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Eur J Cardiothorac Surg 2001;19:482-486
© 2001 Elsevier Science NL

Phenoxybenzamine is more effective and less harmful than papaverine in the prevention of radial artery vasospasm

^a University Laboratory of Physiology, University of Oxford, Parks Road, Oxford, OX1 3PT, UK
^b Oxford Heart Centre, John Radcliffe Hospital, Oxford, OX3 9DU, UK

Received 4 November 2000; received in revised form 18 January 2001; accepted 21 January 2001.

Corresponding author. Tel.: +44-1865-221121; fax: +44-1865-221956
e-mail: david.taggart{at}orh.anglox.nhs.uk

	Abstract

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

 
Objectives: There is an increasing use of arterial conduits for coronary artery bypass grafting, and the radial artery is commonly used as the third graft. The major drawback of the radial artery is its proclivity to spasm. Both papaverine and phenoxybenzamine have been recommended as topical vasodilators in clinical practice. We compared the efficacy of both drugs to prevent radial artery spasm and their ability to preserve endothelial function. Methods: The ability of both drugs to prevent alpha-adrenoreceptor mediated constriction was tested in vitro in an organ bath in radial artery segments obtained from 20 patients. Vessel viability was determined by potassium (K⁺) constriction, and endothelial function was assessed by observing endothelium-dependent relaxation by a synthetic analogue of acetylcholine, carbachol. Results: Papaverine consistently abolished and prevented spasm for up to a maximum of 30 min in all segments. In contrast, phenoxybenzamine consistently abolished and prevented radial artery spasm in all segments for at least 6 h. Whereas papaverine damaged the endothelium of 70% of vessels, there was no evidence of endothelial damage in any arterial segments after exposure to phenoxybenzamine. Conclusions: Phenoxybenzamine more effectively prevents alpha-adrenoreceptor mediated spasm of the human radial artery than papaverine. It is also less harmful to the endothelium.

Key Words: Radial • Vasospasm • Phenoxybenzamine • Papaverine

	1. Introduction

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

 
Arteries are increasingly used exclusively as conduits for coronary artery bypass grafting (CABG) due to their clinical and survival benefits [1]. Internal mammary artery (IMA) grafts are the conduits of first choice for CABG [2], with the radial artery probably the next most useful arterial conduit in terms of length, ease of use, versatility and long-term patency (reviewed in [3]). One potential disadvantage of the radial artery is its increased proclivity to spasm because of its greater muscular content compared with other arteries [4]. This is of particular relevance in patients who may require inotropic or vasoconstrictor therapy during the post-operative period. Vasospasm can cause short-term hypoperfusion, and can also adversely affect long-term patency (reviewed in [3]).

Various methods of reducing the incidence of vasospasm during the post-operative period have been used [5–8], but most of these have significant limitations. Intravenous infusions of calcium channel blockers can cause hypotension, bradycardia, and arrhythmia [5], while topical applications of papaverine [6], are relatively short-lived. The combination of verapamil and nitroglycerine has non-specific effects, for example, abolishing the response to KCl [7]. The molecular biology technique of transferring endothelial nitric oxide (NO) synthase via an adenoviral vector [8] is not yet ready for clinical application.

We recently reported the efficacy of phenoxybenzamine, an alpha-adrenoreceptor blocker, in abolishing and preventing radial artery spasm [9]. Papaverine, a phosphodiesterase inhibitor, is also commonly used as an internal and/or external topical vasodilator to prevent radial artery spasm. This work compares the efficacy and duration of action of papaverine and phenoxybenzamine, in preventing and abolishing radial artery spasm in vitro along with their effects on endothelium-dependent relaxation.

	2. Materials and methods

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

 
2.1. Patients
Left radial arteries were harvested (standard techniques) using only Hartmann’s solution, from 20 patients undergoing CABG. A total of 20 vessels from 20 patients were tested. Ten were tested only with papaverine, six were tested only with phenoxybenzamine, and four were divided so that both papaverine and phenoxybenzamine could be individually tested on the same vessel.

2.2. Experimental methods
One centimetre of the distal (wrist) radial artery was excised and placed in chilled (4°C, pH 7.4), HEPES-buffered physiological saline solution (HEPES-PSS constituents in: 118 mM NaCl, 4 mM KCl, 10 mM NaHCO₃, 14 mM HEPES, 1 mM MgSO₄, 1.2 mM NaH₂PO4, 2 mM CaCl₂, 5.56 mM glucose). These specimens were then transported on ice, in a 20-min bicycle ride, from the John Radcliffe Hospital to the University Laboratory of Physiology. Specimens were then immediately transferred to warmed (37°C) PSS (recipe as above, but with 24 mM NaHCO₃ and no HEPES) and bubbled with 75% N₂, 20% O₂, (PO₂ 154–160 Torr) and 5% CO₂ to maintain a pH of 7.4. The pH of the myograph bath was checked at 5-min intervals throughout all experiments (via a pH electrode immersed in the bath) and corrected, when necessary, to 7.4 by the addition of NaOH.

2.3. Vessel mounting and normalization
Arteries were placed in an organ bath and mounted onto the hooks of an automated myograph (AM10, Cambustion Biological, Cambridge, UK). The theory and protocol have been described by Mulvany and Halpern [10]. The vessels were normalized, and then initial tension was set to be equivalent to 100 mmHg according to the Laplace relation.

2.4. Experimental protocol
In order to determine their viability, vessels were first constricted by high K⁺-PSS containing 75 mM K⁺ and by a 5-min exposure to a supra-maximal concentration of 1 mM adrenaline. The vessels were then incubated for one hour in the presence of either papaverine (5 mg/ml PSS) or phenoxybenzamine (1 mg/ml PSS). After the 1-h incubation, the vessels were washed with PSS and subsequently exposed at 5-min intervals to adrenaline. After the effectiveness of papaverine or phenoxybenzamine had been determined, the ability of carbachol (100 µM; an analogue of acetylcholine) to relax constrictions by 75 mM K⁺ was tested. The degree of this relaxation was used as a direct index of the integrity of the endothelium and its function.

2.5. Analysis
A Dell (386) microcomputer was used with Cambustion software (1991) to digitize tension at 1 Hz. The data were plotted using a custom written Turbo Pascal microcomputer program and Microsoft Excel. The latter was used to give average responses and to normalize each trace to the baseline and peak tensions obtained in response to the first addition of K⁺.

	3. Results

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

 
The results for the 20 individual radial artery segments are presented in Figs. 1 and 2 . All segments were markedly constricted by K⁺ and all promptly relaxed to baseline upon washing. Adrenaline also produced a marked constriction, which was abolished by both papaverine and phenoxybenzamine.

View larger version (28K): [in this window] [in a new window]   Fig. 1. The effects of papaverine on ten rings of radial artery (in vitro). A 5-min constriction by 75 mM K+ (K+) is washed off with PSS (W). (*) Adrenaline (1 mM) then gives a constriction of about 80% of K+ and is completely relaxed by 5 mg/ml papaverine. Repeated additions of adrenaline (*), at 5-min intervals, cause constriction which is reversed by a second addition of papaverine. Finally, K+ constriction is abolished in three vessels by 100 µM carbachol (C, an endothelium-dependent vasodilator). The K+ is then washed with PSS (W), and all vessels return to baseline tension.

View larger version (16K): [in this window] [in a new window]   Fig. 2. The effects of phenoxybenzamine on ten rings of radial artery (in vitro). A 5-min constriction by 75 mM K+ (K+) is washed off with PSS (W). (*) Adrenaline (1 mM) then gives a constriction of about 80% of K+ and is completely relaxed by 1 mg/ml phenoxybenzamine. Eight additions of adrenaline (*) are then given, first at 5-min intervals, and thereafter, at hourly intervals. These elicit no response for 6 h. Finally, in all vessels, K+ constriction is fully relaxed by 100 µM carbachol (C).

3.2. Response to adrenaline challenges during incubation with phenoxybenzamine (Fig. 2)
Exposure to phenoxybenzamine prevented constriction by adrenaline for at least 6 h in all vessels. The phenoxybenzamine-treated vessels were also tested for the integrity of the endothelium. In all ten vessels, the K⁺ constriction was relaxed completely by carbachol, indicating that the endothelium was still functional.

	4. Discussion

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

 
This study confirms our previous observation [9] that phenoxybenzamine prevents radial artery vasospasm for at least 6 h without damage to the endothelium. In contrast, papaverine only prevented spasm for a maximum of 30 min, and also appeared to compromise endothelium-dependent relaxation.

The limited duration of action of papaverine was a surprising observation as it is widely used to prevent spasm of the internal mammary [11–13] and radial artery [6]. Papaverine, an opiate, is a smooth muscle relaxant, for which the mechanism(s) of action is not yet precisely understood, but which is believed to act predominantly by inhibiting phosphodiesterase [13,14]. Furthermore, we could find no report regarding the half-life of papaverine, but our data suggest that it is unlikely to be as long as 30 min. Our findings also imply that papaverine is unlikely to bind to receptors and is presumably washed off or metabolized rapidly.

It is also interesting to note that after incubation with papaverine, the response to adrenaline was all or nothing, as opposed to graded. There was either no response to adrenaline, or the response was similar to that at the start of the experiment. This may be because of the use of a supra-maximal concentration of adrenaline. Perhaps if lower concentrations of adrenaline were used, a graded response would be seen.

There is consistent evidence from several studies that papaverine damages the endothelium, and the most likely mechanism for this is through a fall in pH [11,15,16]. Although the pH of our extracellular bathing medium was buffered at a pH of 7.4, papaverine still appeared to cause endothelial cell dysfunction. This dysfunction was clearly independent of changes in the extracellular pH, suggesting other mechanisms of damage. One possibility here is a reduction in the intracellular pH, which can damage the endothelium by decreasing ATP levels [17]. ATP is required to drive the Na⁺/H⁺ exchange pump necessary for endothelial cells to recover from acid-load [17]. Furthermore, a fall in the pH decreases the activity of NO synthase and the synthesis of vasodilator prostaglandins [17].

Other studies, which have tested the effect of papaverine on the IMA [11–13] and on vein segments [16,18], indicate that it damages the endothelium. Cooper and colleagues reported no significant morphological changes in the mammary artery, as assessed by scanning electron microscopy, after treatment with papaverine [11]. In contrast, however, when endothelial function was assessed by prostaglandin I₂ release, there was a decrease in production following papaverine exposure [11]. This is consistent with our observation of significant endothelial dysfunction in the majority of radial arteries within 1 h of exposure to papaverine.

Similarly, Rubens and colleagues [16] reported endothelial cell damage by papaverine, which correlated with the duration of exposure. Only 22% of their cells survived an hour of incubation with papaverine followed by a 4-h recovery period. Three days later, the survival had fallen to 8%.

This study also confirms our previous report that phenoxybenzamine is an effective vasodilator which does not cause endothelial dysfunction as evidenced by the carbachol-induced relaxation of K⁺-induced constriction [9]. While our experiments clearly show that the effect of phenoxybenzamine persists for at least 6 h, we were unable to study it for longer periods because this is the maximum period for which vessels remain fully responsive in our organ bath. Nevertheless, as phenoxybenzamine binds covalently and irreversibly to alpha-adrenoreceptors, this effect is likely to persist for at least 24 h [9,14].

The duration of action of vasodilators is of particular importance because, as we previously reported [19], the post-operative levels of endogenous adrenaline and noradrenaline are significantly elevated for at least 24 h after cardiac surgery. Elevation in these circulating catecholamines is one of the likely contributors to perioperative spasm of the radial artery [3].

Adrenaline is an alpha- and beta-receptor agonist that is used clinically during the post-operative period for those patients needing vasoconstrictor therapy. Phenoxybenzamine is specifically an alpha1-antagonist; however, activation of beta-receptors by adrenaline is not significant as it is known that the radial artery is an alpha1-dominant artery [20].

In conclusion, our study suggests that phenoxybenzamine is a more effective and less harmful pharmacological agent than papaverine for preventing and abolishing alpha-adrenoreceptor mediated vasoconstriction. It may therefore permit more widespread use of the radial artery in CABG patients who are likely to require perioperative vasoconstrictors.

	References

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Dipp, M.A. Articles by Taggart, D.P. Search for Related Content PubMed PubMed Citation Articles by Dipp, M.A. Articles by Taggart, D.P. Related Collections Cardiac - pharmacology Coronary disease