Duration of action of antispasmodic agents: novel use of a mouse model as an in vivo pharmacological assay.
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 15 min in organ chambers. Isometric tension responses to phenylephrine and prostaglandin F2alpha were measured at 0, 2, 6 and 12 h post-incubation. In parallel, 36 murine infrarenal aortic interposition grafts (2 mm) were performed. Twelve grafts were pre-treated (15 min) 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 23 h after surgery.


RESULTS
Phenoxybenzamine prevented alpha-adrenergic vasoconstriction for up to 16 h in vivo (grafts), and 12h in vitro (ungrafted segments). Verapamil/nitroglycerin was effective for at least 2 h in vitro, but did not prevent vasoconstriction after 2 h 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.
Mussa
Shafi
S
Department of Cardiothoracic Surgery, John Radcliffe Hospital, Headley Way, Headington, Oxford OX3 9DU, UK.
Prior
Tash
T
Alp
Nicholas
N
Wood
Kathryn
K
Channon
Keith M
KM
Taggart
David P
DP
D000818:Animals; D001011:Aorta / Q000187:drug effects; D001026:Coronary Artery Bypass; D003329:Coronary Vasospasm / Q000517:prevention & control*; D004338:Drug Combinations; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D023421:Models, Animal; D005996:Nitroglycerin / Q000494:pharmacology; D009924:Organ Culture Techniques; D010643:Phenoxybenzamine / Q000494:pharmacology; D011183:Postoperative Complications / Q000517:prevention & control*; D013997:Time Factors; D014661:Vasoconstriction / Q000187:drug effects*; D014665:Vasodilator Agents / Q000494:pharmacology*; D014700:Verapamil / Q000494:pharmacology
D004338:Drug Combinations; D014665:Vasodilator Agents; D010643:Phenoxybenzamine; D014700:Verapamil; D005996:Nitroglycerin