor antagonist, BMS-182874, reduces acute hypoxic pulmonary hypertension in pigs in vivo. Cardiovasc Res (1998) 37:765–771.[Abstract/Free Full Text]
  57. Albertini M, Clement M.G. Hypoxic pulmonary vasoconstriction in pigs: role of endothelin-1, prostanoids and ATP-dependent potassium channels. Prostaglandins Leukot Essent Fatty Acids (1998) 59:137–142.[CrossRef][Web of Science][Medline]
  58. McEniery C.M, Wilkinson I.B, Jenkins D.G, et al. Endogenous endothelin-1 limits exercise-induced vasodilation in hypertensive humans. Hypertension (2002) 40:202–206.[Abstract/Free Full Text]

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