Hyperkalemia alters endothelium-dependent relaxation through non-nitric oxide and noncyclooxygenase pathway: a mechanism for coronary dysfunction due to cardioplegia.

Abstract

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. 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). 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). 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.