Inhibition of endogenous endothelin during cardioplegia improves low coronary reflow following prolonged hypothermic arrest.
OBJECTIVE
Endothelin-1 (ET) is a potent endogenous vasoconstrictor which has been shown to be increased following ischaemia and cardiopulmonary bypass. We tested the hypothesis that inhibition of ET synthesis during cardioplegic arrest using phosphoramidon (an ET converting enzyme inhibitor) or blockade of ET receptors using bosentan (a mixed ET(A)/ET(B) antagonist), might improve the postischaemic recovery of coronary flow.


METHODS
Using an isolated Langendorff perfused rat heart model we compared the addition of phosphoramidon or bosentan to St Thomas' Hospital No. cardioplegia vs. control (plain cardioplegia). We measured recovery of coronary flow following 4 h of cardioplegic arrest at 4 degrees C. In a second series of experiments using an isolated working rat heart model we measured the recovery of cardiac function following 4 h of cardioplegic arrest at 4 degrees C. Results are expressed as percentages of preischaemic values (+/- S.E.M).


RESULTS
In the first series of experiments, addition of phosphoramidon to cardioplegia improved the postischaemic recovery of coronary flow after 30 min of reperfusion: control 81.3% (+/- 3.5); phosphoramidon 10(-6) M 86.2% (+/- 3.1); phosphoramidon 10(-5) M 95.0% (+/- 3.0) P = 0.03 vs. control. Likewise, addition of bosentan 10(-5) M improved coronary flow following 20 min of reperfusion: control 96.7% (+/- 4.0), and bosentan 109.6% (+/- 4.7) P = 0.04. The addition of phosphoramidon or bosentan had no effect on the postischaemic recovery of mechanical function following 30 min of reperfusion.


CONCLUSIONS
Both inhibition of ET synthesis and ET receptor blockade during prolonged hypothermic arrest improves postischaemic coronary flow, but appears to have no effect on the recovery of cardiac mechanical function.
Goodwin
A T
AT
Department of Cardiac Surgery, Heart Science Centre, Harefield Hospital, Middlesex, UK. Andrew.Goodwin@harefield.nthames.nhs.uk
Amrani
M
M
Gray
C C
CC
Chester
A H
AH
Yacoub
M H
MH
D000818:Animals; D001639:Bicarbonates; D000077300:Bosentan; D002122:Calcium Chloride; D002314:Cardioplegic Solutions; D003326:Coronary Circulation / Q000187:drug effects / Q000502:physiology; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000037:antagonists & inhibitors* / Q000502:physiology; D006020:Glycopeptides / Q000627:therapeutic use*; D006324:Heart Arrest, Induced; D007036:Hypothermia, Induced; D008274:Magnesium; D008297:Male; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors; D009200:Myocardial Contraction / Q000187:drug effects / Q000502:physiology; D015428:Myocardial Reperfusion Injury / Q000517:prevention & control*; D011189:Potassium Chloride; D011480:Protease Inhibitors / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012965:Sodium Chloride; D013449:Sulfonamides / Q000494:pharmacology*; D013997:Time Factors
D001639:Bicarbonates; D002314:Cardioplegic Solutions; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D006020:Glycopeptides; D011480:Protease Inhibitors; C041711:St. Thomas' Hospital cardioplegic solution; D013449:Sulfonamides; D012965:Sodium Chloride; D011189:Potassium Chloride; D008666:Metalloendopeptidases; D008274:Magnesium; D002122:Calcium Chloride; D000077300:Bosentan; C008890:phosphoramidon