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
aThe Cardiothoracic Centre, Thomas Drive, Liverpool, UK
bDepartment of Human Anatomy & Cell Biology, University of Liverpool, UK
Received 10 January 2008; received in revised form 9 June 2008; accepted 11 June 2008; Available online 3 August 2008
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 treatedgraft. This study investigated the use of two clinically applied drugs; fluphenazine
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 mM; 50 mg/ml) or 10 mM 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.
# 2008 European Association for Cardio-Thoracic Surgery. Published by Elsevier B.V. All rights reserved.
Keywords: Arteries; Artery biochemistry/pharmacology; CABG; Arterial grafts; CABG; Pharmacology/physiology; Cell signaling; Receptors
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 . These results have
encouraged surgeons towards a complete arterial revas-
cularisation strategy. Promising patency rates obtained
with the radial artery have now also established this graft
as a good alternative to the right ITA . 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 a 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 . 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 complica-
Phenoxybenzamine has demonstrated the potential ben-
efits of irreversible antagonists in CABG as treatment
completely abolishes noradrenaline-induced contraction in
European Journal of Cardio-thoracic Surgery 34 (2008) 839—844
§Supported by theBritishHeart 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.
* Corresponding author. Current address: Physiology Dept, University of
Liverpool, Crown St, Liverpool L69 3BX, UK. Tel.: +44 151 7945510;
fax: +44 151 7945517.
E-mail address: email@example.com (A.R. Conant).
1010-7940/$ — see front matter # 2008 European Association for Cardio-Thoracic Surgery. Published by Elsevier B.V. All rights reserved.
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M.J. Shackcloth et al./European Journal of Cardio-thoracic Surgery 34 (2008) 839—844