Intravenous administration of the endothelin-1 antagonist BQ-123 does not ameliorate myocardial ischaemic injury following acute coronary artery occlusion in the dog.
OBJECTIVE
It has been proposed that myocardial ischaemic injury is modulated in part by the release of endothelin-1 from the coronary endothelium either during ischaemia or following reperfusion. Release of sufficient amounts of endothelin-1 would result in coronary vasoconstriction and could potentiate ischaemic damage. An endothelin-1 antagonist, BQ-123, was given intravenously to evaluate the role of endothelin-1 in postischaemic injury and determine whether blockade of the ETA receptor would afford protection from ischaemia/reperfusion injury.


METHODS
Myocardial injury was induced in anaesthetised dogs using 90 min of left circumflex coronary artery occlusion followed by 4 h of reperfusion. Animals treated with a continuous intravenous infusion of BQ-123 (0.1 mg.kg-1.min-1), begun 10 min before ischaemia and continued throughout ischaemia and reperfusion, were compared to saline treated animals.


RESULTS
After 4 h of reperfusion the myocardial infarct size measured by triphenyltetrazolium chloride staining was not different between the two groups. Infarct size in the control group was 25.7 (SEM 5.4)% of the area at risk while BQ-123 treatment resulted in an infarct size of 29.2(7.1)% of the area at risk (p = 0.70). Plasma endothelin-1 concentration measured at the coronary sinus was only significantly increased following 5 min of reperfusion.


CONCLUSIONS
The intravenous administration of a specific ETA receptor antagonist does not protect against ischaemia/reperfusion injury. These results suggest that endothelin-1 receptor antagonists require access to the area at risk during occlusion to protect the myocardium from ischaemic injury.
Department of Pharmacology, Merck Research Laboratories, West Point, PA 19486.
S M
SM
Krause
J J
JJ
Lynch
I I
II
Stabilito
R F
RF
Woltmann
D000818:Animals; D003331:Coronary Vessels; D004285:Dogs; D065128:Endothelin Receptor Antagonists; D016232:Endothelins / Q000097:blood; D007262:Infusions, Intravenous; D008026:Ligation; D017202:Myocardial Ischemia / Q000097:blood / Q000517:prevention & control*; D015428:Myocardial Reperfusion Injury / Q000517:prevention & control; D010456:Peptides, Cyclic / Q000008:administration & dosage*; D011897:Random Allocation
D065128:Endothelin Receptor Antagonists; D016232:Endothelins; D010456:Peptides, Cyclic; C072247:cyclo(Trp-Asp-Pro-Val-Leu)