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Eur J Cardiothorac Surg 2008;34:839-844. doi:10.1016/j.ejcts.2008.06.016
Copyright © 2008, European Association for Cardio-thoracic Surgery. Published by Elsevier. All rights reserved.
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Attenuation of receptor-dependent and -independent vasoconstriction in the human radial artery

Michael J. Shackclotha, Alan R. Conanta,*, Joyce Thekkudana, Sanjay Ghotkara, Alec W.M. Simpsonb, Walid C. Dihmisa

a The Cardiothoracic Centre, Thomas Drive, Liverpool, UK
b Department of Human Anatomy & Cell Biology, University of Liverpool, UK

Received 10 January 2008; received in revised form 9 June 2008; accepted 11 June 2008.

* Corresponding author. Current address: Physiology Dept, University of Liverpool, Crown St, Liverpool L69 3BX, UK. Tel.: +44 151 7945510; fax: +44 151 7945517. (Email: conant{at}liv.ac.uk).


   Abstract
Top
 Abstract
1. Introduction
 2. Material and methods
 3. Results
 4. Discussion
 References
 
Background: Vasodilator strategies used to treat bypass grafts in the operating theatre, such as nitrates, phosphodiesterase inhibitors and calcium channel antagonists have a broad but short-lived effect against a variety of vasoconstrictor stimuli. Treatments that react irreversibly with proteins modulating vasoconstriction have the advantage that their effects can last well into the postoperative period. In addition systemic effects are avoided as the treatment is localised to the treated graft. This study investigated the use of two clinically applied drugs; fluphenazine (SKF7171A, HCl), an irreversible calmodulin antagonist and minoxidil sulphate, an irreversible potassium channel opener. Treatments were tested against receptor and non-receptor-mediated contraction in the human radial artery. Method: Isometric tension was measured in response to angiotensin II, KCl and vasopressin in 108 radial artery rings (taken from 31 patients undergoing coronary artery bypass grafting). Control responses were compared with rings pretreated with fluphenazine or minoxidil sulphate. Vasopressin responses were also compared in the presence of glyceryl trinitrate or the reversible Rho kinase inhibitor Y27632. Results: Fluphenazine pretreatment significantly suppressed vasoconstriction to all agonists tested. Maximal responses to angiotensin II, vasopressin and KCl were reduced by 42 ± 19%, 35 ± 8% and 48 ± 15% respectively, without any measurable effect on the EC50. Minoxidil sulphate showed no discernable effect. Vasopressin-induced contraction was also reduced by high levels of glyceryl trinitrate (220 µM; 50 µg/ml) or 10 µM Y27632. Conclusions: The irreversible calmodulin antagonist fluphenazine has potential to be developed as an inhibitor of contraction in arterial graft vessels. The involvement of Rho kinase indicates that other vasoconstrictors and surgical stress can sensitize radial artery to vasopressin-induced contraction. Strategies targeting this pathway also have future potential.

Key Words: Arteries • Artery biochemistry/pharmacology • CABG • Arterial grafts • CABG • Pharmacology/physiology • Cell signaling • Receptors


   1. Introduction
Top
 Abstract
 1. Introduction
2. Material and methods
 3. Results
 4. Discussion
 References
 
In coronary artery bypass graft surgery (CABG) superior patient survival rates and increased freedom from major adverse cardiac events have been obtained in patients receiving left internal thoracic artery (ITA) grafts as opposed to saphenous vein grafts [1]. These results have encouraged surgeons towards a complete arterial revascularisation strategy. Promising patency rates obtained with the radial artery have now also established this graft as a good alternative to the right ITA [2]. The radial artery is a comparatively reactive graft and vasodilator strategies are topically applied by many surgeons in theatre and intravenously in the postoperative period to ameliorate vasospasm, which is believed to account for a proportion of early graft failures [2,3]. Vasodilator therapies include combinations of nitrates, phosphodiesterase inhibitors or calcium channel antagonists, and the recently introduced irreversible {alpha} adrenoceptor antagonist phenoxybenzamine [4,2,5]. The beneficial effects of this agent have been shown in a recent prospective study. Patients receiving phenoxybenzamine-treated grafts had a lower level of perioperative myocardial injury and a reduced incidence of adverse cardiac events when compared to a verapamil/glyceryl trinitrate treated group [5]. The strategy of using an irreversible inhibitor is very attractive, since it means that pharmacologically effective concentrations can be applied selectively to the graft and the effect maintained in the perioperative period without systemic complications.

Phenoxybenzamine has demonstrated the potential benefits of irreversible antagonists in CABG as treatment completely abolishes noradrenaline-induced contraction in radial artery for up to 16 h in vivo; unfortunately however the beneficial effects are limited to catecholamine-mediated vasoconstriction [6–8]. Vasoconstrictors other than catecholamines, released into the plasma in the immediate postoperative period [9] can still reduce flow through the treated graft [3]. Our aim was to test the potential for clinical application of other irreversible antagonists, with a broader range of activity and the potential to inhibit both receptor and non-receptor-mediated contraction in the radial artery. We tested two drugs used currently in other clinical settings, fluphenazine and minoxidil sulphate. Fluphenazine is a cell permeable, irreversible antagonist of calmodulin [10], the cellular protein that translates an increase in intracellular calcium into contraction. Minoxidil sulphate binds irreversibly to the vascular ATP-sensitive K+ channel (KATP channel) and is used as an antihypertensive agent [11].

Radial artery produces stronger vasoconstriction than ITA to virtually all vasoconstrictors studied [12–15]; however vasoconstriction is equivalent when normalised to account for the different vessel diameters in most cases. However, normalised responses to both angiotensin II and vasopressin in the radial artery are stronger and more sensitive than in the ITA, and occur irrespective of the presence of endothelium [12,14,15]. In addition, vasopressin-induced contraction in the radial artery is comparatively resistant to milrinone and glyceryl trinitrate, two of the most commonly used vasodilator strategies [15]. The inhibition of the vasopressin-induced contraction in radial artery grafts would be particularly advantageous for surgeons, since they may wish to use vasopressin to treat hypotension in the postoperative period [16]. In this study we investigated the ability of fluphenazine and minoxidil to inhibit contraction to vasopressin, angiotensin II and high potassium. Vasopressin data were compared with glyceryl trinitrate and with a Rho kinase inhibitor Y27632, as the inhibition of Rho kinase has been shown to reduce coronary artery vasospasm [17]. The potential of these treatments, particularly fluphenazine, as graft treatments in bypass surgery is discussed.


   2. Material and methods
Top
 Abstract
 1. Introduction
 2. Material and methods
3. Results
 4. Discussion
 References
 
2.1 Sample preparation
Samples of radial artery were obtained from 31 patients undergoing CABG at the Cardiothoracic Centre, Liverpool NHS Trust, UK. The clinical characteristics of these patients are given in Table 1 . The study was approved by the Liverpool Research ethics committee and informed consent was obtained from each patient. The radial artery was harvested with surrounding fat and the two satellite veins. Depending on the practice of the surgeons concerned, radial arteries were treated in the theatre with either 1.6 mM papaverine (Martindale Pharmaceuticals, Romford, UK) or 6 mM phenoxybenzamine (Goldshield Pharmaceuticals Ltd., Croydon, UK) in a solution of the patients’ whole blood for 30 min. Arterial sections surplus to surgical requirements were collected from theatre into Dulbecco's Modified Eagle's Media (Invitrogen, UK) on ice and immediately transported to the research laboratories.


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  		Table 1 Clinical characteristics of patients
 
2.2 Organ bath contraction studies
Radial artery sections were cut into 2–3 mm rings giving 108 rings in total. Arterial rings were suspended in thermostatically controlled organ chambers at 37 °C, filled with 25 ml Krebs–Henseleit buffer composed of 118 mM NaCl, 4.7 mM KCl, 25 mM NaHCO3, 1.2 mM KH2PO4, 1.2 mM MgSO4, 10 mM D-glucose, 1 mM CaCl2, gassed with carbogen (95% O2/5% CO2). Rings were mounted between wire stirrups connected to a force transducer and changes in isometric force recorded on a PowerLab 16SP data recording system, connected to an Octal ML119 bridge amplifier (ADInstruments Ltd., Chalgrove, Oxfordshire, UK). Prior to stimulation radial artery rings underwent a pretensioning protocol based on that described by He and Yang [14]. Arterial rings were set at a pretension equivalent to 100 mmHg, calculated from the internal circumference and the wall tension derived from the Laplace relationship. The tension was readjusted to the equivalent of 100 mmHg every 20 min over a 40-min period. All rings were then partially relaxed and left resting at approximately 90% of their maximal circumference for 20 min prior to study. To test for functional contractility, arterial rings were first stimulated with 90 mM KCl and all other responses, including later KCl responses, expressed as % of this response. Following surgical preparation and our contraction protocol, endothelial function, as evidenced by a vasodilatory response to 10 µM acetylcholine in rings precontracted with 30 mM KCl, was found to be negligible. Responses were terminated by washing with three complete changes of media. Rings pretreated with fluphenazine-N-2-chloroethane, diHCl (SKF7171A, HCl; Merck Chemicals Ltd., Nottingham, UK) were incubated in the presence of the drug for 40 min at 100 µM, 10-fold greater than the IC50 concentration for calmodulin [10]. Rings treated with minoxidil sulphate (Merck Chemicals Ltd.) were incubated for 30 min at 10 µM, a concentration reported to completely reverse noradrenaline-induced contraction in vascular smooth muscle [18]. Following incubation with fluphenazine or minoxidil sulphate the drug was removed by three complete changes of media. Responses to angiotensin II (Sigma, Poole, UK) were recorded within 20 min of drug washout and responses to Arg-vasopressin (Sigma) at either 30 or 120 min. Responses in treated rings were normalised to control rings stimulated in parallel and pretreated with vehicle alone (dimethylsulphoxide; DMSO). Y27632 (Merck Chemicals Ltd.) or glyceryl trinitrate (DBL, Warwick, UK) were added to the organ chamber 5 min prior to and during agonist addition.

2.3 Data analysis
Data are presented as mean ± standard deviation of the mean (SD), where n refers to the number of independent samples tested. The threshold vasopressin concentration was defined as the concentration at which tension was significantly raised above baseline tension. Data were tested for normal distribution and appropriate comparisons were undertaken as the analysis dictated using a one-way ANOVA and a Bonferroni correction for multiple comparisons. All analyses were carried out using the program Arcus QuickStat Biomedical using a p value of 0.05 (Hearne Scientific Software, Dublin, Eire).


   3. Results
Top
 Abstract
 1. Introduction
 2. Material and methods
 3. Results
4. Discussion
 References
 
The internal diameter at a pressure of 100 mmHg was 3.8 ± 0.9 mm. To test for functional vasoconstriction, sections of human radial artery were stimulated with 90 mM KCl that raised tension from a mean basal value of 1.93 ± 0.92 g (n = 31) to 7.70 ± 3.66 g. Data were collected from distal arterial sections treated with phenoxybenzamine in theatre (6.26 ± 2.18 g; n = 17) and proximal sections treated with papaverine (9.72 ± 4.49 g; n = 14). As previously reported by other investigators [19], proximal sections gave significantly higher KCl-induced contraction than distal (p < 0.05). All data were therefore expressed as % of this initial KCl response.

3.1 Vasoconstrictor responses in radial artery
Robust concentration dependent contraction was observed to vasopressin and angiotensin II giving mean maximal responses of 109 ± 10% KCl (n = 13; 95% confidence interval 104–115) and 87 ± 20% KCl (n = 14; 95% confidence interval 104–79) respectively (Fig. 1a and b). When expressed as % KCl, maximal responses to vasopressin and angiotensin II were not significantly different from proximal and distal sections. Maximal responses to vasopressin were also reproducible when arterial rings were compared from the same sample giving an average standard deviation 6.3 ± 4.0% for the response (n = 5). Maximal responses to angiotensin II were more variable giving an average standard deviation 15 ± 8% for the response (n = 3). Mean EC50 values (–log10 M) of 9.16 ± 0.39 (95% confidence interval 8.94–9.39) and 8.33 ± 0.52 (95% confidence interval 7.93–8.73) were obtained for vasopressin and angiotensin II respectively. Whilst maximal responses to both KCl and angiotensin II returned to baseline within 10 min following agonist washout, vasopressin-induced contraction was completely reversed only by glyceryl trinitrate. A mean EC50 value for the reversal of maximal vasopressin-induced contraction with glyceryl trinitrate was 4.05 ± 1.02 (–log10 M; n = 6).


Figure 1
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  		Fig. 1. Representative traces from individual rings of radial artery showing standard responses to increasing concentrations of either vasopressin or angiotensin II. Responses are shown in relation to an initial response to 90 mM KCl (A). Following washout (B) of the KCl response with two complete changes of media, rings were stimulated with increasing concentrations of either vasopressin (a) where C = 0.1, D = 0.3, E = 1, F = 10, G = 30 and H = 100 nM vasopressin) or angiotensin II (b) where C = 1, D = 3, E = 10, F = 30 and G = 100 nM angiotensin II).

 
3.2 Effect of treatments against vasopressin-induced contraction
Pretreatment with fluphenazine consistently reduced the maximal vasopressin-induced contraction (Fig. 2a; Table 2 ). When inhibition was measured at 30 min (n = 3) and 140 min (n = 3) after the drug had been washed out there was no loss of effect. In addition, inhibition was identical in vessels treated with phenoxybenzamine in theatre (n = 4) compared to papaverine (n = 3). Arterial rings pretreated with minoxidil failed to show any measurable inhibition (Fig. 2a; Table 2). The effects of the Rho kinase inhibitor Y27632 were also tested against vasopressin-induced contraction and compared with glyceryl trinitrate (Fig. 2b). The addition of 10 µM Y27632 to the organ chamber reduced the basal tension by 33 ± 15% (n = 5) and resulted in a significant reduction in the maximal vasopressin-induced contraction (Fig. 2b). Y27632 did not demonstrate any measurable effect on the EC50 of the response for vasopressin and the degree of inhibition of contraction was comparable to that produced by 220 µM glyceryl trinitrate (Table 2). One consequence of the inhibitory effects of Y27632 and glyceryl trinitrate was to increase the threshold vasopressin concentration at which a significant contraction could be measured from 0.1 to 1.0 nM vasopressin.


Figure 2
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  		Fig. 2. Effect of treatments against vasopressin-mediated vasoconstriction. Cumulative concentration response curves were obtained to vasopressin following pretreatment (a) with vehicle alone (control; n = 12), 100 µM fluphenazine (n = 6) or 10 µM minoxidil sulphate (n = 6) or in the presence of (b) 10 µM Y27632 (n = 5) and 22 µM (n = 5) and 220 µM (n = 5) glyceryl trinitrate, where n refers to the number of independent samples tested. Average responses ± SD, are shown relative to a contractile response to 90 mM KCl applied prior to treatment.

 

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  		Table 2 Maximal responses and affinity of response to vasopressin in radial artery for treatment groups compared with vehicle treated controls
 
3.3 Effect of minoxidil sulphate and fluphenazine pretreatment against angiotensin II and KCl-induced vasoconstriction
Maximal responses to angiotensin II were also significantly reduced by pretreatment with fluphenazine but not minoxidil when compared to controls (Table 3 ). No measurable change in EC50 values for vasopressin was observed with either treatment. In addition, following fluphenazine treatment, responses to 90 mM KCl were reduced by 48 ± 15%, when compared to the initial KCl response. In control rings, KCl responses were maintained, giving average values 107 ± 21% of the initial contraction (n = 8). Pretreatment with minoxidil sulphate showed no measurable effect against KCl-induced contraction giving an average response 112 ± 17% (n = 6) of the initial contraction.


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  		Table 3 Comparison of maximal responses and affinity of response to angiotensin II in human radial artery pretreated with minoxidil sulphate or fluphenazine
 

   4. Discussion
Top
 Abstract
 1. Introduction
 2. Material and methods
 3. Results
 4. Discussion
References
 
The major finding of this study was that pretreatment of radial artery grafts with the calmodulin inhibitor, fluphenazine (SKF7171A), significantly attenuated receptor-mediated contraction evoked by angiotensin II and vasopressin, and depolarisation-induced contraction by high potassium. Calmodulin is the cellular protein, which integrates the calcium response and activates the myosin light chain kinase responsible for contraction. Since an increase in smooth muscle calcium is the primary initiating stimulus for contraction, this makes calmodulin an excellent target for inhibiting contraction evoked by a wide range of agonists. The true incidence of vasospasm in the human radial artery is difficult to determine as many cases may go undetected [2,3]. Reports of perioperative ischaemia in patients with radial artery bypass grafts [20] and the observed reduction in postoperative markers of myocardial infarction in patients receiving radial artery grafts treated with phenoxybenzamine as compared with those treated with verapamil/glyceryl trinitrate [5], would support the need for effective, postoperative vasodilator therapy.

The radial artery is a muscular artery with a larger medial layer and a higher concentration of myocytes, when compared with the ITA, and this is believed to underlie its reactive nature [21]. In the immediate postoperative period when circulating vasoconstrictor levels are still elevated [9] systemic vasodilators are used by many surgeons to minimise the potential for vasospasm. Strategies include glyceryl trinitrate used either alone or in combination with calcium channel antagonists and the phosphodiesterase inhibitor milrinone [2–4]. A key observation is that fluphenazine inhibited vasopressin-induced contraction by a similar extent to that of the maximal dose of glyceryl trinitrate used. Since many of the samples used in this study were already treated with the irreversible {alpha} adrenergic antagonist phenoxybenzamine the effects of fluphenazine are additional to those of phenoxybenzamine. Phenoxybenzamine is now used by many surgeons and our results suggest that fluphenazine can be used alongside phenoxybenzamine, to provide inhibition to a broader spectrum of stimuli.

Potent vasodilatation with nicorandil, a combined potassium channel opener and nitric oxide donor, has been reported against endothelin-mediated contraction in radial artery [22]. Pinacidil, which shares a common binding site with minoxidil sulphate and nicorandil on the KATP channel, has also demonstrated its ability to reverse phenylephrine-induced contraction in human radial artery [23]. Therefore the activation of KATP channels would be expected to reverse membrane depolarisation, inhibit calcium influx across the plasma membrane and relax the precontracted radial artery [11]. We found minoxidil sulphate to be ineffective at inhibiting contractions in the radial artery. This occurred irrespective of the use of potassium channel blockers in the preoperative medication. Interestingly, minoxidil sulphate demonstrates a high degree of tissue and species selectivity. For example, minoxidil sulphate is a potent vasodilator in rat aorta but not in rabbit aorta or rat mesenteric artery, whereas other KATP channel openers were equally effective in all tissues [18]. The lack of effect measured in human radial artery in this study indicates that minoxidil sulphate has poor activity in this vessel also.

The effect of the reversible Rho kinase inhibitor Y27632 was also investigated. Rho kinase controls the activation state of the myosin light chain kinase responsible for the phosphorylation of myosin. Activation of Rho kinase leads to vasoconstriction at basal intracellular calcium levels in smooth muscle [17]. This study demonstrated that Y27632 reduced the maximal vasopressin-induced contraction. Rho kinase is activated by serotonin, endothelin 1 and thromboxane A2 [17] and by the stress hormone cortisol [24]. Therefore the involvement of the Rho kinase pathway in vasopressin-induced contraction in the radial artery indicates that both surgical stress and elevated levels of other vasoconstrictors can increase the sensitivity of the graft to vasopressin. This may be pertinent to the management of postoperative contraction in radial artery grafts or the use of vasopressin in the management of hypotension following CABG [16], particularly as vasopressin-induced contraction in radial artery is refractory to two of the most commonly used vasodilator strategies [15].

4.1 Limitations of this study
This study demonstrated significant inhibition of both receptor and non-receptor-mediated vasoconstriction in radial artery with fluphenazine. Although effects were only measured up to 2 h after treatment they would be expected to be similar in duration to phenoxybenzamine, since irreversible interactions of this type will last until the smooth muscle cells of the vessel wall replace the inactivated protein [7,8]. Inhibition with fluphenazine should therefore last well into the postoperative period [8]; however it would be useful to verify this in vivo. The animal model used to confirm the duration of action of phenoxybenzamine would suit this purpose [8]. Using this model it was demonstrated that the effects of phenoxybenzamine lasted for 16 h in vivo and we would expect a similar duration of action for fluphenazine. In addition, calmodulin inhibition could also affect the generation of endothelium-derived vasodilators. However the generation of vasodilators by the endothelium is not necessarily calmodulin-mediated [25] and it is unclear how calmodulin inhibition would affect endothelium-dependent vasodilatation in the radial artery. Interestingly, the presence or absence of endothelium has been shown not to influence vasopressin-induced vasoconstriction [15]; however, the effects of fluphenazine treatment on endothelium-mediated vasodilatation should also be considered.

4.2 Conclusion
Fluphenazine has potential to be developed as a useful treatment in graft vessels and demonstrates long-lasting effects against vasoconstriction induced by several unrelated agonists. Further studies are required to investigate the duration and breadth of effect of fluphenazine against a broader range of vasoconstrictors in radial artery. The development of clinically useful Rho kinase inhibitors may also provide a future therapeutic opportunity for the management of arterial contraction in the postoperative period, especially if Rho kinase inhibitors can be developed to give long-lasting protection [17].


   Footnotes
 
{star} Supported by the British Heart Foundation and the Merseybeat Appeal (The Cardiothoracic Centre, Liverpool, UK). MS was supported by a British Heart Foundation Junior Research Fellowship (FS/03/057) during this project.


   References
Top
 Abstract
 1. Introduction
 2. Material and methods
 3. Results
 4. Discussion
 References
 

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