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Ann Thorac Surg 2001;72:1977-1984
© 2001 The Society of Thoracic Surgeons

Original article: cardiovascular

Brief pretreatment of radial artery conduits with phenoxybenzamine prevents vasoconstriction long term

Daniel A. Velez, MDa,b, Cullen D. Morris, MDa,b, Satoshi Muraki, MDa,b, Jason M. Budde, MDa,b, Rachel N. Otto, BSa,b, Zhi-Qing Zhao, PhDa,b, Robert A. Guyton, MDa,b, Jakob Vinten-Johansen, PhD*a,b

a Cardiothoracic Research Laboratory, Carlyle Fraser Heart Center, Crawford Long Hospital of Emory University, Atlanta, Georgia, USA
b Section of Cardiothoracic Surgery, Emory University, Atlanta, Georgia, USA

* Address reprint requests to Dr Vinten-Johansen, Cardiothoracic Research Laboratory, Carlyle Fraser Heart Center, Crawford Long Hospital of Emory University, 550 Peachtree St NE, Atlanta, GA 30308-2225, USA
e-mail: jvinten{at}emory.edu

Presented at the Poster Session of the Thirty-seventh Annual Meeting of The Society of Thoracic Surgeons, New Orleans, LA, Jan 29–31, 2001.


   Abstract
Top
 Abstract
Introduction
 Material and methods
 Results
 Comment
 Acknowledgments
 References
 
Background. Radial artery bypass conduits are prone to early vasospasm or "string sign" with use of vasopressor therapy intraoperatively and postoperatively, causing increased resistance in coronary artery grafts. Current intraoperative treatment with papaverine fails to provide sustained inhibition of vasoconstriction. We tested the hypothesis that a 30-minute pretreatment of radial artery segments with the {alpha}-adrenergic antagonist phenoxybenzamine (PB) or the putative protein phosphatase 2,3-butadione monoxime (BDM) attenuates vasoconstriction induced by the vasopressors phenylephrine or norepinephrine for as long as 48 hours compared with papaverine.

Methods. Canine radial arteries were harvested, incubated in control buffer or solutions of papaverine 10-6 M, BDM 10-6 M or phenoxybenzamine 10-6 M for 30 minutes, washed, and stored in drug-free culture medium for 2, 24, or 48 hours. After storage, constriction was induced by norepinephrine at incremental concentrations ranging from 0.7 to 3.5 µmol/L or by phenylephrine (0.300 to 1.5 µmol/L) with or without the inhibitors, and the degree of vasoconstriction was quantified in organ chambers. Responses to norepinephrine or phenylephrine were compared to constriction with receptor-independent potassium chloride KC1 (30 mmol/L).

Results. Maximum responses to phenylephrine and norepinephrine were comparable at 2, 24, and 48 hours after harvest in the control group (phenylephrine: 67% ± 4%, 62% ± 6%, 65% ± 6% of KC1 response; norepinephrine: 75% ± 4%, 62% ± 1%, 58% ± 7%, respectively). Papaverine failed to attenuate constriction to phenylephrine and norepinephrine 2, 24, or 48 hours posttreatment. Pretreatment with BDM did not reduce vasoconstriction responses to phenylephrine or norepinephrine 2 hours after incubation but did reduce constriction responses thereafter. In contrast, phenoxybenzamine completely attenuated constriction to both phenylephrine (19% ± 8%, 1% ± 4%, -12% ± 4%) and norepinephrine (7.1% ± 1%, -5% ± 5%, -20% ± 5%) at 2, 24, and 48 hours posttreatment, respectively. Phenoxybenzamine did not alter endothelial function relative to controls at any time point.

Conclusions. Thirty-minute pretreatment of RA conduits with 10-6 M phenoxybenzamine completely inhibits vasoconstriction to phenylephrine and norepinephrine for as long as 48 hours. Soaking radial artery grafts briefly in phenoxybenzamine solution before implantation may be effective in preventing postoperative vasospasm caused by two common {alpha}-adrenergic agonists used in postoperative hemodynamic management.


   Introduction
Top
 Abstract
 Introduction
Material and methods
 Results
 Comment
 Acknowledgments
 References
 
As the patient population presenting with coronary artery disease becomes older and 10% to 30% of patients undergo cardiac reoperations [1], new sources of bypass graft conduits must be identified. The radial artery has emerged as a feasible and convenient alternative to venous conduits. In 1973 Carpentier and associates [2] reported the first series of patients in which a radial artery had been used as a conduit for coronary artery surgery. However, the use of the radial artery for bypass conduit was abandoned owing to a high failure rate (35% at 2 years) attributed largely to vasospasm [3]. In 1992, Acar and associates [4] revitalized interest in the use of the radial artery as alternative bypass conduit. Calcium-channel blockers and aspirin administered postoperatively made it possible to increase the short-term patency rate to 93.5% at 2 years [4]. Despite the use of calcium-channel blockers and vasodilators such as nitroglycerin, sodium nitroprusside, and papaverine during the harvesting period [5], vasospasm, hypoperfusion, and graft failure were still observed, which tempered the enthusiasm for widespread use of the radial artery conduit. The increased tendency of the radial artery to vasospasm is due in part to the greater muscularity relative to the more commonly used internal mammary artery [6]. The radial artery has a thicker media than the internal mammary artery, with a more dense organization of myocytes and less connective tissue. Hence the radial artery undergoes a more robust contraction to vasoactive substances such as potassium, serotonin, and the alpha agonists norepinephrine and phenylephrine [6–13]. Therefore the radial artery graft is at greater risk for vasospasm during catecholamine surges that occur during cardiopulmonary bypass and postsurgical events (discontinuation of ventilation, removal of chest tubes) and during the administration of pressor agents to sustain the patient’s blood pressure during the postoperative period. In addition catecholamines are used during periods of hypotension during off-pump coronary artery bypass and during resuscitation from cardiac arrest. The phosphodiesterase inhibitor and vasodilator papaverine is often used to attenuate vasospasm of the radial artery. Calcium-channel blockers have also been used to attenuate vasospasm of arterial grafts. However, these strategies are limited by the temporary reduction in constrictor responses with papaverine and significant side effects of calcium-channel blocker therapy. In addition, Dipp and colleagues [14] have reported that papaverine was associated with endothelial damage in 70% of radial artery segments tested.

Phenoxybenzamine is a nonsubtype selective ({alpha}1 and {alpha}2) {alpha}-adrenergic antagonist that binds irreversibly to {alpha}-adrenergic receptors. Mellor and associates [15] demonstrated in a preliminary report that 10-6 M phenoxybenzamine attenuated vasoconstrictor responses to norepinephrine as long as 18 hours after a 20-minute exposure of human radial arteries in organ chambers. Subsequently Taggart and colleagues [16] reported that incubating the harvested radial artery in 1 mg/mL phenoxybenzamine for 1 hour attenuated vasoconstrictor responses to epinephrine. However, the duration of antagonist effect, and the optimal (lowest effective) concentration of phenoxybenzamine were not determined in that study. In a follow-up study, Dipp and associates [14] reported that 1 hour soaking in a 1 mg/mL solution of phenoxybenzamine (diluted in buffer) attenuated vasoconstrictor responses to epinephrine for as long as 6 hours whereas papaverine only attenuated constrictor responses for 30 minutes. Longer durations of action of phenoxybenzamine were not observed. However, the 1-hour soaking period may delay the surgical momentum and postoperative complications secondary to radial artery vasospasm that occur beyond 6 hours, ie, as long as 24 to 48 hours after treatment. Other inhibitors of adrenergically induced vasospasm, such as the protein phosphatase and inhibitor of vascular smooth muscular contraction 2,2-butanedione monoxime (BDM), have been suggested but have not been tested for their use in radial artery grafts.

Accordingly, the present study was designed to test the hypothesis that a brief exposure of the radial artery to BDM or phenoxybenzamine during the harvesting procedure attenuates alpha agonist-induced radial artery spasm for long-term periods (ie, 48 hours) compared with the more conventionally used papaverine. The study was limited to {alpha}-agonist induced contraction to address the use of vasopressors during the postoperative period to stabilize hemodynamics and to counteract the adrenergic surges that occur during postoperative maneuvers.


   Material and methods
Top
 Abstract
 Introduction
 Material and methods
Results
 Comment
 Acknowledgments
 References
 
Surgical preparation
Dogs were used as a source of radial arteries for these ex vivo studies. Canine radial arteries are anatomically similar to human radial arteries compared with internal mammary and coronary artery counterparts (Fig 1). In addition, multiple segments of radial arteries could be obtained for the required concentration-response studies compared with the limited short segments available from human radial artery grafts. Pilot studies indicated that responses of canine radial arteries to vasoconstrictors were similar to that of human radial artery segments. Fifteen mongrel dogs of either sex weighing 25 to 34 kg were premedicated with morphine sulfate (4 mg/kg), and anesthesia was induced with intravenous sodium thiopental (25 mg/kg). After endotracheal intubation anesthesia was maintained using a mixture of diazepam (0.03 mg · kg-1 · min-1) and fentanyl citrate (0.3 µg · kg-1 · min-1) administered by continuous intravenous infusion. Both forelimbs were prepared and bilateral radial arteries were dissected free with the surrounding tissue and adjacent nerves using a "no-touch" technique. After systemic anticoagulation with sodium heparin (300 U/kg), both radial arteries were excised in skeletonized fashion, and placed in oxygenated Krebs-Henseleit (KH) buffer at room temperature and rinsed free of adherent blood. After placing the vessels in fresh cold KH buffer, superficial adipose and connective tissue was removed under magnification. The vessels were then cut into rings of 3 to 5 mm lengths for quantifying vascular contraction and relaxation according to assigned experimental groups.



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  		Fig 1. Histologic sections of (top panel) coronary artery, (middle panel) internal mammary artery, and (bottom panel) canine radial artery. Sections were prepared in hematoxalin and eosin. Note the more muscular wall morphology of the radial artery than the coronary artery.

 
Experimental protocol
Vascular rings were soaked for 30 minutes in the test solutions containing phenoxybenzamine, BDM, or papaverine (all at a concentration of 10-6 M, based on pilot concentration-response experiments). Control rings were soaked in buffer for the same period of time. After pretreatment with the assigned drug, radial artery rings assigned to immediate analysis were mounted on stainless steel hooks, connected to FT-03 force displacement transducers, and placed into Radnoti organ chambers (Radnoti Glass, Monrovia, CA) containing 7 mL of oxygenated (95% O2, 5% CO2) KH solution at 37°C. Indomethacin (10 µmol/L) was included in the buffer to inhibit responses to prostanoids. The rings were stabilized for 60 minutes. The optimal baseline force that gave maximal constrictor responses to 30 mmol/L KCI (force-tension relation) was determined and used as the initial prestretch tension in subsequent procedures. Contractile responses to incremental concentrations of norepinephrine (0.7 to 3.5 µmol/L) and phenylephrine (0.3 to 1.5 µmol/L) were tested. At the end of the protocol, a final exposure of the vessels to potassium chloride was used to quantify nonreceptor-mediated contraction and to determine viability in long-term stored arterial segments. Changes in isometric force were digitized at 2 Hz by using an analog-to-digital converter and responses were analyzed using a Windows-based videographics program (SPECTRUM; Wake Forest University, Winston-Salem, NC) on a PC computer. The constriction responses to norepinephrine or phenylephrine (with or without inhibitors) were expressed in absolute tension (grams) and as a percent of the KC1 contraction. The processing and equilibration of segments after exposure to treatment (or no drug) took approximately 2 hours (hence the 2-hour time point).

The vascular rings stored for 24 or 48 hours after treatment were incubated in Dulbeco’s Modified Eagle’s Media (DMEM, Gibco) culture media and placed in a CO2 incubator with 95% oxygen and 5% CO2 for the allotted time. The culture media was changed every 12 hours. After the allotted time, the segments were transferred to fresh KH buffer, mounted in organ chambers, equilibrated for 60 minutes, and contractile responses quantified as described above. In a subset of radial artery rings, endothelial viability and function were tested at the end of the storage interval by preconstricting the vessel segments with the thromboxane A2 mimetic agent, U46619 (5 nmol/L) and administering incremental concentrations of the endothelium-dependent stimulator of nitric oxide synthase, acetylcholine (1 to 186 nmol/L). Drugs concentrations are expressed as final concentrations in the organ chamber.

The dogs were handled in compliance with the Guide for the Care and Use of Laboratory Animals published by the National Institutes of Health (National Institutes of Health publication no. 85-23, revised 1985). The Institutional Animal Care and Use Committee of Emory University approved the experimental protocol.

Chemicals
The following drugs were purchased from Sigma (St. Louis, MO): acetylcholine chloride, KC1, norepinephrine, phenylephrine, 2-3 butanedione monoxime (BDM), phenoxybenzamine, and papaverine. All solutions were prepared daily and discarded after each experiment.

Statistical analysis
Vasoconstrictor responses to incremental concentrations of adrenergic agents (with or without inhibitors) were calculated as a percent of KC1-induced vasoconstriction, and concentration-response curves were drawn. In the endothelium function assay, endothelium-dependent vascular relaxation responses to acetylcholine were calculated as a percentage of the decrease of U46619-induced isometric constrictor force. Data were evaluated for statistical significance by applying one-way analysis of variance or Student’s t test (control versus drug treatment) at each concentration. A probability value of less than 0.05 (p < 0.5) was considered statistically significant. All data are reported as mean ± SEM.


   Results
Top
 Abstract
 Introduction
 Material and methods
 Results
Comment
 Acknowledgments
 References
 
Contractile responses to norepinephrine and phenylephrine
In control radial artery segments the concentration-dependent contractile responses to norepinephrine and phenylephrine were not significantly different at any concentration after 2, 24, and 48 hours of storage. Figure 2 shows an example of the concentration-response curve to norepinephrine in untreated (control) and phenoxybenzamine-treated radial artery segments. The maximum responses of untreated and treated radial artery segments to KCl, phenylephrine and norepinephrine (in grams of tension) are summarized in Table 1. The maximal constriction response to norepinephrine was observed at 3.5 µmol/L, and averaged 54% ± 2% at 2 hours, 52% ± 3% at 24 hours, and 58% ± 7% at 48 hours relative to contractile responses to KC1. Phenylephrine-induced constrictor responses followed a similar concentration-dependent contractile pattern with the maximum contractile response being observed at 1.5 µmol/L. There were no significant differences in contractile responses at any concentration of phenylephrine between 2 hours, 24 hours, and 48 hours of storage; maximum contraction responses (% of KCl-induced response) averaged 67% ± 4% at 2 hours, 62% ± 6% at 24 hours, and 65% ± 6% at 48 hours.



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  		Fig 2. Representative concentration-response curve for norepinephrine-induced contraction in untreated and phenoxybenzamine-treated (10-6 M) canine radial artery segments. *p < 0.05 versus untreated segments.

 

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  		Table 1. Contraction Responses (Grams) to Norepinephrine and Phenylephrine from Resting Forcea in Untreated and Treated Radial Artery Segments

 
Effect of papaverine pretreatment on radial artery contractile responses
There was no significant attenuation of vasoconstrictor responses to either norepinephrine or phenylephrine 2 hours, 24 hours, or 48 hours after pretreatment with the vasodilator papaverine versus untreated arteries as shown in Figure 3A and B. Interestingly, there was a paradoxic trend toward increased maximal constrictor response to both norepinephrine (Fig 2A) and phenylephrine (Fig 2B) in papaverine-treated radial artery rings at 48 hours of storage compared with the respective control vessels. However, this increased constrictor response did not reach significance. There was no significant difference in maximum constriction relative to KC1 responses in the control vessels with 3.5 µmol/L norepinephrine (54% ± 2% at 2 hours, 53% ± 1.0% at 24 hours, and 58% ± 7.2% at 48 hours) or 1.5 µmol/L phenylephrine (67.0% ± 3.5% at 2 hours, 62.0% ± 1.6% at 24 hours, and 65.2% ± 5.7% at 48 hours) that might have accounted for these apparent increased responses to either vasoconstrictor in the papaverine-treated vessels. Therefore papaverine had no inhibitory effect on norepinephrine or phenylephrine-induced contraction after washing (2 hours) or 24 or 48 hours after the 30-minute pretreatment.



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  		Fig 3. Constrictor responses (percent of KCl-induced contraction) in radial artery segments untreated and pretreated for 30 minutes with papaverine (Pap) after 2, 24, and 48 hours of storage of the vessels in a nutritive cell culture medium. (A) Maximum constriction responses to norepinephrine (3.5 µmol/L). (B) Maximum constriction responses to phenylephrine (1.5 µmol/L). The maximum constriction responses were derived from incremental concentrations of norepinephrine and phenylephrine. *p < 0.05 versus respective control.

 
Effect of BDM pretreatment on contractile responses of radial artery
Maximal constriction responses to norepinephrine in radial artery segments pretreated with BDM were significantly greater compared with the respective control vessels at 2 hours (Fig 4A). However, after 24 hours and 48 hours of drug-free storage, constriction responses to norepinephrine were similar between control vessels and drug-tested vessels. Constrictor responses of BDM-treated radial artery segments exposed to phenylephrine were similar to control segments at 2 hours and 24 hours but were significantly attenuated only after 48 hours of storage (Fig 4B).



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  		Fig 4. Constriction responses (percent of KCl-induced contraction) of radial artery segments untreated and pretreated for 30 minutes with the muscle contraction inhibitor 2,3-butanedione monoxime (BDM) after 2, 24, and 48 hours of storage of the vessels in a nutritive cell culture medium. (A) Maximum constriction responses to norepinephrine (3.5 µmol/L). (B) Maximum constriction responses to phenylephrine (1.5 µmol/L). The maximum constriction responses were derived form incremental concentrations of norepinephrine and phenylephrine. *p < 0.05 versus respective control.

 
Effect of phenoxybenzamine pretreatment on radial artery contractile responses
A concentration-response curve for constrictor responses to norepinephrine in phenoxybenzamine-treated radial artery segments is shown in Figure 1. Note that at all concentrations of norepinephrine, constriction was attenuated in phenoxybenzamine-treated segments compared with untreated segments. Pretreatment of the radial artery segments with 1 x 10-6 M phenoxybenzamine for 30 minutes significantly attenuated constrictor responses to the maximum concentration of norepinephrine and phenylephrine at all three time points as shown in Figure 5A and B. Two hours after exposure to phenoxybenzamine, constrictor responses to the entire range of concentrations of norepinephrine were significantly inhibited, with the maximal constriction response averaging -7% ± 1% of KC1 response compared with 49% ± 2% in untreated vessels. Significant inhibition of maximal constrictor responses were still observed 24 hours (-5% ± 5% versus 42% ± 3%) and 48 hours (-20% ± 5% versus 58% ± 7%) after treatment with phenoxybenzamine versus untreated vessels, respectively. In addition, constriction responses to phenylephrine were also significantly attenuated in vessels pretreated with phenoxybenzamine (Fig 5B). Constriction response to the maximum concentration of phenylephrine were significantly lower 2 hours after treatment versus untreated vessels (19% ± 8% versus 67 ± 4), which was sustained and even enhanced at 24 (1% ± 4% versus 62% ± 2%) and 48 hours (-12% ± 4% versus 65% ± 6%) after a 30 minute pretreatment with phenoxybenzamine, respectively.



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  		Fig 5. Constriction responses (percent of KCl-induced contraction) of radial artery segments untreated and pretreated for 30 minutes with phenoxybenzamine (PXB) after 2, 24, and 48 hours of storage of the vessels in a nutritive cell culture medium. (A) Maximum constrictor responses to norepinephrine (3.5 µmol/L). (B) Maximum constrictor responses to phenylephrine (1.5 µmol/L). The maximum constrictions were derived from incremental concentrations of norepinephrine and phenylephrine. *p < 0.05 versus respective control.

 
Effect of phenoxybenzamine pretreatment and prolonged storage on endothelial vasodilator function of radial arteries
Although comparable contractile responses to KC1 over the 2, 24, and 48 hour period of observation suggested that the vascular smooth muscle was viable after prolonged storage of the radial artery segments, the viability of the endothelium was also a concern with prolonged storage. The endothelium contributes to the overall vascular tone by tonic release of autacoids such as nitric oxide among other vasoactive substances. In addition, any attenuation of function related to autacoid release by phenoxybenzamine or its diluent would be undesirable. Endothelial relaxation responses to all concentrations of acetylcholine were comparable with or without phenoxybenzamine treatment over the 48-hour storage period. With phenoxybenzamine treatment the maximum relaxation response to the highest concentration of acetylcholine at 2 hours was 61% ± 5% after 24 hours was 57% ± 6% and 30% ± 5% after 48 hours; these levels of relaxation responses were comparable to untreated control radial artery segments. These data suggest that treatment of the radial artery segments with phenoxybenzamine did not alter viability or function of the endothelium although endothelial responsivity declined over the 48-hour storage period.


   Comment
Top
 Abstract
 Introduction
 Material and methods
 Results
 Comment
Acknowledgments
 References
 
Clinical outcomes in coronary artery surgery depend on the long-term as well as immediate patency and longevity of the grafts used. Although the radial artery is a morphologically ideal alternative bypass graft conduit reports of vasospasm and "string signs" postoperatively have dampened the enthusiasm for the vessel as a bypass graft. The dominance of {alpha}1 adrenergic receptors in this conduit determines the robust contractile responses to circulating catecholamines as well as to perioperatively administered adrenergic pressor agents commonly used in the postoperative period [6, 7, 11]. The current regimens used to counteract or prevent vasospasm in radial artery bypass conduits (papaverine, lidocaine, nitroglycerin, calcium-channel blockers) suffer either from a temporary effect limited to the immediate operative period or from side effects in the case of systemic administration of calcium-channel blockers. In addition, calcium-channel blockers have not been particularly effective in preventing postoperative vasospasm of radial artery grafts.

The present study was designed to identify a new method of inhibiting radial artery vasospasm over a longer period of time covering the postoperative occurrence of vasospasm induced by alpha adrenergic agonists most commonly used in postoperative hemodynamic management. Our results demonstrate that pretreatment of the radial artery segment for 30 minutes with papaverine failed to attenuate constrictor responses to norepinephrine or phenylephrine. A purported protein phosphatase activator with inhibitory effects on both smooth and cardiac muscle contraction, BDM, failed to attenuate constrictor responses in the immediate posttreatment period but had some limited inhibitory effect thereafter. The concentration used in the present study was considerably less than that used in other studies (up to 25 mmol/L [17]) and the concentration used in the present study may have been inadequate to attenuate vasoconstriction. In contrast, a 30-minute treatment of the segments with low concentrations of phenoxybenzamine attenuated constrictor responses to both norepinephrine and phenylephrine shortly after treatment in agreement with others [14, 16]. Furthermore we found that attenuation of adrenergically induced contraction was completely attenuated for up to 48 hours after a 30-minute treatment with phenoxybenzamine. Interestingly, the vasodilator effects of norepinephrine mediated by ß-adrenergic actions were unmasked at 24 and 48 hours after phenoxybenzamine treatment thereby further contributing to avoidance of constrictor responses to this pressor agent. While the maximum concentration of noreinephrine or phenylephrine used in this study exceeded the physiologic concentrations observed in patients, significant inhibition of contraction responses were still observed at the lower physiologic concentrations (approximately 1 µmol/L). This treatment regimen with phenoxybenzamine avoids prolonged soaking periods before implantation of the radial artery in the aortocoronary position and avoids the use of systemic drugs to attenuate vasospasm.

Dose considerations
The concentration of phenoxybenzamine used in this study was considerably lower than that used in studies by Taggart and associates [16] and Dipp and associates [14] in which 1 mg/mL (approximately 3 mmol/L) phenoxybenzamine was used to soak the radial artery. In contrast, we observed a maximum effect with 1 x 10-6 M in the skeletonized radial artery preparation. There is little likelihood that exposing the radial artery to higher concentrations of phenoxybenzamine would have direct deleterious effects and little likelihood that systemic effects would be observed by leeching out of drug from the radial artery into the general circulation. However, intravenous formulations of phenoxybenzamine have stabilizers such as alcohol and propylene glycol that may be deleterious to blood (in a clinical soaking solution) and the radial artery tissue if given in high concentrations. With the commercial formulation of phenoxybenzamine used in the present study (50 mg/mL in 48.5% alcohol), only 0.0068 mL of phenoxybenzamine solution from the vial was used in the final soaking solution, making it unlikely that toxic levels of diluent would be achieved.

One approach investigated in the present study was to attenuate vasoconstriction of the radial artery by inhibiting the contractile process itself with BDM. BDM inhibits contraction of skeletal muscle [18], vascular smooth muscle [19], and cardiac muscle [20]—effects that are reversible after washout of the compound [20]. BDM decreases the phosphorylation state of the regulatory proteins troponin I and phospholamban through activation of the respective phosphatases, resulting in a decrease in cross-bridge formation [21]. In myocardium, BDM inhibits excitation-contraction coupling not only by reducing actin-myosin cross-bridge force development, but also by reducing Ca2+ sensitivity of the myofilaments. In vascular smooth muscle, BDM may also inhibit voltage-dependent cytosolic calcium transient currents [22]. BDM has been used to prevent contractile activity in the heart during the initial phase of reperfusion thereby attenuating postischemic injury and has been used in cardioplegic solutions. The use of an agent such as BDM has the advantage of attenuating contraction induced by all mechanisms, rather than attenuating only contraction induced by adrenergic receptor stimulation as with phenoxybenzamine. However, the disadvantage is the reversal of the inhibitory effect after washout of BDM, similar to the situation with papaverine and other vasorelaxant agents. Previous studies reported a decrease in force of contraction of vessels after exposure to BDM [19] achieved at higher concentrations than that used in the present study. In the present study, treatment with BDM failed to block {alpha}-adrenergic stimulation by either norepinephrine or norepinephrine immediately on longer term after treatment. In fact, there was a hyperconstrictor response when constriction was induced by norepinephrine 2 hours after treatment, which is an observation that remains unexplained. However, there was a modest decrease in responses to norepinephrine and phenylephrine at 24 and 48 hours after treatment. Hence BDM did not provide the dramatic and long-lasting attenuation of constrictor responses to adrenergic stimulation observed with phenoxybenzamine.

Clinical application and implications
Vascular conduits are exposed to agonists that promote vasoactive responses originating from several sources: the catecholamine surge secondary to initiation of cardiopulmonary bypass or release of the aortic cross-clamp and {alpha}-adrenergic agents given parenterally to sustain the patient’s blood pressure during periods of hemodynamic instability or resuscitative efforts. Adrenergic agents are often administered to counteract hemodynamic instability during rotation or elevation of the heart to exposure lateral and posterior target vessels during off-pump bypass surgery. Although catecholamines are not the only source of vasoconstrictor agent present in the postoperative period, they are a primary contributor to postoperative vasoconstriction. Hence the radial artery, with its greater {alpha}-adrenergic receptor density and greater muscularity than its other arterial counterparts, encounters a potentially hostile environment in the coronary position in which vasospasm is a likely consequence and which requires therapeutic attention. The desirable attributes of phenoxybenzamine include immediate onset of inhibition, prolonged duration of inhibition, and localized versus systemic administration. A brief period of soaking of the harvested vessel does not interrupt or delay the momentum of the operation. In clinical practice phenoxybenzamine may be used in combination with blood for a more physiologic soaking solution rather than the buffer used in the present study. In addition the surgeon may wish to introduce the phenoxybenzamine-blood soaking solution into lumen of the radial artery to increase exposure to the drug. Preliminary studies in human radial arteries harvested as a pedicle with surrounding tissue suggest that a 100-fold increase in concentration (1 x 10-4 M) may be necessary to achieve the same degree of inhibition as observed in the present canine study in which the radial arteries were skeletonized. Skeletonized radial arteries may be an alternative to pedicled grafts [23].

The immediate and sustained actions of phenoxybenzamine on adrenergically induced contraction may give the surgeon more confidence in using the radial artery as a primary or alternative graft without concern for graft vasospasm secondary to the use of {alpha}-adrenergic agonists, especially during off-pump coronary artery bypass surgery or during stress-induced release of endogenous catecholamines. These laboratory observations must be confirmed by clinical studies verifying both the immediate and longer-term effects of a brief treatment of the harvested radial artery with phenoxybenzamine, as well as its potential to improve graft function after implantation. In addition, further laboratory studies are required to define the duration of action of phenoxybenzamine by observing longer time periods and to determine whether a "receptor escape" occurs owing to upregulation of newly formed {alpha}-adrenergic receptors.


   Acknowledgments
Top
 Abstract
 Introduction
 Material and methods
 Results
 Comment
 Acknowledgments
References
 
The authors appreciate the technical assistance of L. Susan Schmarkey, Sara Katzmark, and Jill Robinson, and the manuscript preparation assistance of Laurie Berley. The authors are grateful to the Carlyle Fraser Heart Center for continued support of the research and educational activities of the Cardiothoracic Research Laboratory.


   References
Top
 Abstract
 Introduction
 Material and methods
 Results
 Comment
 Acknowledgments
 References
 

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