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European Journal of Heart Failure 2001 3(3):293-299; doi:10.1016/S1388-9842(01)00138-6
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© 2001 European Society of Cardiology

Enhanced endothelin-1-induced contractions in mesenteric arteries from rats with congestive heart failure: role of ETB receptors

Anders Bergdahla, Stig Valdemarssona, Mikael Adnera, Xiang-Ying Sunb, Tomas Hednerb and Lars Edvinssona,*

a Department of Internal Medicine, Lund University Hospital 221 85 Lund, Sweden
b Department of Clinical Pharmacology, Gothenburg University Gothenburg, Sweden

* Corresponding author. Tel.: +46-46-17-14-84; fax: +46-46-18-47-92 E-mail address: lars.edvinsson{at}med.lu.se (L. Edvinsson).


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 
Studies of congestive heart failure (CHF) in man and in experimental CHF have demonstrated elevated circulating levels of endothelin (ET). In order to examine whether there are concomitant ET receptor alterations, the vasomotor effects of endothelin-1 (ET-1) and sarafotoxin 6c (S6c) were examined in endothelium-intact and -denuded isolated mesenteric arteries from rats with CHF. CHF was induced by ligation of the left anterior descending coronary artery. Vasomotor responses were studied using small mesenteric arteries (approx. 250 µm in diameter, determined after normalisation). The antagonists IRL2500 and FR139317 were used in order to characterise the ET-1-induced response. In mesenteric arteries with intact endothelium, ET-1-induced contractions were more potent in CHF as compared to sham (pEC50 9.6 ± 0.2 and 9.1 ± 0.1, respectively, P < 0.01). In endothelium-denuded arteries, there was no difference in potency of ET-1 between CHF and sham arteries, or in maximum contraction. In the presence of IRL2500, a selective ETB-receptor antagonist, ET-1 was more potent in endothelium-denuded arteries of CHF rats, while this difference was not seen in sham arteries. S6c had no consistent contractile or dilatory effect in CHF and sham rats. The results indicate that the enhanced contractile effects of ET-1 noted in CHF might be due to an attenuated endothelial function and that inhibition of smooth muscle cell ETB receptors increase the effects of contractile ETA receptors in CHF rats.

Key Words: Congestive heart failure • Endothelin-1 • Mesenteric artery • Endothelin A (ETA) • Endothelin B (ETB) • Receptor • In vitro pharmacology

Received July 29, 2000; Revised January 15, 2001; Accepted February 12, 2001


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 References
 
Endothelin (ET) has, since its discovery in 1988 [1], been the subject of extensive research. The peptide is present in three isoforms, ET-1, -2 and -3 [2] and induces a variety of effects, the most important with regard to CHF being the influence on and maintenance of peripheral vascular tone [3] and the suggested mitogenic effects on the vascular smooth muscle cells [4]. So far, two subtypes of ET receptors are claimed to mediate the actions of ET in humans, the ETA and ETB receptors. These receptors are widely distributed in the vascular system; the ETA receptor being the predominant receptor in vascular smooth muscle, mediating contraction [5], while the ETB receptor was initially found on endothelial cells mediating vasodilatation [6]. However, ETB receptor mRNA has also been detected in vascular smooth muscle cells [7,8], where these receptors have been shown to mediate vasoconstriction [9].

In vivo studies, including in man, have clearly demonstrated an ETB-mediated contractile response with increase in mean arterial pressure and reduced regional blood flow in the mesenteric and renal vascular bed [9,10], while in vitro stimulation of the ETB receptor generates only weak responses [11,12]. Under active tonic conditions in vitro however, a contractile response to ETB stimulation with the selective ETB-receptor agonist sarafotoxin 6c (S6c) [13] has been demonstrated [14,15].

In human and animal models of CHF, the plasma concentration of ET-1 is increased (for review see [16]), which has led to intense studies of the effects of ET and several ET antagonists in experimental CHF models and in humans with CHF. Alterations at the receptor level seem to occur, since there are reports of increased contractile effect to S6c in humans with CHF [17]. Furthermore, increased contractile response to S6c has been reported in the coronary circulation of dogs with CHF [18].

The contribution of ETB-receptor function to vascular resistance might thus be enhanced in CHF [16,17]. In the present study, we have examined the response to ET-1 and S6c in small mesenteric arteries from coronary-ligated CHF rats [19]. In addition, the effect of the selective ETB antagonist IRL2500 [20] and specific ETA-receptor antagonist FR139317 [21] on ET-1-induced contractions were studied. To elucidate the role of the endothelium for the function of the ETB-receptor, experiments with IRL2500 were performed both on denuded and endothelium-intact arteries.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 References
 
2.1. Experimental animals
Male Sprague–Dawley rats (ALAB, Sollentuna, Sweden) weighing 150–200 g were used. All animals were maintained on standard rat pellets and tap water ad libitum and housed in groups of 5, at 26°C, with 60% humidity and 05:00–19:00 h light regime. After coronary ligation or sham operation, the rats were housed individually. The study was approved by the Committee of Ethics for Animal Experiments at the Lund University Hospital and conforms to the Guide for Care and Use of Laboratory Animals published by the US National Institute of Health (NIH Publication No. 85-23, revised 1985).

2.2. Induction of congestive heart failure
During methohexital sodium (Brietal®, 60 mg kg–1; Eli Lilly, Indianapolis, USA) anaesthesia, the rats were intubated and artificially oxygenated with a respirator. A left thoracotomy was performed, exposing the left ventricular wall. The left coronary artery was ligated by positioning a suture between the pulmonary artery out-flow tract and the left atrium. The lungs were thereafter hyperinflated using positive end-expiratory pressure and the thorax immediately closed. The rats were thereafter allowed to recover for 10–12 weeks before experiments. In parallel, rats were sham-operated: i.e. they were subjected to the same surgical procedure, but without coronary artery ligation. These sham-operated rats served as controls.

2.3. In vitro preparation
The animals were killed under carbon dioxide anaesthesia. The intestinal tract was removed and kept in a cold physiological salt solution containing (in mM): NaCl, 119; NaHCO3, 15; KCl, 4.6; MgCl2, 1.2; NaH2PO4, 1.2; CaCl2, 1.5; and glucose, 5.5. The solution was continuously gassed with carbogen (5% CO2 in O2) to maintain a pH near 7.4. Ring segments from the second- and third-order branch of the superior mesenteric artery were carefully dissected. The dissected vessels were threaded onto two 40-µm-diameter stainless steel wires and mounted in a Mulvany–Halpern myograph (model 600M, JP Trading, Aarhus, Denmark), allowing direct determination of the vessel-wall force, while the internal circumference was controlled [22]. After the temperature had reached 37°C, arteries were normalised to their optimal lumen diameter for active tension development.

The normalised effective lumen diameter is an estimate of 90% of the diameter the vessel would have, if relaxed and exposed to a transmural pressure of 100 mmHg [22].

The contractile capacity of the vessels was examined by repetitive exposure to a potassium-rich (123 mM) buffer solution prepared by exchanging all NaCl in the buffer-solution for KCl in equimolar amounts. After each K+-induced contraction, the vessels were allowed to stabilise at resting tension by means of repeated washing with the standard solution. Vessels were included in the study if the contractions were reproducible and did exceed 100 mmHg.

2.4. Endothelial denudation
Endothelial denudation was performed by placing a thin syringe needle (0.2 mm o.d.) into the lumen of the mounted vessel and thereafter blowing an air stream through the vessel using a syringe attached to the needle. The denudation was confirmed by lack of dilatory response of acetylcholine (10 nM–0.1 mM) in noradrenaline-precontracted vessels. No differences in K+- or noradrenaline-induced contractions were observed between endothelium-intact and -denuded arteries.

2.5. Application of drugs
The inhibitory agents were added 15 min before the contractile drug was given. The effect of ET-1 was examined by stepwise application of increasing concentrations of the peptide (1 pM–0.3 µM). S6c was added either stepwise, or by single high-dose application, to both normalised and precontracted vessels. Precontraction was induced using U46619, a stable thromboxane A2 analogue, which induces a stable (1-h) contraction. All results are given as contractile responses in % compared to potassium-induced contraction, and pEC50 (negative logarithm of agonist concentration eliciting 50% of Emax). The potency of FR139317 was calculated and expressed as pKB using the following equation: pKB=–log{[B]/(r–1)}, where [B] denotes the concentration of the antagonist and r denotes the ratio between the EC50 values for the antagonist and for the control.

2.6. Drugs
Endothelin-1 and sarafotoxin 6c (S6c) were obtained from Auspep, Parkville, Australia. IRL 2500 [N-(3,5-dimethylbenzoyl)-N-methyl-(D)-(4-phenylphenyl)-alanyl-L-tryptophan], a selective ETB antagonist, was purchased from Neosystem Laboratoire, France. The peptides were dissolved in saline containing 0.1% bovine serum albumin (BSA) to avoid adhesion to glass material. All dilutions of the peptides were prepared with saline. U46619 [GenBank] (9,11-dideoxy-11{alpha},9{alpha}-epoxymethano-prostaglandin F2{alpha}) was supplied by ICN Biochemicals, Ohio, USA, and noradrenaline hydrochloride by ICI, UK.

FR 139317, a selective ETA antagonist, (R)2-{(R)-2-[(S)-2-{[1-(hexahydro-1H-azepinyl)]-carbonyl}amino-4-methyl-pentanoyl]amino-3-[3-(1-methyl-1H-indolyl)]propionyl}amino-3-(2-pyridyl)propionic acid (Fujisawa Pharmaceuticals Co., Osaka, Japan) and IRL2500 were dissolved in ethanol and methanol, respectively.

2.7. Statistics
Statistical analyses were performed using a Mann–Whitney U-test in unpaired studies (CHF vs. sham) and Wilcoxon signed rank test in paired studies (CHF vs. CHF, sham vs. sham). Differences were considered statistically significant at P values <0.05. The number of rats used in experiments is denoted by ‘n’.

2.8. Study protocol
The following experiments were performed:

  1. The contractile effect of S6c in endothelium-intact and -denuded arteries.
  2. The dilatory effect of S6c in noradrenaline- and U46619-precontracted arteries with intact endothelium.
  3. The contractile effect of ET-1 in endothelium-intact and -denuded arteries.
  4. The effect of IRL2500 (3 µM) on ET-1-induced contraction in arteries with and without endothelium and of FR139317 (1 µM) on endothelium-intact arteries from CHF and sham-operated animals.


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 References
 
3.1. Induction of myocardial infarction and CHF status
Heart/body wet wt. ratio was 0.47±0.1 and 0.34±0.05% in CHF and sham animals, respectively (mean±S.D., n=8, P=0.008). The hearts showed post-infarction signs comprising fibrosis and enlargement of the left ventricle, as confirmed by microscopic evaluation (data not shown). Signs of pulmonary oedema and pleural effusion were noted in some CHF rats. This was not evident in the sham-operated animals. The infarct size in operated rats was 38.1±3.8% (mean±S.D., n=8) of left ventricular circumference. Evaluation was carried out according to earlier reports [19]. The mortality rate was approximately 20% in coronary-ligated rats.

3.2. K+-induced responses
Initial potassium-induced contraction after normalisation of the vessels generated a contraction of 12.4±0.5 mN in CHF and 12.0±0.7 mN in sham rats, n>15 in each group (n.s.).

3.3. ET-1-induced responses in arteries with and without endothelium
ET-1 induced a slowly developing and long-lasting contraction in both CHF and sham mesenteric arteries with intact endothelium. There was no difference in Emax between CHF and sham arteries; however, ET-1 was more potent in CHF arteries compared to sham (pEC50 9.6±0.2 and 9.1±0.1 for CHF and sham, respectively, P<0.01, n=17) (Fig. 1a and Table 1). After endothelium denudation, there was no difference in the ET-1-induced contractile response between CHF and sham arteries (Fig. 1b). The ET-1-induced contraction was shifted to the right in both CHF and sham endothelium-intact arteries by the specific ETA antagonist FR139317 (1 µM, Table 1) indicating an ETA-mediated contraction with similar potency of inhibition of the ETA receptor response [pKB mean 7.9 (range 7.1–8.2) and 7.8 (range 7.7–8.1) for CHF and sham, respectively, n=3].


Figure 1
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  		Fig. 1 ET-1-induced contraction in congestive heart failure (CHF, •) and control-operated (sham, {circ}) mesenteric arteries: (a) with endothelium (E+); and (b) without endothelium (E–). *=P<0.05, **=P<0.01 (Mann–Whitney U test). Figures represent mean±S.E.M., n≥8 rats in each group.

 


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  		Table 1 Contractile responses (%) of K+-induced contraction to endothelin-1 (ET-1) in endothelium intact (E+) and denuded (E–) mesenteric arteries of congestive heart failure (CHF) and sham-operated (sham) ratsa

 
Comparison of the contractile response in endothelium-denuded and -intact vessels revealed no difference in ET-1-induced contraction in CHF (Fig. 2a). In sham-operated rats, ET-1 was more potent in endothelium-denuded arteries compared to arteries with preserved endothelium (pEC50 9.1±0.1 and 9.6±0.2 for sham with and without endothelium respectively, P<0.01, n=10) (Fig. 2b).


Figure 2
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  		Fig. 2 (a) ET-1-induced contraction in congestive heart failure (CHF) mesenteric arteries with endothelium (E+, {blacksquare}) and without endothelium (E–, {square}). Figures represent mean±S.E.M., n≥8 rats in each group. (b) ET-1-induced contraction in control-operated (sham) mesenteric arteries with endothelium (E+, {blacksquare}) and without endothelium (E–, {square}). *=P<0.05 (Wilcoxon signed rank test). Mean±S.E.M., n≥8 rats in each group.

 
3.4. S6c-induced responses
Several study protocols were used in order to examine S6c-induced responses. Both contraction and dilation were studied. Under normalised tension, S6c induced a weak contraction in 3/7 vessels from CHF (range 1–18, mean 12%) and in 4/7 vessels from sham rats (range 4–8, mean 6%). In vessels precontracted with U46619 or noradrenaline (approx. 60% of initial KCl-induced contraction) dilations were occasionally achieved, both when performing stepwise application (10 pM–0.3 µM) of S6c and when giving a high, single dose (0.3 µM). However, the responses varied between the segments tested. While one segment responded with a powerful dilation (after precontraction) to a single maximum dose of S6c, another segment from the same rat responded with a contraction which was superimposed on the precontraction applied. Thus, it was not possible to demonstrate any consistent differences between CHF and sham rats with regard to direct ETB-induced relaxant or contractile responses.

3.5. Effects of IRL2500 in arteries with and without endothelium
In the presence of IRL2500 (3 µM) there was no difference between CHF and sham to ET-1-induced contractions in arteries with intact endothelium (Table 1). However, in endothelium-denuded CHF arteries, IRL2500 induced a leftward shift (pEC50 10.0±0.2 and 9.4±0.1, with and without IRL2500, respectively, P=0.016, n=8) (Fig. 3a). In contrast, IRL2500 did not alter the contractile response in endothelium-denuded sham arteries (Fig. 3b).


Figure 3
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  		Fig. 3 (a) ET-1-induced contraction in endothelium-denuded (E–) mesenteric arteries from rats with congestive heart failure (CHF) with ({blacksquare}) and without ({square}) treatment of the specific ETB antagonist IRL2500 (1 µM). Figures represent mean±S.E.M., n=8 rats in each group, *=P<0.05 (Wilcoxon signed rank test). (b) ET-1-induced contraction in endothelium-denuded (E–) mesenteric arteries from control-operated (sham) rats with ({blacksquare}) and without ({square}) treatment of the specific ETB antagonist IRL2500 (1 µM). Figures represent mean±S.E.M., n=8 rats in each group

 

   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
References
 
The main results of this study are: (i) the increased sensitivity to ET-1 in CHF compared to sham mesenteric arteries with intact endothelium; and (ii) ETB receptors on the vascular smooth muscle cells reduced the sensitivity to ET-1 in CHF arteries, since treatment of denuded CHF arterial segments with the ETB-receptor antagonist IRL2500 potentiated the contractile responses induced by ET-1.

According to our results, resistance mesenteric arteries from CHF rats appear to be more sensitive to ET-1, an effect probably due to altered endothelial function, since removal of the endothelium eliminated the difference between CHF and sham rats.

The interpretation of a change of the endothelial function is supported by the observations from the second set of experiments (Fig. 2), where the removal of the endothelium did not influence the contractile responses to ET-1 in the CHF arteries, while removal of the endothelium in sham arteries induced an increased sensitivity. Generally, removal of the endothelium is followed by a potentiation of the contractile responses to ET-1. Thus, the potentiation of the ET-1 response in CHF arteries might be the result of a defect or altered endothelial function, and a subsequent impaired ETB-mediated relaxation. This might suggest that the resistance vasculature in CHF reacts as if it was devoid of a functional endothelium, which may be a possible mechanism to the increased vascular resistance noted in CHF [23,24]. A defective endothelium and subsequent reduced NO formation could be of importance in CHF, since NO has been claimed to inhibit the formation of ET in the endothelial cells [25], an effect that would be beneficial in CHF. The NO production and NO-induced response are generally accepted to be blunted in CHF [23,24].

In endothelium-intact vessels, ET-1 contraction in the presence of ETB-receptor inhibition by IRL2500 was, to some extent, potentiated in sham (Table 1), but not in CHF, arteries, a tendency noted by others [15]. The lack of potentiation of ET-1 in the presence of IRL2500 in endothelium-intact arteries of CHF therefore indirectly suggests that the endothelial ETB receptors are unable to modulate the response to ET-1 in the mesenteric arteries of CHF rats. This was further elucidated in the present study by the data from the IRL2500 studies on denuded arteries. Addition of this ETB-receptor antagonist did not have any effect on ET-1-induced contraction in denuded sham arteries. On the contrary, in denuded CHF arteries, ETB-receptor antagonism was followed by an enhanced sensitivity to ET-1 contraction. This might suggest that smooth muscle ETB receptors are preserved and also functional in CHF or, indirectly, a possibility that ETB receptors may inhibit ETA receptors. Indeed, data supporting this hypothesis have recently been presented showing an upregulation of smooth muscle ETB receptors in CHF rats 12 weeks post coronary ligation. Furthermore, the increased number of ETB receptors induced an attenuated contractile response to ET1 in CHF rats, an effect opposed by ETB-receptor desensitisation. The effect was not observed in sham [26]. Furthermore, it was proposed in a study by Seo [27] that ETB receptors on the smooth muscle cells inhibit or negatively modulate ETA receptor-mediated contraction.

This support the findings in our study that the ET-1-induced contractions were potentiated in CHF arteries in the presence of IRL2500 (Fig. 3), and could have been more closely evaluated in the S6c experiments. There were, however, no consistent results from direct ETB-receptor stimulation. This has been observed by others [14,26], and we have no clear-cut explanation for these results. However, since a pressurised, as compared to isometric, in vitro system has been shown to produce more consistent ETB-receptor stimulated responses [14], perhaps the effect of ETB-receptor stimulation depends on the method used, in the aforementioned pressurised in vitro or in vivo systems.

Although the responses to S6c were weak and inconsistent in the present study, we would suggest the presence of smooth muscle ETB receptors, at least in CHF rats, since inhibition of the receptor with IRL2500 influenced the response to ET-1 in denuded vessels in CHF, as discussed above. However, an observation that ETA receptors mask the effect of ETB receptors by intracellular ‘cross talk’ has also been reported [15]. Thus, ETA and ETB receptors may influence each other, and the responses observed are in turn the result of changes in their relative distribution, a distribution affected by the disturbed circulation noted in CHF. The enhanced response to ET-1 in CHF (Fig. 1) and the absence of an increased effect of ET-1 in denuded CHF arteries (Fig. 2) might thus represent the consequences of such a phenomenon. Although the number of rats used was low, the pKB values obtained with FR139317 were close to values reported in humans [8] and somewhat increased compared to values noted in the rat aorta [21], and did not differ between CHF and sham rats. This would, in line with the results discussed so far, suggest that the results obtained are more likely due to a change in the ETB- than in the ETA-receptor function.

In summary, this study has shown that contractile responses to ET-1 are altered in experimental CHF and that alterations of ETA/ETB receptors, or interactions between these two receptors, seem to occur at both the endothelial and the smooth muscle cell level. According to our results, ETB receptors might induce a beneficial haemodynamic effect in CHF and reduce peripheral vascular resistance mediated by ETA receptors.


   Acknowledgements
 
This study was supported by a grant from the Swedish Medical Research Council (grant no. 5998).


   References
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 

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