Hyperkalemia alters endothelium-dependent relaxation through non-nitric oxide and noncyclooxygenase pathway: a mechanism for coronary dysfunction due to cardioplegia.
BACKGROUND
Reported results of hyperkalemia (cardioplegia or organ preservation solutions) on endothelial function are contradictory. The endothelium-dependent relaxation is related to three major mechanisms: cyclooxygenase, nitric oxide, and endothelium-derived hyperpolarizing factor (K+ channel related). The present study was designed to test the hypothesis that hyperkalemia may alter endothelial function through non-nitric oxide and noncyclooxygenase pathways.


METHODS
Porcine coronary artery rings (5 to 10 in each group) were studied in organ chambers under physiologic pressure. After incubation with 20 or 50 mmol/L K+ for 1 hour, the response to substance P, an endothelium-dependent vasorelaxant peptide, in K+ (25 mmol/L)-induced contraction was studied in the presence of the cyclooxygenase inhibitor indomethacin (7 mumol/L), the nitric oxide biosynthesis inhibitor NG-nitro-L-arginine (L-NNA) (300 mumol/L), or the adenosine triphosphate-sensitive K(+)-channel blocker glybenclamide (3 mumol/L) in comparison with control arteries (69.8 +/- 4.6% of K+ contraction).


RESULTS
Without exposure to hyperkalemia, indomethacin (with or without glybenclamide) did not alter but L-NNA significantly reduced the relaxation (39.7% +/- 3.7%, p < 0.001). After exposure to K+, the indomethacin- and L-NNA-resistant relaxation was further reduced (7.4% +/- 3.2% for 20 mmol/L K+, p < 0.0001; or 13.5% +/- 8.4% for 50 mmol/L K+, p < 0.05, compared with rings without exposure), whereas the indomethacin- and glybenclamide-resistant relaxation was not altered. Incubation with hyperkalemia (50 mmol/L) also significantly reduced the sensitivity (increased EC50) of the indomethacin- and L-NNA-resistant relaxation (-9.75 +/- 0.06 versus -9.33 +/- 0.04 log M, p < 0.01).


CONCLUSIONS
Exposure to hyperkalemia reduces the indomethacin- and L-NNA-resistant, endothelium-dependent (endothelium-derived hyperpolarizing factor-related) relaxation. Our study may suggest a new mechanism of coronary dysfunction after exposure to hyperkalemia and open a new area for protection of coronary endothelium in cardiac surgery and for organ preservation in transplantation surgery.
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Department of Surgery, University of Hong Kong, Grantham Hospital, Aberdeen, Hong Kong.
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D000818:Animals; D002314:Cardioplegic Solutions / Q000494:pharmacology*; D003331:Coronary Vessels / Q000187:drug effects* / Q000502:physiology; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D006324:Heart Arrest, Induced / Q000009:adverse effects; D006331:Heart Diseases / Q000209:etiology / Q000503:physiopathology; D066298:In Vitro Techniques; D007213:Indomethacin / Q000494:pharmacology; D009569:Nitric Oxide / Q000494:pharmacology / Q000502:physiology*; D013552:Swine
D002314:Cardioplegic Solutions; D016861:Cyclooxygenase Inhibitors; D009569:Nitric Oxide; D007213:Indomethacin