© 2001 by European Society of Cardiology
Copyright © 2001, European Society of Cardiology
Aprotinin impairs endothelium-dependent relaxation in rat aorta and inhibits nitric oxide release from rat coronary endothelial cells
aDepartment of Pharmacology, School of Medicine, Ege University, 35100 Bornova, Izmir, Turkey
bDepartment of Medicine, Institute of Clinical Science, Queen's University Belfast, Belfast, UK
* Corresponding author. Tel.: +90-232-388-2862; fax: +90-232-342-2142 sgoksel{at}alpha.med.ege.edu.tr
Objective: Aprotinin, a non-specific serine protease inhibitor, reduces postoperative bleeding after coronary artery surgery. The mechanism of action for this ‘blood-sparing’ effect of aprotinin is only partially clarified. We therefore aimed to investigate the effect of aprotinin on the release of nitric oxide (NO), a vasodilator and antiaggregant factor, from rat coronary microvascular endothelial cells and on the NO-mediated endothelium-dependent relaxation of rat thoracic aorta. Methods: Endothelium-intact and endothelium-denuded thoracic aortic rings from Wistar rats (250–300 g) were suspended in organ chambers. Contractile and relaxant responses in the absence and presence of aprotinin (125, 250 and 500 KIU/ml) were recorded via a mechanotransducer. Coronary microvascular endothelial cells (CMEC) were isolated on a Langendorff system by collagenase perfusion of the hearts from the same rats. Calcium ionophore- (1 µM) induced release of NO from confluent cells was determined spectrophotometrically by measuring its stable metabolites, nitrite and nitrate, via Griess reaction. Results: Aprotinin selectively enhanced phenylephrine-induced contractions in endothelium-intact rat thoracic aortic rings, but not in the endothelium-denuded rings. The use of a nitric oxide synthesis inhibitor N
-nitro-L-arginine methyl ester (100 µM) on endothelium-intact rings produced a similar increase in phenylephrine-induced contractions. KCl-induced contractions remained unaltered. Aprotinin inhibited acetylcholine-, calcium ionophore- and L-arginine-induced endothelium-dependent relaxations, but not sodium nitroprusside-induced endothelium-independent relaxation. Aprotinin had no significant effect on basal nitrite–nitrate release from CMEC, while it inhibited calcium ionophore-induced total nitrite accumulation in the supernatants. Conclusion: Aprotinin selectively impairs endothelium-dependent relaxation as well as basal NO availability in rat thoracic aortic rings and inhibits NO release from rat CMEC. This effect of the drug may contribute to its ‘blood-sparing’ action and may also account for the increase in perioperative restenosis risk observed in clinical practice during aprotinin therapy.
KEYWORDS Arteries; Cell culture/isolation; Endothelial function; Nitric oxide; Vasoconstriction/dilation
1 Drs Sibel Ülker and Mehtap G. Çinar have contributed equally to this paper.
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