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Cardiovascular Research 1999 43(3):755-761; doi:10.1016/S0008-6363(99)00170-4
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Copyright © 1999, European Society of Cardiology

Effects of endothelin receptor antagonists and nitric oxide on myogenic tone and {alpha}-adrenergic-dependent contractions of rabbit resistance arteries

Thanh-Dung Nguyen, Philippe Véquaud and Eric Thorin*

Institut de Cardiologie de Montréal, Centre de Recherche, 5000, Rue Bélanger Est, Montréal, Que., Canada H1T 1C8

* Corresponding author. Tel.: +1-514-376-3330, ext: 3589; fax: +1-514-376-1355 thorin{at}icm.umontreal.ca

Received 14 December 1998; accepted 29 April 1999


   Abstract
Top
 Abstract
1 Introduction
 2 Methods
 3 Results
 4 Discussion
 References
 
Regulation of vascular contractions by endothelium-derived endothelin-1 (ET-1) and nitric oxide (NO) may vary depending on the stimulus. Objectives: To investigate if ET-1 receptor stimulation and NO contributed to a similar extent to the regulation of pressure- and {alpha}-adrenergic receptor (AR) agonist-induced smooth muscle contraction. Methods: Rabbit mesenteric arteries (150–200 µm) were isolated, cannulated and pressurized. Changes in diameter were recorded as a function of the perfusion pressure (PP) or {alpha}-AR agonist addition at a PP of 60 mmHg. All experiments were performed in the presence of indomethacin (10 µmoll–1). Results: At a PP of 60 mmHg, myogenic tone (MT) developed to represent 17±1% of the minimal diameter. The magnitude of the MT was increased by 140% (P<0.05) by the inhibition of NO production with N{omega}-nitro-L-arginine (L-NOARG). Bosentan, an ETA/B receptor antagonist, and BQ 123, a selective ETA receptor antagonist, decreased (P<0.05) MT either alone or in combination with L-NOARG by {approx}30%. Phenylephrine (Phe), an {alpha}1-AR agonist, induced contraction; the sensitivity to Phe (pD2, 6.2±0.2) was unaffected by bosentan or BQ 123 alone but increased (P<0.05) by L-NOARG (pD2, 7.3±0.5). Further addition of bosentan or BQ 123 restored the sensitivity to Phe to its control value. Oxymetazoline (OXY), an {alpha}2-AR agonist, induced contraction; the sensitivity to OXY (pD=2, 7.7±0.2) was unaffected by L-NOARG, bosentan or BQ 123. Conclusion: Our results indicate that pressure-induced tone is independently regulated by endothelium-derived NO and ET-1. In contrast, {alpha}1-AR stimulation-induced tone is sensitive to ET-1 in the absence of NO, whereas occupation of {alpha}2-AR mediates a contraction unregulated by the endothelium.

KEYWORDS AR, adrenergic receptor; EDHF, endothelium-derived hyperpolarizing factor; ET-1, endothelin-1; L-NOARG, N{omega}-nitro-L-arginine; MT, myogenic tone; NO, nitric oxide; OXY oxymetazoline; Phe, phenylephrine; PP, perfusion pressure; PSS, physiological salt solution


   1 Introduction
Top
 Abstract
 1 Introduction
2 Methods
 3 Results
 4 Discussion
 References
 
Myogenic vasoconstriction, an increase in vascular tone in response to an increase in transmural pressure independent of neural or hormonal influences, is one of the fundamental mechanisms regulating blood perfusion in several vascular beds. Under normal conditions, myogenic tone (MT) displayed by resistance arteries plays an important role in autoregulation of blood flow in the brain [1,2], coronary [3], skeletal muscle [4] and mesentery [5]. The cellular mechanisms of the myogenic response include depolarization and the opening of voltage-operated Ca2+ channels [5] but a series of nonelectromechanical coupling mechanisms also appears to be involved. Although MT is endothelium-independent [6], its magnitude has been shown to be modulated by the endothelial lining. Inhibition of NO production [7] and prostanoids [4] increases the myogenic response. The role of endothelium-derived endothelin-1 (ET-1), however, is not elucidated. Huang and Koller [4] recently reported that in resistance arteries from hypertensive rats only, ET-1 contributed to the myogenic response suggesting that in these hypertensive animals, the endothelium potentiates the myogenic response partly through an exaggerated release of ET-1 or an increased sensitivity of the underlying smooth muscle to ET-1. A contribution of ET-1 in the regulation of MT in normotensive animals remains to be demonstrated.

Alternatively, the contractile state of the vessel may influence the endothelium-dependent regulation of vascular tone [8]. It has been shown that in baseline conditions, NO has no effect on ET-1 release, whereas receptor-operated ET-1 release is blunted by NO [9]. Thus, factors that influence wall tension and endothelial ET-1 production may be important in controlling vascular tone.

The aim of this study was to investigate the regulatory function of the endothelium during pressure- and agonist-mediated contractions of isolated and pressurized rabbit mesenteric arteries. We hypothesized that ET-1 influences agonist- and pressure-mediated responses differently.


   2 Methods
Top
 Abstract
 1 Introduction
 2 Methods
3 Results
 4 Discussion
 References
 
Experiments were conducted on isolated resistance arteries (150–200 µm) of the mesenteric bed of male New Zealand white rabbits (weight, 2.5 to 3.5 kg). The procedures and protocols were in accordance with our institutional guidelines. Rabbits were anesthetized with intra-venous injection of sodium pentobarbital (65 mg kg–1) and exsanguinated. The mesenteric bed was harvested and a fifth branch of the mesenteric artery was dissected-out and placed in ice-cold physiological salt solution (PSS) containing indomethacin (10 µmol l–1) and of the following composition (mmol l–1): NaCl 130, KCl 4.7, KH2PO4 1.18, MgSO4 1.17, NaHCO3 14.9, CaCl2 1.6, EDTA 0.026, glucose 10 and aerated with 12% O2/5% CO2/83% N2 (pH 7.4). A 2- to 3-mm length segment was isolated and transferred to the vessel chamber. The chamber contained a pair of glass micropipettes filled with PSS (see below) at room temperature.

The inflow micropipette was connected to a silicon rubber tube linked to a pressure–servo pump system (Living Systems, Burlington, VT, USA). The distal (outflow) pipette was equipped with a three-way stopcock. The continuously aerated PSS in the vessel chamber (2 ml) was replaced every 10 min.

After the vessel was mounted on the proximal pipette and secured with a suture, the perfusion pressure (PP) was raised to 10 mmHg to clear the clotted blood from the lumen. The other end of the vessels was then mounted on the distal pipette.To flush the vessel and cannulas, the system was perfused for several minutes, then the outflow cannula was closed and the PP was slowly ({approx}1 min) increased to 60 mmHg. At this time, the pressure–servo control system was placed in the manual mode (i.e., no automatic maintenance of PP) in order to ascertain that there were no leaks in the system. If no leaks were detected (i.e., PP remained constant), the pressure–servo control was set in the automatic mode. The temperature was set to 37°C (Omega CN9000A temperature controller), and the vessel was allowed to equilibrate for 30 min.

In all protocols, the changes in diameter of arteries in response to increases in PP or agonists at constant PP under no-flow conditions were measured with an image shearing monitor and recorded on a computer with the DATAQ DI-220 acquisition software. Only vessels that developed spontaneous constriction to pressure (60 mmHg) were used (15% of the vessels did not develop MT).

In the first protocol, after the equilibration period, PP was decreased to 10 mmHg, then increased to 20 mmHg, and then increased, in 20 mmHg steps, to 160 mmHg. Each pressure step was maintained for 10 min to allow the vessels to reach a stable condition before the diameter of the arteries was measured. At the end of the experiment, the PSS of the vessel chamber was changed to a 127 mmol l–1 KCl PSS. The vessels were incubated for 10 min, then the step increases in pressure were repeated and the maximum constricted diameter of the arteries at each pressure step was obtained. Then, the PSS of the vessel chamber was changed to a Ca2+-free PSS that contained sodium nitroprusside (1 µmol l–1) and EGTA (1 mmol l–1). The vessels were incubated for 10 min, then the step increases in pressure were repeated and the passive diameter of arteries at each pressure step was obtained. Myogenic tone (MT) was calculated as follows:

Formula
where dCa-free is the diameter obtained at a given PP in Ca2+-free PSS, d is the steady state diameter reached by the vessel at a given luminal pressure, and dKPSS is the diameter obtained at a given PP in 127 mmol l–1 KCl PSS.

In a second protocol, after the equilibration period at a PP of 60 mmHg, cumulative concentration–response curves to phenylephrine (Phe, 10–10 to 3x10–5 mol l–1), an {alpha}1-adrenergic receptor ({alpha}1–AR) agonist, or oxymetazoline (OXY, 10–10 to 3x10–5 moll–1), an {alpha}2-AR agonist, were obtained. After a washout period of 20 min, the cumulative concentration–response curve to the selected agonist was repeated after NO formation blockade for 20 min with N{omega}-nitro-L-arginine (L-NOARG, 0.1 mmol l–1) or ET-1 receptor inhibition with bosentan (10 µmol l–1) or BQ 123 (1 µmol l–1). In another series of experiments, L-NOARG and bosentan or L-NOARG and BQ 123 were combined before agonist challenges. One agonist per vessel was used and only two cumulative concentration–response curves were obtained. At the conclusion of each experiment, passive and active diameters at a PP of 60 mmHg were obtained. Contractile responses are expressed as changes (percentage) in diameter, normalized to the passive and minimum active diameter. They are calculated according to the formula:

Formula
where dCa-free is the diameter obtained at a PP of 60 mmHg in Ca2+-free PSS, d is the steady-state diameter reach by the vessel at 60 mmHg, and dKPSS is the diameter obtained at 60 mmHg in 127 mmol l–1 KCl PSS. A value of 100% represents complete dilation and 0% a full constriction.

In a last series of experiments, the endothelium was removed by perfusion of the vessels with air. Before cannulating the distal end of the vessel, 1 ml of air was injected through the proximal pipette into the lumen for 1 min. The vessel was mounted on the proximal pipette. Then, the artery was perfused with PSS for 10 min at a pressure of 20 mmHg to clear the debris. The outflow stopcock was then closed and the PP raised to 60 mmHg for 30 min to reach a stable tone. At this pressure, the efficacy of endothelial denudation was ascertained by testing the arterial responses to acetylcholine (1 µmol l–1) of vessels constricted with Phe or OXY (1 µmol l–1). Infusion of air resulted in a loss of function of the endothelium as indicated by the absence of relaxation to acetylcholine (data not shown). After removal of the endothelium, cumulative concentration–response curves to Phe or OXY were obtained.

Experiments in calcium-free solution were performed at the end of each protocol because of the presence of SNP and EGTA which was difficult to wash-out contrary to 127 mmol l–1 KCl.

All drugs were added directly to the vessel chamber and final concentrations are given. Salts and chemicals were obtained from Sigma Chemical (St. Louis, MO) except for BQ 123 (American Peptide Comp., Sunnyvale, CA) and were prepared on the day of the experiment (except for BQ 123 which was aliquoted and stored at –80°C). Bosentan was a generous gift from Dr. Sebastien Roux (Hoffmann–La Roche, Basel, CH). To prepare K+-rich solutions, equimolar amounts of NaCl were replaced with KCl. The half-maximum effective concentrations (EC50) of Phe and OXY were measured from each individual dose–response curve using a logistic curve-fitting program (Allfit®, Dr. Deléan, University of Montréal). The pD2 value is the negative log of the EC50. Results are presented as mean±SEM. Only two vessels were used from each rabbit; n refers to the number of rabbits (one segment from one rabbit was used for one protocol).

Statistical analyses were done by ANOVA followed by a Scheffe’s F test. A value of P<0.05 was considered significant.


   3 Results
Top
 Abstract
 1 Introduction
 2 Methods
 3 Results
4 Discussion
 References
 
In the first series of experiments (n=10), the pressure–diameter relationship were obtained in the presence of the endothelium. As shown by Fig. 1, a PP of 40 to 120 mmHg induced contractions. In these conditions, MT represented 16±4, 16±6, 21±5 and 14±2% of the minimal diameter at PP of 60, 80, 100 and 120 mmHg, respectively. Below and above this range of PP, contractions were not significant. All subsequent experiments were performed at a PP of 60 mmHg.


Figure 1
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  		Fig. 1 Artery diameter as a function of PP in control conditions, in the presence of Ca2+-free solution (passive diameter, see Methods) or 127 mmol l–1 PSS (minimal diameter, see Methods). *: P<0.05 vs. two other experimental conditions (n=10). The data are mean±SEM.

 
3.1 Influence of NO and ET-1 on myogenic tone
In vessels with an intact endothelium (n=23), MT at a PP of 60 mmHg was 17±1%. As shown in Fig. 2, MT was augmented (P<0.05) by 140% by NO synthase inhibition (i.e. in the presence of L-NOARG, n=20).


Figure 2
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  		Fig. 2 Variation of the amplitude of the MT at a PP of 60 mmHg (% minimal diameter). Results were obtained in the absence of endothelium (–Endo) or in the presence of an intact endothelium (+Endo) in control solution (control, n=23), after inhibition of NO production alone (L-NOARG, n=20), ET-1 receptors alone (BOS, n=20; BQ 123, n=14) or combined inhibition (L-NOARG+BOS, n=21; L-NOARG+BQ, n=14). *: P<0.05 vs. control; {dagger}: P<0.05 vs. L-NOARG. The data are mean±SEM.

 
By contrast, blockade of ETA/B receptors (i.e. in the presence of bosentan, n=20) or ETA receptors (i.e. in the presence of BQ 123, n=14) decreased (P<0.05) the magnitude of the MT by ~30% compared to control. Combination of L-NOARG and bosentan (n=21) or L-NOARG and BQ 123 (n=14) reduced MT by {approx}30% compared to the MT obtained in the presence of L-NOARG alone (P<0.05).

After removal of the endothelium (n=25), the MT was lower (P<0.05) than in the presence of an intact endothelium but similar to the MT developed in the presence of bosentan or BQ 123 alone (Fig. 2). Furthermore, it was neither affected by L-NOARG nor bosentan.

3.2 Influence of NO and ET-1 on {alpha}1-AR-dependent contraction
The sensitivity of Phe-induced contraction (Fig. 3) was augmented by L-NOARG as indicated by the increase (P<0.05) in the pD2 value from 6.18±0.17 in control solution (n=11) to 7.31±0.49 (n=10). By contrast, the sensitivity of Phe was neither affected by bosentan (pD2=6.19±0.14, n=11) nor BQ 123 (pD2=6.11±0.11, n=7).


Figure 3
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  		Fig. 3 Contractile response to phenylephrine at PP 60 mmHg expressed as a function of passive and minimal diameter (see Methods). Results were obtained in the presence of an intact endothelium in control solution (control, n=11), after inhibition of NO production alone (+L-NOARG, n=10), ET-1 receptors alone (+BOS, n=11; +BQ 123, n=7) or combined inhibition (+L-NOARG+BOS, n=11; +L-NOARG+BQ 123, n=7). The data are mean±SEM.

 
In the absence of NO production, addition of bosentan (pD2=6.27±0.11, n=11) or BQ 123 (pD2=5.90±0.18, n=7) restored (P<0.05) the sensitivity to Phe.

Removal of the endothelium (Fig. 4) decreased (P<0.05) the sensitivity to Phe (pD2=5.2±0.19, n=13) compared to control (n=11).


Figure 4
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  		Fig. 4 Contractile response to phenylephrine at PP 60 mmHg expressed as a function of passive and minimal diameter (see Methods). Results were obtained in the presence (+EC, n=11) or in the absence (–EC, n=13) of an intact endothelium in control solution. The data are mean±SEM.

 
3.3 Influence of NO and ET-1 on {alpha}2-AR-dependent contraction
The sensitivity of OXY-induced contraction (Fig. 5) was not affected by the different antagonists and inhibitors used in the study. pD2 values were 7.73±0.19 in control solution (n=12), 7.85±0.27 in the presence of L-NOARG (n=10), 7.91±0.16 in the presence of bosentan (n=10), and 7.11±0.19 in the presence of BQ123 (n=7). Combination of L-NOARG and bosentan (pD2=8.42±0.44, n=10) or L-NOARG and BQ 123 (pD2=7.60±0.14, n=7) did not affect the sensitivity of OXY.


Figure 5
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  		Fig. 5 Contractile response to oxymetazoline at PP 60 mmHg expressed as a function of passive and minimal diameter (see Methods). Results were obtained in the presence of an intact endothelium in control solution (control, n=12), after inhibition of NO production alone (+L-NOARG, n=10), ET-1 receptors alone (+BOS, n=10; +BQ 123, n=7) or combined inhibition (+L-NOARG+BOS, n=10; +L-NOARG+BQ 123, n=7). The data are mean±SEM.

 
Removal of the endothelium (Fig. 6) did not affect the sensitivity to OXY (pD2=7.23±0.15, n=12) compared to control (n=12).


Figure 6
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  		Fig. 6 Contractile response to oxymetazoline at PP 60 mmHg expressed as a function of passive and minimal diameter (see Methods). Results were obtained in the presence (+EC, n=12) or in the absence (–EC, n=12) of an intact endothelium in control solution. The data are mean±SEM.

 

   4 Discussion
Top
 Abstract
 1 Introduction
 2 Methods
 3 Results
 4 Discussion
References
 
The results of this study indicate that the magnitude of the MT is regulated by NO and ET-1 via activation of smooth muscle ETA receptors. No interaction between NO and ET-1 was observed since blockade of ET-1 receptors reduced MT to a similar extent with or without NO production. By contrast, {alpha}1-AR-dependent contractions were largely dependent on endogenous ET-1 in the absence of NO release, whereas {alpha}2-AR-dependent contractions were insensitive to the inhibition of NO and ET-1 receptors. This highlights a fundamental difference in the endothelium-dependent regulation of vascular tone between non-stimulated and stimulated states.

Alteration in intravascular pressure leads to well-established changes in blood vessel diameter: an increase in intraluminal pressure induces myogenic contraction, while a decrease results in myogenic dilation [10]. This phenomenon is a characteristic of resistance arteries which is to a great extent responsible for the autoregulation of blood flow. We first determined the level of MT developed by isolated pressurized mesenteric arteries; as shown by Fig. 1, vessels exhibited myogenic responses within an expected range of pressures for vessels of this size [11] i.e. between 60 and 120 mmHg. All subsequent experiments were performed at 60 mmHg.

Although MT is smooth muscle-dependent, the endothelium greatly influences the magnitude of the myogenic response to pressure [4,12]. Our data extend these observations to the rabbit mesenteric bed and demonstrate that NO production prevents to a great extent myogenic responses to pressure (Fig. 2). However, our data show that the endothelium-dependent regulation of MT is not limited to NO; ET-1 plays an important role by facilitating the myogenic response via activation of ETA receptors. However, blockade of ET-1 receptors either with bosentan or BQ 123 reduced MT to a similar extent (~30%) in the presence or in the absence of NO production. This indicates that pressure-induced tone is regulated independently by NO and ET-1, i.e. no interaction was evident between the two endothelium-derived factors either directly or indirectly through activation of endothelial ETB receptors. Thus, activation of ETB receptors by ET-1 does not play a significant role in the endothelium-dependent regulation of the MT. Furthermore, smooth muscle-derived ET-1 could not account for the observed effects of L-NOARG since bosentan had no influence on MT in denuded arteries (Fig. 2). It further suggests that blockade of ET-1 receptors was complete in the presence of the antagonists since bosentan and BQ 123 decreased MT to a level similar to that observed in denuded arteries.

On the contrary to pressure, contractile responses to {alpha}-AR agonists were affected differently by endothelium-derived factors. For pharmacological agents used in this study to block the production of NO and ET-1 receptors modified resting diameters, pD2 values (i.e. sensitivity) were best representative of changes in {alpha}-AR agonist-dependent responses in the presence or in the absence of ET-1 receptor antagonists, L-NOARG or the endothelium.

The sensitivity of Phe-induced contractions was increased by NO synthase inhibition as recently reported in human myometrial resistance arteries [13]. However, our data demonstrate that endogenously produced ET-1 is responsible for this increase in sensitivity to Phe. This ET-1-dependent increase in sensitivity to Phe was only apparent after NO blockade since bosentan or BQ 123 alone did not affect the Phe-induced response in the presence of normal background NO. This contrasts with the response to pressure that was sensitive to ET-1 receptor blockade with or without NO. Most importantly, the increase in sensitivity to Phe after blockade of NO production may be due to endothelium-derived ET-1 rather than the elimination of a vasodilator acting directly on the smooth muscle. This statement is strengthened by the following evidences: first, ET-1 receptor antagonists totally reversed the sensitivity to Phe to control values. Secondly, endothelial denudation decreased the sensitivity to Phe indicating that the endothelium exerts a pro-contractile influence, most likely via the release of ET-1 that increases smooth muscle contractile elements sensitivity to Ca2+ [14,15]. Thus, {alpha}1-AR agonist-induced contraction is largely dependent on endothelium-derived ET-1 in the absence of NO production. This is not the case for {alpha}2-AR agonist-induced contraction. The sensitivity to OXY was neither affected by bosentan, BQ 123, L-NOARG nor endothelial denudation. These results indicate that {alpha}2-AR agonist-induced contraction is mostly myogenic and unregulated by the endothelium. This is in agreement with previous results obtained in rat cerebral arteries [16].

The differences in endothelium-dependent regulation of {alpha}-AR-mediated contractions are difficult to explain. {alpha}2-AR, but not {alpha}1-AR, are expressed both on endothelial and smooth muscle cells [17,18]. The apparent lack of involvement of the endothelium in {alpha}2-AR-mediated responses may be due to the compensatory effect of endothelial {alpha}2-AR: when activated, the release of an endothelium-derived hyperpolarizing factor (EDHF) may reduce the pro-contractile effect of ET-1. We previously reported that in the absence of NO production [19], activation of endothelial {alpha}2-AR induced a relaxation via the release of an EDHF in mouse mesenteric arteries. A proposed mechanism evidencing the heterogeneity of the two adrenergic pathways [20] and the possible influence of the endothelium and its factors on these pathways is presented in Fig. 7.


Figure 7
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  		Fig. 7 Diagram representing the possible interactions between {alpha}-adrenergic pathways and the endothelium. By increasing protein kinase C (PKC) activity, ET-1 potentiates the contraction mediated by {alpha}1-AR agonists which activate phospholipase C (PLC) to produce the endogenous activator of PKC, diacylglycerol (DG), and inositol trisphosphate (IP3) which trigger the release of intracellular calcium (Ca2+) from the stores. {alpha}2-AR stimulation, however, increases intracellular free Ca2+via Ca2+ influx. On endothelial cells, activation of {alpha}2-AR stimulates NO synthase to produce NO that counteracts the contraction mediated by smooth muscle {alpha}2-AR stimulation. In the absence of NO, {alpha}2-AR agonists stimulate the release of an endothelium-derived relaxing factor (EDHF). In the absence of {alpha}-AR agonists, the myogenic contraction is modulated by the basal release of ET-1 and NO.

 
In conclusion, our results indicate that, in the absence of vaso-active prostanoids, pressure-induced tone is regulated by endothelium-derived NO and ET-1 but no interaction between the two factors was evident. In contrast, {alpha}1-AR stimulation-induced contraction of pressurized mesenteric arteries is sensitive to ET-1 receptor blockade in the absence of NO synthase activity, whereas occupation of {alpha}2-AR mediates a contraction that appears to be unregulated by the endothelium.

Time for primary review 21 days.


   Acknowledgements
 
This work was supported by the Research Foundation of the Montreal Heart Institute, the Heart & Stroke Foundation of Quebec and the Medical Research Council of Canada. We are grateful to Dr. Sébastien Roux for generously providing bosentan.


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

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