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Cardiovascular Research 2001 49(1):218-225; doi:10.1016/S0008-6363(00)00224-8
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Copyright © 2000, European Society of Cardiology

Increased {alpha}1- and {alpha}2-adrenoceptor-mediated contractile responses of human skeletal muscle resistance arteries in chronic limb ischemia

Yagna P.R. Jarajapua, Paul Coatsa, John C. McGrathb, Allan MacDonalda and Chris Hilliera,*

aVascular Assessment Group, School of Biological and Biomedical Sciences, Glasgow Caledonian University, Cowcaddens Road, Glasgow G4 0BA, UK
bAutonomic Physiology Unit, West Medical Building, University of Glasgow, Glasgow, UK

* Corresponding author. Tel.: +44-141-331-3952; fax: +44-141-331-3208

Received 7 June 2000; accepted 28 July 2000


   Abstract
Top
 Abstract
1 Introduction
 2 Methods
 3 Results
 4 Discussion
 References
 
Objective: Recently, we have shown augmented contractile responses of skeletal muscle resistance arteries to noradrenaline in patients with critical limb ischemia. We investigated whether this increased sensitivity in skeletal muscle resistance arteries is due to either {alpha}1- or {alpha}2-adrenoceptor-mediated responses or both. Methods: Skeletal muscle resistance arteries were isolated from the proximal (non-ischemic) and distal (ischemic) parts of limbs amputated for critical limb ischemia and mounted on a small vessel wire myograph. Cumulative concentration response curves of the vessel segments to noradrenaline, phenylephrine and brimonidine were obtained in the presence or the absence of the selective antagonists, prazosin and RS79948. Results: Noradrenaline and phenylephrine produced almost equal maximal contractile responses. Brimonidine responses were smaller and were almost abolished by 0.1 µM RS 79948 while those of phenylephrine and noradrenaline were not affected. Prazosin reduced the maximum responses to brimonidine, shifted the concentration response curves of noradrenaline and phenylephrine rightwards giving pKB values of 9.86 and 9.33, respectively. Maximum responses produced by all three agonists in distal vessels were significantly higher than those obtained in proximal vessels. Conclusions: Noradrenaline contractile responses in skeletal muscle resistance arteries are predominantly mediated by {alpha}1-adrenoceptors. Both {alpha}1- and {alpha}2-adrenoceptor-mediated responses are increased in the arteries from ischemic regions that may aggravate the decreased blood flow to the limbs due to arterial occlusion.

KEYWORDS Adrenergic (ant)agonists; Arteries; Ischemia; Receptors; Vasoconstriction/dilation


   1 Introduction
Top
 Abstract
 1 Introduction
2 Methods
 3 Results
 4 Discussion
 References
 
Critical limb ischaemia (CLI) is a chronic ischaemic condition produced by the occlusion of the large conducting arteries. A reduced perfusion pressure in the distal circulation is manifested in the early stages as a reduction in blood flow to the skeletal muscle vascular bed during mild exercise, termed intermittent claudication [1,2].

There is presently no perfect animal model to simulate this complex condition caused by a variety of factors. The ischaemic limb amputated for CLI offers a good pharmacological model to study the resistance arteries for vascular dysfunction since both ischaemic and non-ischaemic (from the incision level selected for optimum wound healing) arteries can be isolated from the same amputated limb. There have been few studies that have focussed on the functional and structural alterations in the resistance vasculature of the skin and skeletal muscle in CLI. The haemodynamic environment in the resistance vasculature during CLI is characterized by a low-flow, low-pressure environment [1], which may directly or indirectly regulate the structure and function of the resistance vasculature [3,4]. The effect of CLI on human resistance arteries appears to be dependent on the vascular bed studied. Recently it was shown that the subcutaneous resistance arteries from the distal part of the ischaemic limb produced impaired vasoconstrictor responses to noradrenaline whereas those from skeletal muscle showed exaggerated responses [5,6].

In this study we characterised the increased reactivity to noradrenaline in skeletal muscle resistance arteries in CLI to examine whether this was mediated by either {alpha}1- or {alpha}2-adrenoceptors or both, using the agonists noradrenaline, phenylephrine and brimonidine non-selective, {alpha}1-selective and {alpha}2-selective [7] agonists, respectively. The selectivity of the agonists in these arteries was confirmed using the selective antagonists prazosin and RS 79948. Prazosin is a selective {alpha}1-adrenoceptor antagonist [8] without subtype selectivity which has been extensively used to characterise {alpha}1-adrenoceptors in in vivo and in vitro studies [9]. RS 79948, an ethyl derivative of delequamine [10], is a potent and selective {alpha}2-antagonist (but not selective for any of the three {alpha}2-subtypes identified) [11].


   2 Methods
Top
 Abstract
 1 Introduction
 2 Methods
3 Results
 4 Discussion
 References
 
This study was performed according to the Declaration of Helsinki (Cardiovascular Research 1997;35:2–3). Patient details are given in Table 1. Most of these patients had underlying diseases such as diabetes, hypertension, angina or ischaemic heart disease. In some patients, smoking alone was the reason for the chronic limb ischaemia. Tissues from patients of either sex were taken for experimentation.


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  		Table 1 Clinical information on patients with CLI

 
2.1 Preparation of skeletal muscle resistance arteries
Skeletal muscle biopsies (~1 cm3) were obtained from patients who fulfilled the criteria for CLI defined in the European Consensus Document 1991 [12], immediately after leg amputation. The level of amputation was always selected to be in a non-ischaemic area where the haemodynamics were physiologically normal and the vessel segments obtained from this area represented an internal non-ischaemic control (proximal arteries). The distal portion of the limb represented an ischaemic region and so the vessel segments isolated from these tissues represent ischaemic ones (distal arteries). Proximal specimens were obtained either from medialis (in case of above the knee amputation) or gastrocnemius muscle (in case of below the knee amputation). Preliminary experiments showed no difference in the reactivity of the arteries, isolated from either of the proximal non-ischaemic sites, to different agonists. Distal specimens were always taken from soleus muscle. Biopsies were transported to the laboratory in physiological saline solution (PSS) under ice cold conditions. Small arteries were isolated from the biopsies under a stereomicroscope (Zeiss) within 2–3 h of the time of amputation.

2.2 Small vessel wire myography
Small arteries were isolated from the biopsies and arterial segments of 2 mm length were mounted in a small vessel wire myograph (Danish MyoTech, Aarhus, Denmark) for isometric tension measurements. The vessel segments were incubated in physiological saline solution (PSS) of composition in mM: NaCl (119), KCl (4.5), NaHCO3 (25), KH2PO4 (1.0), MgSO4·7H2O (1), glucose (6) and CaCl2 (2.5), at 37°C and gassed with carbogen. One hour after mounting, the resting tension–internal circumference relation was determined for each vessel segment [13]. Then, the resting tension was set to a normalised internal circumference of L0.9 where L0.9=0.9L100 and L100 is the internal circumference that the vessel would have under a transmural pressure of 100 mmHg. The software programs Myodaq and Myodata were used for data-acquisition. Subsequently, the vessels were stimulated twice with high potassium solution (123 mM) and then with 10 µM noradrenaline. Arterial segments were considered viable if they produced an effective pressure of more than 100 mmHg or 13.3 kPa when stimulated with 123 mM KCl. Effective pressure was calculated from the Laplace equation:

Formula
which corrects for differences in length and diameter of arterial segments [13]. According to this criterion all the vessel segments used in this study were found to be viable. The presence of functional endothelium was checked with 1 µM carbachol after pre-contracting with 1 µM noradrenaline. All the vessels in the study produced at least 30% relaxation. In some vessels, the endothelium was mechanically removed by gently rubbing the luminal side of the vessel wall with hair that had been stored in ethanol and rinsed in PSS before use. Endothelial removal was confirmed by the lack of relaxation to carbachol when tested as described above. After an equilibration period, concentration response curves (CRCs) to the adrenoceptor agonists noradrenaline (non-selective), phenylephrine ({alpha}1-selective) and brimonidine ({alpha}2-selective) were constructed over a concentration range from 1 nM to 30 µM in PSS containing 1 µM propranolol, 3 µM cocaine and 3 µM corticosterone (to block β-adrenoceptors, neuronal uptake and non-neuronal uptake of noradrenaline, respectively). In experiments where the efficacy of the agonists was compared, the order of the exposure to the three agonists was chosen randomly in order to overcome the influence of the order of exposure on the vessel response. In experiments using antagonists, the vessels were incubated for 30 min with 0.1 µM of the antagonist before a second CRC was obtained. Preliminary experiments showed that repeated CRCs were reproducible and no corrections for time-dependent changes were required.

2.3 Drugs
(±)-Noradrenaline (arterenol) bitartrate, L-phenylephrine hydrochloride and prazosin hydrochloride were obtained from Sigma (Poole, Dorset, UK); brimonidine (UK 14304) and RS 79948 ((8aR,12aS,13aS)-5,8,8a,9,10,11,12,12a,13a-Decahydro-3-methoxy-12-(ethylsulphonyl)-6H-isoquino[2,1-g][1,6]-naphthyridine) were obtained from Tocris (Avonmouth, Bristol, UK). Noradrenaline, phenylephrine and prazosin were dissolved in distilled water and the stock solution of brimonidine was prepared by dissolving in 25% ethanol. PSS containing 123 mM KCl was prepared by replacing NaCl with an equimolar quantity of KCl.

2.4 Statistical analysis
Results are presented as mean±S.E. mean. Lumen diameters (L0.9), KCl responses, pEC50 values and maximum responses of the proximal and distal arterial segments were compared by Student's paired t-test. Maximum responses of the agonists in proximal arterial segments were compared by ANOVA with a Newman–Keuls test for multiple comparison. Complete CRCs were compared by ANOVA for repeated measures. pEC50 values of the agonists were obtained from their CRCs using the software program Graphpad Prism. pKB values for prazosin were calculated from the equation:where [antagonist] is the molar concentration of the antagonist and DR is the ratio of the EC50 of the agonist in the presence of antagonist to that in the absence.


   3 Results
Top
 Abstract
 1 Introduction
 2 Methods
 3 Results
4 Discussion
 References
 
3.1 Efficacy of the agonists
In order to compare the efficacies of the agonists in human skeletal muscle resistance arteries, CRCs of the three agonists were obtained in the same vessel. This set of experiments was done in vessel segments isolated from proximal, i.e. non-ischaemic, skeletal muscle (n = 7). Lumen diameter (L0.9) of the vessels used in this set of experiments was 281±32 µm. Table 2 shows the pEC50 values and maximum contractile responses, expressed as per cent of KCl responses, of the three agonists. The maximum responses to noradrenaline and phenylephrine were not significantly different. Maximum responses to brimonidine were significantly smaller than both noradrenaline and phenylephrine (P<0.05). No significant differences were observed in the pEC50 values of the three agonists.


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  		Table 2 Effect of different {alpha}-adrenoceptor agonists in human skeletal muscle resistance arteriesa

 
3.2 Selectivity of the agonists
Selectivity of the agonists used in the study was checked by the {alpha}2-selective antagonist RS 79948 and the {alpha}1-selective antagonist prazosin. Lumen diameter (L0.9) of the vessels used in this set of experiments was 353±22 µm, isolated from proximal–non-ischaemic skeletal muscle.

Incubation of the proximal arterial segments with 0.1 µM RS 79948 had no significant effect on the pEC50 values (6.4±0.1 and 6.1±0.2 before and after treatment with RS 79948, P>0.05) values or the maximum responses of noradrenaline (n = 7) (Fig. 1A). However the CRCs were significantly different when tested with ANOVA (P<0.05). Additional exposure of vessels to 0.1 µM prazosin (n = 5) produced a 366-fold right-ward shift of the CRC with no significant change in the maximum response (% maximum control responses before and after treatment with prazosin, 103±13 and 70±8, respectively). The shift produced by prazosin gave an estimated pKB value of 9.56.


Figure 1
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  		Fig. 1 Effect of RS 79948 and prazosin on the CRCs of (A) noradrenaline (B) phenylephrine and (C) and (D) brimonidine in proximal–non-ischaemic skeletal muscle resistance arteries. Contractile responses are expressed as percent of the maximum response obtained in the control CRC. *CRCs are significantly different at P<0.05 (ANOVA); **Highly significant at P<0.001 (ANOVA).

 
RS 79948 had no effect on the pEC50 values (6.2±0.2 and 5.9±0.3 before and after treatment with RS 79948, P>0.05) or maximum responses obtained with phenylephrine (n = 6) (Fig. 1B) and the CRCs were not significantly different when tested by ANOVA. Addition of 0.1 µM prazosin (n = 3) produced a 215-fold rightward shift of the phenylephrine CRC without affecting the maximum response. The shift produced by prazosin gave an estimated pKB value of 9.33.

Incubation of the proximal arterial segments (n = 5) with 0.1 µM RS 79948 almost abolished the contractile responses of brimonidine (Fig. 1C). In the presence of this antagonist, two of the five arterial segments did not show any contractile response to brimonidine in the concentration range used and so the pEC50 values were not calculated. In a separate set of experiments (n = 3), incubation of the arterial segments with 0.1 µM prazosin had no effect on the pEC50 values (control: 6.7±0.2; prazosin: 6.6±0.2) but significantly decreased the maximum response to 67±6% of the control (P<0.05) (Fig. 1D).

3.3 Influence of endothelium on the contractile responses of brimonidine
In order to evaluate the influence of endothelium on brimonidine contractile responses, arterial segments isolated from proximal–non-ischaemic skeletal muscle were denuded of the endothelium. Lumen diameters (L0.9) and contractile responses to KCl were not significantly different in the arterial segments with and without endothelium (L0.9 (microns): 313±32 and 299±36; KCl responses (mN): 3.2±0.7 and 2.5±0.4 in the arterial segments with and without endothelium, respectively). Arterial segments which were denuded of the endothelium showed less than 20% relaxation to carbachol whereas those with intact endothelium showed 60–100% relaxation (n = 5). The contractile responses to brimonidine in the arterial segments with and without endothelium showed no significant difference in either maximum responses expressed as percent of KCl responses (4.7±1.3 and 5.7±1.8 in arterial segments with and without endothelium, respectively) or pEC50 values (5.8±0.6 and 5.8±0.6 in arterial segments with and without endothelium, respectively).

3.4 Effect of chronic ischaemia on the contractile responses of the agonists
Table 3 gives the lumen diameters (L0.9) of the arterial segments, KCl responses and pEC50 and maximum contractile responses for the three agonists in proximal and distal arteries. The lumen size of the vessels used from ischaemic (distal) and non-ischaemic (proximal) tissues were similar and no significant difference was observed in the KCl-induced contractile responses. Maximum contractile responses to the three agonists were significantly increased in the distal–ischaemic arterial segments compared to that in the proximal–non-ischaemic arteries (Table 3 and Fig. 2). No significant differences were observed in pEC50 for any of the three agonists between proximal and distal arteries. Analysis of individual vessels (Fig. 3) shows that distal arteries from almost all patients showed increased contractile responses compared to proximal arteries.


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  		Table 3 Lumen diameter (L0.9) and the contractile responses to 123 mM KCl and the agonists — noradrenaline (NA), phenylephrine (PE) and brimonidine (BR) — with their pEC50 values in proximal–non-ischaemic and distal–ischaemic skeletal muscle resistance arteries

 

Figure 2
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  		Fig. 2 Contractile responses of the agonists (A) noradrenaline, (B) phenylephrine and (C) brimonidine in proximal–non-ischaemic ({blacksquare}) and distal–ischaemic ({blacktriangleup}) skeletal muscle resistance arteries. *CRCs obtained in distal arteries with all three agonists are significantly greater than those obtained in proximal arteries at P<0.0001.

 

Figure 3
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  		Fig. 3 Maximum contractile responses of the agonists (A) noradrenaline, (B) phenylephrine and (C) brimonidine in proximal–non-ischaemic ({blacksquare}) and distal–ischaemic ({blacktriangleup}) skeletal muscle resistance arteries from individual patients. Contractile responses are expressed as percent of KCl response. (—) indicates the mean value of the responses.

 

   4 Discussion
Top
 Abstract
 1 Introduction
 2 Methods
 3 Results
 4 Discussion
References
 
We have confirmed that responses to noradrenaline are increased in the resistance arteries from ischaemic skeletal muscle [5,16]. The present study shows for the first time that both {alpha}1- and {alpha}2-adrenoceptor mediated contractile responses are exaggerated as shown by the responses to the agonists phenylephrine and brimonidine (UK 14304). The increase in contractile responses to noradrenaline is not via non-specific mechanisms since the contractile responses to KCl in ischaemic and non-ischaemic vessels were not significantly different. Although the patient group is heterogeneous with regard to sex, underlying complications, drug treatment and smoking history, these factors do not account for the changes as non-ischaemic vessels from each patient served as an internal control. Despite patient heterogeneity, the ischaemic vessels from all patients show exaggerated responses to the agonists used in the study compared to paired non-ischaemic vessels.

Increased contractile responses to {alpha}1- and {alpha}2-adrenoceptor activation have previously been reported after a 3-h acute ischaemic condition in canine femoral arteries [14]. The increased contractile responses were associated with an increased density of {alpha}1- and {alpha}2-adrenoceptors. However, the effect of ischaemia on resistance arteries from the same vascular bed was not investigated in that study. In another similar study, increased sensitivity to noradrenaline in skeletal muscle arteries from iliac-ligated rats was reported [15]. These observations agree with our findings that ischaemic conditions lead to an alteration in the vascular responsiveness to noradrenaline. However, whereas this previous study showed an increased sensitivity to noradrenaline, we have observed increased maximum responses only. In the animal studies it was possible to compare the functional properties of the ischaemic arteries limbs with those from healthy animals. We have not been able to study skeletal muscle resistance arteries from healthy subjects; however the findings from the animal studies lend some support to the hypothesis that ischemia leads to hyper-responsiveness of the skeletal muscle vascular bed to noradrenaline.

This study also quantified for the first time the contribution of {alpha}1- and {alpha}2-adrenoceptors to the contractile responses of noradrenaline in human skeletal muscle resistance arteries. Contractions obtained to selective {alpha}1- and {alpha}2-adrenoceptor agonists phenylephrine and brimonidine suggest that both {alpha}1- and {alpha}2-adrenoceptors contribute to the contractile response of noradrenaline. In experiments where the contractile responses of all the three agonists were obtained in the same arterial segments, phenylephrine-mediated contractions were found to be similar to those of noradrenaline while brimonidine-mediated responses were significantly smaller than the other two agonists. These results suggest that noradrenaline responses are predominantly mediated by {alpha}1-adrenoceptors in these arteries and that {alpha}2-adrenoceptors mediate only a small contractile response. An alternative explanation for these results is that brimonidine is acting in these arteries as partial agonist. Previous studies have shown brimonidine to be a full agonist at the {alpha}2-adrenoceptors and in fact more potent than noradrenaline and clonidine in rabbit pulmonary artery and ileum [7]. Full agonist properties were also observed in rabbit and human platelets and rat atrium [17,18]. Based on these reports we may assume that brimonidine is a full agonist in the arterial preparation used in this study.

Studies with antagonists support this conclusion. RS 79948 had no significant effect on the pEC50 values and maximum responses of noradrenaline and phenylephrine but almost completely blocked responses to brimonidine. However, analysis of the noradrenaline CRCs in the presence of this antagonist did detect a significant difference indicating either a small contribution of {alpha}2-adrenoceptors to the noradrenaline responses or a small degree of {alpha}1-antagonism. The large shift produced by the selective {alpha}1-adrenoceptor antagonist prazosin in the CRCs of noradrenaline and phenylephrine in the presence of RS 79948, with respective estimated pKB values of 9.56 and 9.33, clearly shows the predominance of {alpha}1-adrenoceptors in the responses of these agonists. pKB values obtained are in agreement with published affinity values for the {alpha}1-adrenoceptor [19]. Similar pKB values were also obtained for noradrenaline and prazosin in the absence of RS 79948 (data not shown). These results confirm the selectivity of the agonists phenylephrine and brimonidine at {alpha}1- and {alpha}2-adrenoceptors although prazosin produced a decrease in the contractile responses of brimonidine. This might be due to some synergism between the predominant {alpha}2-mediated response with a small {alpha}1-component to brimonidine [20].

The small contribution of {alpha}2-adrenoceptors to noradrenaline responses observed in the present study is in agreement with other studies of blood vessels in vitro [20,21]. However, in vivo animal studies show that vascular post-junctional {alpha}2-adrenoceptors significantly contribute to vascular smooth muscle contraction [22]. The differences between in vivo and in vitro {alpha}2-mediated responses may be explained as follows. Firstly, in vivo {alpha}2-mediated responses may be facilitated by endogenous vasoconstrictors since it has been shown in in vitro studies that {alpha}2-mediated responses are uncovered by contractile agonists such as noradrenaline, phenylephrine, angiotensin II, vasopressin, serotonin, Bay K8644 or KCl [20,23,24]. These reports apparently show some synergism between the {alpha}2-adrenoceptor responses and those mediated by other receptors, possibly at the second messenger level. Secondly, in vivo {alpha}2-adrenoceptor mediated responses may be facilitated in situations where cAMP levels are high since pharmacological manipulation — pre-contraction with the thromboxane mimetic U46619 [GenBank] followed by relaxation with forskolin — revealed a large {alpha}2-adrenoceptor mediated response in porcine arteries [25] although facilitation by contractile agonists was not observed [26].

The role of a functional endothelium is also an important consideration with regard to {alpha}2-adrenoceptor-mediated responses since it has been shown in rat aorta that contractile responses to {alpha}2-adrenoceptor agonists were significantly smaller in the presence of endothelium than in its absence [27]. In the present study, no potentiation of the contractile responses to brimonidine was observed in arterial segments denuded of endothelium. Therefore, the small responses observed to brimonidine are not due to the release of endothelium-derived relaxing factors [27].

In contrast to the present study, showing a poor {alpha}2-adrenoceptor-mediated contractile response in skeletal muscle resistance arteries in vitro, a marked contractile response to an {alpha}2-adrenoceptor agonist in human subcutaneous resistance arteries has been observed [28]. It has also been shown that {alpha}2-adrenoceptor-mediated contractile responses are inversely proportional to the lumen diameter in human omental small arteries [29].

Increased responses of the skeletal muscle vasculature to adrenergic agonists contrasts with the reduced vasoconstrictor responses in the resistance arteries of ischaemic skin to noradrenaline and angiotensin II despite both vascular beds showing atrophic changes due to ischaemia [5,16]. These findings on ischaemic arteries may explain some of the clinical manifestations of CLI, in particular, impaired microvascular constriction and oedema in the skin [30,31], and severe muscular pain at rest [32]. These contrasting responses of vasculature from the skin and skeletal muscle may participate in a redistribution of blood flow to the skin and away from muscle particularly during exercise when there is sympathetic activation and plasma catecholamine levels increase. The reduced blood flow to the limb distal to the arterial occlusion in CLI would be further aggravated by the increased adrenoceptor-mediated responsiveness. If the skeletal muscle vasculature in the affected limb has an increased responsiveness to endogenous, neuro-hormonally released catecholamines, this may also explain the severity of symptoms during pain and stress peri- and post-operatively when levels of circulating catecholamines are again known to increase significantly.

In conclusion, we have shown that the hyper-responsiveness of the resistance arteries from the ischaemic skeletal muscle to noradrenaline is mediated by both {alpha}1- and {alpha}2-adrenoceptors. The particular subtypes of {alpha}1- and {alpha}2-adrenoceptors [33] involved in this response have yet to be characterised. It is also not known whether the observed hyper-responsiveness to {alpha}-adrenoceptor activation is due to either increased receptor density or hyperactive transduction mechanisms or the interaction with other endogenous vasoconstrictors.

Time for primary review 26 days.


   Acknowledgements
 
We thank the surgeons and the theatre staff from the Department of Vascular Surgery at Glasgow Royal Infirmary and Gartnavel General Hospital. Yagna P.R. Jarajapu is supported by the School of Biological and Biomedical Sciences, Glasgow Caledonian University.


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

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