Sialyl lewis oligosaccharide preserves cardiopulmonary and endothelial function after hypothermic circulatory arrest in lambs.
OBJECTIVE
Neutrophil adhesion to endothelium contributes to cardiopulmonary dysfunction after cardiac surgical procedures. Initial neutrophil-endothelial interactions involve selectins, which bind carbohydrate ligands, such as sialyl-Lewis(X). Blockade of selectin-mediated neutrophil interactions with CY1503, a synthetic oligosaccharide analog of sialyl-Lewis(X), could limit neutrophil-mediated injury after cardiopulmonary bypass.


METHODS
The efficacy of CY1503 treatment was tested in a lamb model of cardiopulmonary bypass with hypothermic circulatory arrest. Neonatal lambs received CY1503 (n = 6, CPB-CY1503) or saline solution vehicle (n = 7, CPB-saline) into the pump prime before bypass and as a continuous infusion throughout reperfusion. Five lambs served as control animals for in vitro microvessel studies. Indexes of myocardial function (preload recruitable stroke work index, and rate of pressure rise) and pulmonary function (compliance, airway resistance, and arterial PO (2)) were measured before bypass and during reperfusion. The effect of CY1503 on endothelium-dependent vascular reactivity was assessed by means of in vitro pulmonary and coronary microvessel studies.


RESULTS
Myocardial function was depressed after circulatory arrest, but CY1503 preserved function near baseline (36% +/- 25% vs 99% +/- 19% of baseline at 3 hours of reperfusion). CY1503-treated animals also demonstrated improved pulmonary function during reperfusion. In vitro microvessel analysis of vascular reactivity revealed endothelial dysfunction after circulatory arrest compared with control lambs. CY1503-treated lambs (CPB-CY1503) had intact endothelial function, as demonstrated by normal vasodilatory responses to endothelium-dependent vasodilators.


CONCLUSIONS
CY1503 preserves cardiopulmonary and endothelial function after cardiopulmonary bypass and hypothermic circulatory arrest in neonatal lambs. This suggests a role for selectin-mediated, neutrophil-endothelial interactions in the inflammatory response after cardiac operations.
Schermerhorn
M L
ML
Departments of Cardiovascular Surgery and Anesthesia, The Children's Hospital, Harvard Medical School, Boston, MA, USA.
Tofukuji
M
M
Khoury
P R
PR
Phillips
L
L
Hickey
P R
PR
Sellke
F W
FW
Mayer
J E
JE
Nelson
D P
DP
D000109:Acetylcholine / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D002315:Cardiopulmonary Bypass; D002448:Cell Adhesion / Q000187:drug effects; D003331:Coronary Vessels / Q000187:drug effects; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D006324:Heart Arrest, Induced; D006439:Hemodynamics / Q000187:drug effects; D007036:Hypothermia, Induced; D015428:Myocardial Reperfusion Injury / Q000517:prevention & control*; D009504:Neutrophils / Q000502:physiology; D009599:Nitroprusside / Q000494:pharmacology; D009844:Oligosaccharides / Q000494:pharmacology*; D011652:Pulmonary Circulation / Q000187:drug effects; D012129:Respiratory Function Tests; D012756:Sheep; D014665:Vasodilator Agents / Q000494:pharmacology
C090410:CY 1503; D009844:Oligosaccharides; D014665:Vasodilator Agents; D009599:Nitroprusside; D000109:Acetylcholine