Effects of aprotinin on endothelium-dependent relaxation of large coronary arteries.
OBJECTIVE
Aprotinin is widely used in heart surgery for reduction of intraoperative blood loss. But recent reports presenting results from rat aorta experiments claimed that aprotinin selectively impairs endothelium-dependent relaxation (EDR) as well as basal NO availability in concentrations similar to doses routinely used in cardiovascular surgery. An impairment of coronary EDR by aprotinin would be a great danger for any cardiothoracic intervention. We therefore tested the influence of aprotinin in the coronary arteries of a non-rodent species.


METHODS
Fresh coronary arteries of pigs were obtained from the local slaughterhouse and transported to our laboratory in cold oxygenated Krebs-Henseleit solution. Five-millimeter long rings were consecutively tested with or without aprotinin in concentrations of 500 KIU/ml (n=7) or 1000 KIU/ml (n=6) in oxygenated normothermic Krebs-Henseleit solution. PGF(2alpha) (10 micromol/l) was used for inducing contraction and substance P (10 nmol/l) for inducing EDR, which was calculated in percentage of the pre-contraction. Indomethacin (10 micromol/l) was added in all measurements to eliminate the influence of prostaglandins. In additional similar experiments (n=5), the influence of 1000 KIU/ml aprotinin on the EDR caused by the endothelium-derived hyperpolarizing factor (EDHF) was tested using l-NNA (300 micromol/l) to block all NO formation.


RESULTS
The EDR of pig coronaries (82+/-5% or 80+/-5% of the pre-contraction in the control tests before and after aprotinin exposure) was not significantly changed by 500 KIU/ml aprotinin (78+/-7%). A small, but significant reduction of less than 1/10 of the EDR was induced by 1000 KIU/ml aprotinin (74+/-5%). After accounting for l-NNA for NO blockage, no aprotinin-related difference remained (59+/-6% vs 60+/-6% in controls).


CONCLUSIONS
For clinically relevant concentrations of aprotinin up to 500 KIU/ml, no significant reduction of the EDR can be found in epicardial coronary arteries of the pig. For higher doses of 1000 KIU/ml, a reduction in NO production seems to be the cause of the small but significant reduction of the EDR by aprotinin. Therefore, danger for impairment of coronary EDR by aprotinin at clinical dosage levels, as suggested by studies on rat aortas, seems to be absent in coronary arteries of a large mammalian model.
Fischer
Jürgen H
JH
Institute of Experimental Medicine, University of Cologne, Robert-Koch-Str. 10, Cologne 50931, Germany.
Steinhoff
Maren
M
D000818:Animals; D007611:Aprotinin / Q000494:pharmacology*; D003331:Coronary Vessels / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000502:physiology; D006490:Hemostatics / Q000494:pharmacology*; D009569:Nitric Oxide / Q000096:biosynthesis; D013552:Swine; D014664:Vasodilation / Q000187:drug effects*
D006490:Hemostatics; D009569:Nitric Oxide; D007611:Aprotinin