Dependence of endothelium-mediated relaxation on oxygen and metabolism in porcine coronary arteries.
Hypoxia has major effects on endothelium-dependent relaxation. To further understand the underlying mechanism(s), we investigated the O2 dependence of the endothelium-dependent relaxations elicited by ionophore A-23187 or agonists substance P (SP) or thrombin (TB) in porcine coronary arteries. A-23187 elicits an endothelium-dependent relaxation of KCl- or U-46619-induced contractures that can be described in terms of a rapid and slow phase. The duration of the relaxation was dose dependent. SP (10 nM) and TB (0.1 U/ml) also elicited endothelium-dependent relaxations that were rapid but transient. Hypoxic conditions (95% N2-5% CO2 instead of 95% O2-5% CO2; PO2 < 1%) abolished the A-23187 rapid phase and the SP and TB transient relaxation but not the A-23187 slow phase. Threshold PO2 for the rapid phase was approximately 35 mmHg. Pretreatment with cyanide (5 mM), to inhibit respiration, or 2-deoxy-D-glucose, to inhibit glycolysis, had little effect. Similarly, propranolol (10 microM) or indomethacin (10 microM) had no effect on the relaxation to A-23187, TB, or SP. In contrast, both NO synthesis inhibitors and ouabain blunted all endothelium-dependent relaxations studied. Our results suggest that the rapid relaxations to A-23187, SP, and TB are sensitive to O2 but not mitochondrial respiration. The slow sustained relaxation induced by A-23187, however, is characterized by a sensitivity to O2 that is distinct from that of the rapid phase, yet is dependent on an intact endothelium and is affected by NO synthesis inhibitors. Thus the endothelium-dependent relaxation to A-23187 is probably mediated by NO, but its sensitivity to O2 suggests that two distinct mechanisms may be involved.
Hashimoto
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Department of Physiology and Biophysics, College of Medicine, University of Cincinnati, Ohio 45267-0576.
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D000818:Animals; D000001:Calcimycin / Q000494:pharmacology; D003331:Coronary Vessels / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology*; D003470:Culture Media; D004730:Endothelium, Vascular / Q000187:drug effects / Q000502:physiology*; D000860:Hypoxia / Q000503:physiopathology; D066298:In Vitro Techniques; D009569:Nitric Oxide / Q000037:antagonists & inhibitors; D009599:Nitroprusside / Q000494:pharmacology; D010100:Oxygen / Q000494:pharmacology*; D010101:Oxygen Consumption; D014664:Vasodilation / Q000502:physiology*
D003470:Culture Media; D009599:Nitroprusside; D009569:Nitric Oxide; D000001:Calcimycin; D010100:Oxygen