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Eur J Cardiothorac Surg 2004;26:988-994
© 2004 Elsevier Science NL

Duration of action of antispasmodic agents: novel use of a mouse model as an in vivo pharmacological assay

^a Department of Cardiothoracic Surgery, John Radcliffe Hospital, Headley Way, Headington, Oxford OX3 9DU, UK
^b Department of Cardiovascular Medicine, University of Oxford, Oxford, UK
^c Nuffield Department of Surgery, University if Oxford, Oxford, UK

Received 9 December 2003; received in revised form 9 June 2004; accepted 16 June 2004.

^* Corresponding author. Tel.: +44-1865-221-121; fax: +44-1865-220-244. (E-mail: david.taggart{at}orh.nhs.uk).

OBJECTIVE: Radial arteries are increasingly used as conduits for coronary artery bypass grafts, but perioperative graft vasospasm remains a concern. In vitro testing has demonstrated the efficacy of phenoxybenzamine and verapamil/nitroglycerin as topical antispasmodic agents, but their duration of action in vivo is unknown. Using an in vivo mouse model, we measured their duration of action in functioning vascular grafts, and compared this to their in vitro duration of action in ungrafted vascular segments. Methods: Two millimetre mouse aortic segments (C57/BL6) were incubated with phenoxybenzamine, verapamil/nitroglycerin, or buffer (controls) for 15min in organ chambers. Isometric tension responses to phenylephrine and prostaglandin F2 were measured at 0, 2, 6 and 12h post-incubation. In parallel, 36 murine infrarenal aortic interposition grafts (2mm) were performed. Twelve grafts were pre-treated (15min) with phenoxybenzamine, 12 with verapamil/nitroglycerin and 12 remained untreated (controls). Isometric tension responses to the same agonists were measured in grafts harvested 2, 6, 13 and 23h after surgery. Results: Phenoxybenzamine prevented -adrenergic vasoconstriction for up to 16h in vivo (grafts), and 12h in vitro (ungrafted segments). Verapamil/nitroglycerin was effective for at least 2h in vitro, but did not prevent vasoconstriction after 2h in vivo. Conclusions: The mouse model appears to be a useful technique for assessing the pharmacological properties of antispasmodic agents in vivo. Phenoxybenzamine has an extended action in arterial grafts in vivo. Verapamil/nitroglycerin is short-lived in vivo but lasts longer in vitro. Measurements of antispasmodic duration of action in vitro should be interpreted with caution.

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