Hyperkalemia alters EDHF-mediated hyperpolarization and relaxation in coronary arteries GUO-WE1 HE, CHENG-QIN YANG, WOLFGANG F. GRAIER, AND JIAN-AN YANG Cardiovascular Research Laboratory, Grantham Hospital, Department of Surgery, University of Hong Kong, Hong Kong; and Cardiovascular Research Laboratories, The Albert Starr Academic Center for Cardiac Surgery, St. Vincent Hospital, Portland, Oregon 97225 He, Guo-Wei, Cheng-Qin Yang, Wolfgang F. Graier, and Jian-An Yang. Hyperkalemia alters EDHF-mediated hyperpolarization and relaxation in coronary arteries. Am. J. Physiol. 271 (Heart Circ. Physiol. 40): H760-H767, 1996.- Hyperkalemic solutions are widely used to preserve organs for transplantation and for cardiac surgery. The present study was designed to test the hypothesis that hyperkalemia may alter endothelial function through a non-nitric oxide (NO) pathway, since preliminary studies have shown that the NO pathway may not be affected. Porcine coronary artery rings were studied in organ chambers. After incubation with 20 or 50 mM K+ for 1 h, the indomethacin- and NG-nitro-L- arginine (L-NNA)-resistant relaxation induced by A23187 or bradykinin, which could be further inhibited by tetraethylam- monium but not glibenclamide, was significantly reduced. Incubation with hyperkalemia also significantly increased the concentration eliciting 50% of the maximal response to A23187 and bradykinin. A23187-induced hyperpolarization of the membrane potential was significantly reduced by hyperkalemic incubation. However, l-h incubation with hyper- kalemia does not affect the endothelial Ca2+ concentration. We conclude that exposure to hyperkalemia reduces the indomethacin- and L-NNA-resistant endothelium-dependent relaxation and endothelium-dependent hyperpolarization. This reduction in the relaxation and hyperpolarization is related to the endothelium-derived hyperpolarizing factor by affecting its effect on the smooth muscle cell, probably through partially depolarizing the membrane, and the Ca2+- activated K+ channels rather than by affecting its biosynthe- sis and/or release in the endothelial cell. Our study may suggest a new mechanism for coronary dysfunction after exposure to hyperkalemic cardioplegia and organ preserva- tion solutions. endothelium-derived relaxing factor; endothelium-derived hy- perpolarizing factor; calcium ionophore; bradykinin; potas- sium channels; coronary artery ENDOTHELIUM-DEPENDENT relaxation is known to be the effect of a variety of different endothelium-derived relaxing factors (EDRFs). These are endothelium- derived nitric oxide (EDNO), prostacyclin (PGI& and endothelium-derived hyperpolarizing factor (EDHF). EDHF induces vascular smooth muscle relaxation via hyperpolarization of the smooth muscle cells (4, 7, 19, 24, 26), which may involve K+ channels (5, 9, 15). In contrast, EDNO relaxes blood vessels through the guanosine 3’,5’-cyclic monophosphate pathway and does not hyperpolarize the vascular smooth muscle cells in some vessels or species (3, 7). All of these EDRFs are released in response to the increase of intracellular (cytosolic free) Ca2+ concentration in the endothelial cell (8). A uniform conclusion regarding the effect of hyperka- lemic solutions on the endothelial function has not been reached, although it is the focus of several recent studies (6,13,14,20). An important question is whether exposure to hyperkalemic solutions alters endothelial function. In perfused rat hearts, previous studies have suggested that infusion of hyperkalemic cardioplegic solution damages coronary endothelium (21). In con- trast, we (13,14) and others (6) have demonstrated that exposure to hyperkalemic solutions for up to 4 h does not alter the noncyclooxygenase pathway-mediated en- dothelium-dependent relaxation in porcine coronary arteries (14) or neonatal rabbit aortas (13). However, the effect of hyperkalemia on noncyclooxygenase and non-EDNO-mediated endothelium-dependent (presum- ably EDHF-mediated) relaxation is unknown. If hyper- kalemia alters this relaxation, it would have strong clinical implications because hyperkalemic solutions (containing 16-140 mM K+) are widely used for myocar- dial protection in cardiac surgery and for preservation of various organs for transplantation. The present study was designed to examine the effect of hyperkale- mia on indomethacin and NG-nitro-L-arginine (L-NNA)- resistant (noncyclooxygenase and non-EDNO medi- ated), i.e., EDHF-mediated, endothelium-dependent relaxation in the porcine coronary artery. MATERIALS AND METHODS Organ Bath Studies Coronary arteries were obtained from porcine hearts that were harvested in a local abattoir. Immediately after the hog (either sex) was killed, the heart was rapidly removed, placed in a container filled with Krebs solution at 4”C, and trans- ferred to the laboratory. Epicardial coronary arteries were dissected free of surrounding connective tissue, cut into 3-mm-long rings, and mounted on a pair of stainless steel wires in organ chambers (10) filled with Krebs solution at 37°C. The Krebs solution had the following composition (in mM): 144 Na+, 5.9 K+, 2.5 Ca2’, 1.2 Mg2+, 128.7 Cl-, 25 HCO,, 1.2 SO;-, 1.2 H2P0,, and 11 glucose. The solution was aerated with a gas mixture of 95% O2-5% Co2 at 37°C. Four organ chamber arrangements were run concurrently. A previously described organ-chamber technique (10) was used to normalize vascular rings under a pressure simulating the conditions encountered at the artery at its normal trans- mural pressure, according to their own length-tension curves. The normalization procedure was performed with a com- puterized program (VESTAND by Y.-H. He, Princeton Univer- sity, NJ). The endothelium was intentionally preserved by cau- tiously dissecting and mounting the rings (10, 12). In some rings, the endothelium was mechanically removed to examine the endothelium dependence of the relaxation to A23187 or H760 0363-6135/96 $5.00 Copyright o 1996 the American Physiological Society by 10.220.33.6 on May 1, 2017 http://ajpheart.physiology.org/ Downloaded from