calcimycin and Hyperkalemia

Endothelium plays an important role in mediating the function of transplanted organs. The widely used University of Wisconsin solution impairs the endothelium-derived hyperpolarizing factor-mediated relaxation in coronary arteries, but little is known about effects of lung preservation on endothelium-derived hyperpolarizing factor-mediated endothelial function. This study examined the effect of organ preservation solutions on the endothelium-derived hyperpolarizing factor-mediated relaxation in the pulmonary microarteries (diameter 200 to 450 microm).. Two segments (1 as control) from the same microartery were allocated in 2 chambers of a myograph. After incubation with hyperkalemia (potassium 115 mmol/L), University of Wisconsin, or Euro-Collins solution (at 4 degrees C for 4 hours), the endothelium-derived hyperpolarizing factor-mediated relaxation was induced by bradykinin (-10 to -6.5 log M, n = 8) or calcium ionophore (A(23187), -9 to -5.5 log M, n = 7) in U(46619) (-7.5 log M) precontracted rings in the presence of indomethacin (7 micromol/L), N(G)-nitro-L-arginine (300 micromol/L), and oxyhemoglobin (20 micromol/L).. Exposure to hyperkalemia and storage with Euro-Collins or University of Wisconsin solution significantly decreased the relaxation to bradykinin (51.9 +/- 8.4% vs 60.3 +/- 6.1%, P =.02 or 49.3 +/- 7.3% vs 65.2 +/- 3.5%, P =.04) or A(23187) (12.5 +/- 0.02% vs 33.8 +/- 0.07%, P =.02 or 13.2 +/- 0.03% vs 31.0 +/- 0.05%, P =.03%).. Endothelium-derived hyperpolarizing factor plays an important role in porcine pulmonary microarteries, and the endothelium-derived hyperpolarizing factor-mediated relaxation is impaired when the lung is preserved with University of Wisconsin or Euro-Collins solution. This impairment may affect the lung function during the reperfusion period after lung transplantation.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Blood Pressure; Bradykinin; Calcimycin; Cold Temperature; Dose-Response Relationship, Drug; Endothelium, Vascular; Hyperkalemia; Hypertonic Solutions; Ionophores; Lung; Models, Animal; Models, Cardiovascular; Muscle Contraction; Nitric Oxide; Organ Preservation Solutions; Pulmonary Artery; Swine; Vasoconstrictor Agents; Vasodilation; Vasodilator Agents

Hyperkalemic solution is widely used to protect the myocardium during open-heart surgery or to preserve donor hearts during heart or heart/lung transplants. The inhibitory effects of hvperkalemic solution on the release of endothelium-derived hyperpolarizing factor (EDHF) of coronary arteries following deep hypothermic storage (4 degrees C) has been well studied. However, it has not been established whether potassium channel openers have protective effects on the coronary endothelial function after cold storage. This study was designed to examine this. Porcine coronary artery rings were studied in organ baths. Relaxation in response to the EDHF stimulus A23187 (nonreceptor-mediated stimulus calcium ionophore) in thromboxane A2 mimetic U46619 (30 nmol/L)-induced precontraction after incubation with hyperkalemic solution (20 mmol/L) with nicorandil (10 micromol/L) (either at 37 degrees C in the oxygenated organ chamber or at 4 degrees C in a refrigerator for 6 h) was compared with the control. There was significant difference between hyperkalemia group and hyperkalemia with nicorandil group under normothermia (p = .04). The difference was significant in the same solution between normothermia and hypothermia. After incubation in hyperkalemic solution without or with nicorandil, the A23187-induced relaxation was 32.8% +/- 9.1% and 72.6% +/- 16.9%, respectively (N = 8, p < .01). Potassium channel opener can attenuate the inhibitory effect of hyperkalemic solution on the release of EDHF after cold storage.

Topics: Animals; Biological Factors; Calcimycin; Cardioplegic Solutions; Cold Temperature; Coronary Vessels; Hyperkalemia; In Vitro Techniques; Muscle Relaxation; Nicorandil; Potassium Channels; Swine; Vasodilator Agents

My colleagues and I have found in the porcine coronary artery that the pathway other than the nitric oxide (NG-nitro-L-arginine [L-NNA]-sensitive) and cyclooxygenase (indomethacin-sensitive) pathways of endothelium-dependent relaxation, related to the endothelium-derived hyperpolarizing factor (K+ channel-related), are altered after exposure to hyperkalemia. The present study was designed to examine whether this effect exists in the human coronary artery.. Coronary artery rings obtained from explanted fresh human hearts were studied in organ chambers under physiologic pressure. The endothelium-dependent relaxation in response to calcium ionophore A23187 was studied in U46619 (30 nmol/L)-induced precontraction in the presence of the cyclooxygenase inhibitor indomethacin (7 mumol/L) and the nitric oxide biosynthesis inhibitor L-NNA (300 mumol/L). The effect of incubation with 20 mmol/L K+ for 1 hour on the relaxation was examined in other coronary rings.. In control rings, A23187 induced a maximal relaxation of 50.7% +/- 3.2% (n = 6). After 1 hour of exposure to 20 mmol/L K+, the relaxation was reduced to 30.4% +/- 4.6% (n = 6; p = 0.005). Incubation with hyperkalemia also significantly reduced the sensitivity (increased effective concentration that caused 50% of maximal relaxation) of the indomethacin- and L-NNA-resistant relaxation (-7.37 +/- 0.17 versus -8.28 +/- 0.27 log mol/L; p = 0.019).. Exposure to hyperkalemia reduces the indomethacin- and L-NNA-resistant, endothelium-dependent (endothelium-derived hyperpolarizing factor-related) relaxation in the human coronary artery. This suggests that the previously proposed mechanism of coronary dysfunction after exposure to cardioplegic and organ preservation solutions in animal vessels is also valid in the human heart.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Biological Factors; Calcimycin; Coronary Vessels; Endothelium, Vascular; Humans; Hyperkalemia; In Vitro Techniques; Indomethacin; Potassium; Prostaglandin Endoperoxides, Synthetic; Thromboxane A2; Vasoconstrictor Agents; Vasodilation

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 tetraethylammonium 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, 1-h incubation with hyperkalemia 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 biosynthesis and/or release in the endothelial cell. Our study may suggest a new mechanism for coronary dysfunction after exposure to hyperkalemic cardioplegia and organ preservation solutions.

Topics: Animals; Arteries; Biological Factors; Bradykinin; Calcimycin; Coronary Vessels; Electrophysiology; Female; Hyperkalemia; Male; Membrane Potentials; Swine; Vasodilation

To determine: a) any heart site or tissue-specific differences in the response to increased perfusion potassium concentrations, and b) the cellular site (intracellular vs. extracellular) of the effect of calcium on reversing electrocardiographic effects of hyperkalemia.. In vitro prospective, repeated-measures, dose-response study.. University/medical school experimental physiology laboratory.. Adult male Sprague-Dawley rats whose hearts were studied in an in vitro perfusion preparation.. One group of hearts was perfused with modified Krebs-Henseleit physiologic salt solution onto which were superimposed infusions of concentrated potassium and/or calcium solutions. Infusion rates increased stepwise the respective ions in order to calculate increased concentrations through the course of the experiment. Calcium concentration was at either 4.0 or 5.4 mEq/L (2.0 or 2.7 mmol/L); potassium concentration was increased from 5.8 to 7.3, 8.0, 8.8, 10.2 and 11.8 mmol/L. Two more groups of hearts were perfused with Krebs-Henseleit solution containing the lower calcium concentration to which was added the calcium ionophore A23187 in one of two doses. A fourth group of hearts was perfused with Krebs-Henseleit solution containing the higher calcium concentration to which was added the a single dose of the calcium-channel blocking agent verapamil.. We tested the effects of a series of ion and drug concentrations on epicardial EKG variables (atrial and ventricular rates, P-wave amplitude, PR interval, QRS complex amplitude and duration, and T-wave amplitude and duration). The effects of these variables were tested by increasing the ionized calcium in the perfusate of isolated rat hearts from 4.0 mEq/L (2.0 mmol/L) to 5.4 mEq/L (2.7 mmol/L) as perfusate potassium was increased stepwise from normal (5.8 mEq/L or mmol/L) to as high as 11.8 mEq/L (mmol/L). In addition, we studied the effect of adding the calcium ionophore A23187 to the perfusate with the lower ionized calcium concentration, and we also studied the effect of adding the calcium-channel blocking agent verapamil to the perfusate containing the higher ionized calcium while increasing the perfusate potassium concentration in a stepwise manner in each of the series. The higher calcium concentration (5.4 mEq/L or 2.7 mmol/L) prevented most of the adverse effects of the highest potassium concentration in the first drug-free series of experiments. When the calcium ionophore A23187 was added to the perfusate, most electrocardiographic variables remained normal even in the presence of a lower ionized calcium concentration. However, the higher ionized calcium concentration was not able to prevent electrical abnormalities in hearts perfused with high potassium when verapamil was in the solution.. We conclude that the mechanism whereby calcium reverses the clinically observable electrocardiographic effects of hyperkalemia is an intracellular one.

Topics: Animals; Calcimycin; Calcium; Dose-Response Relationship, Drug; Electrocardiography; Heart; Heart Rate; Hyperkalemia; Infusion Pumps; Male; Prospective Studies; Rats; Rats, Sprague-Dawley; Verapamil