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Protective effects of an indenoindole antioxidant on coronary endothelial function after long-term storage
L Wiklund1, V M Miller, C G McGregor
1Department of Surgery, Mayo Clinic and Foundation, Rochester, Minnesota 55905, USA.
Insights
Storage of canine hearts in cardioplegia impairs endothelium-dependent relaxations. Adding H 290/51, a lipid peroxidation inhibitor, preserves these vital coronary artery functions, suggesting its therapeutic potential for heart transplantation.
Area of Science:
- Cardiovascular Physiology
- Organ Preservation
- Pharmacology
Background:
- Coronary artery function, specifically endothelium and smooth muscle, is crucial for heart transplantation success.
- Heart storage in cardioplegia can compromise vascular function, impacting post-transplant outcomes.
- Lipid peroxidation is a known factor in cellular damage during ischemia and reperfusion.
Purpose of the Study:
- To evaluate the impact of cardioplegic storage on canine coronary artery endothelium and smooth muscle function.
- To determine if H 290/51, a lipid peroxidation inhibitor, can preserve vascular function during heart storage.
- To differentiate the effects of ischemia/reperfusion from the protective properties of H 290/51 on coronary vessels.
Main Methods:
- Canine hearts were stored in crystalloid cardioplegia with or without H 290/51 for up to 24 hours.
- Isolated left circumflex arteries were studied for isometric force in organ chambers.
- Endothelium-dependent (UK 14,304, bradykinin, A 23187) and endothelium-independent (isoproterenol, nitric oxide) relaxations were measured.
Main Results:
- Twenty-four-hour storage without H 290/51 significantly reduced endothelium-dependent relaxations to UK 14,304 and bradykinin.
- Arteries from hearts stored with H 290/51 exhibited preserved endothelium-dependent relaxations, comparable to non-stored controls.
- Endothelium-independent relaxations to isoproterenol and nitric oxide remained consistent across all storage conditions.
Conclusions:
- Crystalloid cardioplegia storage selectively inhibits receptor-mediated endothelium-dependent relaxations in coronary arteries.
- Inhibition of lipid peroxidation with H 290/51 effectively preserves these critical vascular functions.
- H 290/51 shows promise as a therapeutic agent to improve heart preservation for transplantation.
Abstract:
Experiments were designed to evaluate function of the endothelium and smooth muscle of coronary arteries following storage of hearts in cardioplegia containing an inhibitor of lipid peroxidation (H 290/51, cis-7-methyl-9-methoxy-5,5a, 6,10b tetrahydroindeno [2,1-b] indole). Canine hearts were perfused with crystalloid cardioplegia (Plegisol, 15 ml/kg, 4 degrees C) and left circumflex arteries were isolated and studied either immediately (group I, n = 6), or after storage of the hearts at 4 degrees C for 10 (group II, n = 6) or 24 hr with (group III, n = 6) or without (group IV, n = 6) addition of H 290/51. The final concentration of H 290/51 was 1 mumol/L. Arteries were removed, cut into rings, and suspended in organ chambers for measurements of isometric force. In selected rings, the endothelium was removed in order to study the function of the smooth muscle. In order to discriminate effects of ischemia/reperfusion and protective properties on coronary endothelium or smooth muscle, drugs with different mechanisms were used. The function of the endothelium were studied with the alpha 2-adrenergic agonist UK 14,304, bradykinin and A 23187. The smooth muscle function were studied with isoproterenol and nitric oxide. Endothelium-dependent relaxations to the alpha 2-adrenergic agonist UK 14,304 and bradykinin, but not to A 23187, were reduced significantly in arteries from hearts stored for 24 hr in cardioplegic solution alone. Relaxations of arteries from hearts stored for 24 hr with H 290/51 were comparable to those arteries from hearts that were not stored. Endothelium-independent relaxations to isoproterenol and nitric oxide among the different groups were comparable. These results suggest that storage of canine hearts with crystalloid cardioplegia selectively inhibits endothelium-dependent relaxations mediated by receptor activation. Inhibition of lipid peroxidation with H 290/51 preserves these relaxations and may therefore represent a therapeutic alternative to preserve hearts used for transplantation.