15-hydroxy-11-alpha-9-alpha-(epoxymethano)prosta-5-13-dienoic-acid and Hyperkalemia

Relaxation induced by bradykinin is diminished by hypoxia in epicardial coronary arteries. The bradykinin-degrading enzyme, neutral endopeptidase (NEP, EC.3.4.24.11), is a potential target for coronary artery vasodilators. In this study, we examined the effect of thiorphan, an inhibitor of NEP, on the tone of porcine isolated coronary artery under hypoxic conditions. Endothelium-intact porcine isolated coronary artery rings were isometrically contracted with a prostaglandin F(2alpha) analogue (U46619, 0.75 microM) and potassium chloride (KCl, 30 mM), and relaxed with bradykinin (1-1000 nM) under normoxic (partial pressure of oxygen, pO(2) approximately 90-100 mmHg) and moderately hypoxic (pO(2) approximately 50-60 mmHg) conditions. Experiments were performed to study the effects of 30 min pre-treatment with the NEP-inhibitor, thiorphan (10 microM), both at physiological and at low pO(2)s. Hypoxia inhibited the bradykinin-induced relaxation in porcine epicardial coronary arteries. In normoxia, thiorphan significantly enhanced the decrease of coronary tone produced by bradykinin (1-10 nM) when U46619 was used as contractile agent. Under hypoxic conditions, in U46619 contracture, thiorphan did not influence, but in KCl contracture it enhanced the magnitude of relaxations induced by bradykinin. In the absence of bradykinin, thiorphan had no significant effect on the basal, KCl- and U46619-elevated tones and on the hypoxia-induced decrease of coronary artery tone. Inhibition of NEP-enzyme activity may effectively improve the relaxing capacity of epicardial coronary arteries under hypoxic/hyperkalemic conditions. This effect could be potentially utilized when the endothelial function and relaxation of the coronary arteries are impaired under clinical conditions.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Bradykinin; Coronary Vessels; Drug Synergism; Hyperkalemia; Hypoxia; In Vitro Techniques; Muscle Relaxation; Muscle, Smooth, Vascular; Potassium Chloride; Protease Inhibitors; Swine; Thiorphan; Vasoconstrictor Agents; Vasodilator Agents

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

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

Depolarizing (hyperkalemic) solutions are widely used to preserve organs for transplantation and for cardiac operations. We previously observed that exposure to hyperkalemia reduced endothelium-dependent, noncyclooxygenase- and non-nitric oxide-mediated relaxation. This study was designed to examine the mechanism of this effect with regard to K channels and the associated membrane potential changes.. Porcine coronary artery rings were studied in organ chambers. After incubation of the tissue with 20 or 50 mmol/L doses of potassium for 1 hour, the endothelium-derived hyperpolarizing factor-mediated relaxation in the artery and the membrane hyperpolarization in a single coronary smooth muscle cell were studied.. The endothelium-derived hyperpolarizing factor-mediated relaxation induced by substance P, which could be significantly inhibited by the Ca(2+)-activated K channel blocker tetraethylammonium but only to a lesser extent by the adenosine triphosphate-sensitive K channel blocker glibenclamide, was significantly reduced. Substance P-induced hyperpolarization of the membrane potential was also significantly reduced by the hyperkalemic incubation with a significantly elevated resting membrane potential.. Depolarizing arrest reduces endothelium-derived hyperpolarizing factor-mediated membrane hyperpolarization and relaxation by affecting mainly the Ca(2+)-activated K channels and by depolarizing the membrane for a prolonged period. We suggest that this is one of the mechanisms for coronary dysfunction after exposure to depolarizing (hyperkalemic) cardioplegic and organ-preservation solutions and that, therefore, "perfect" protection of the heart or other organs should restore the endothelium-derived hyperpolarizing factor-related endothelial function.

Topics: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; Animals; Biological Factors; Coronary Vessels; Endothelium, Vascular; Female; Heart; Heart Arrest, Induced; Hyperkalemia; In Vitro Techniques; Indomethacin; Male; Membrane Potentials; Muscle Relaxation; Muscle, Smooth, Vascular; Organ Preservation Solutions; Potassium Channels; Prostaglandin Endoperoxides, Synthetic; Substance P; Swine; Thromboxane A2; Vasoconstrictor Agents