Traverse J H, Judd D, Bache R J
Department of Medicine, University of Minnesota Medical School, Minneapolis 55455, USA.
Circulation. 1996 Feb 1;93(3):558-66. doi: 10.1161/01.cir.93.3.558.
Plasma levels of endothelin-1 (ET-1) increase during ischemia and could potentially contribute to impairment of myocardial blood flow (MBF). Because collateral vessels demonstrate enhanced responsiveness to certain vasoconstrictors, blood flow to collateral-dependent myocardium could be particularly sensitive to increases in ET-1 levels.
Studies were performed in 13 dogs in which collateral vessel development was produced by fluoroscopic embolization of the midleft anterior descending coronary artery with a hollow plug 4 to 6 weeks before the study. MBF was measured with radioactive microspheres at baseline and during 30-minute infusions of ET-1 (1, 10, and 100 ng/min) into the left main coronary artery. Because ET-1 stimulates endothelial prostacyclin release, aortic and coronary sinus levels of ET-1 and 6-keto-prostaglandin F1 alpha were measured at the end of each infusion. ET-1 increased MBF from 0.82 mL.min-1.g-1 at baseline to 0.92 mL.min-1.g-1 at 10 ng/min (P < .05), which corresponded to a coronary plasma concentration of 73 +/- 16 pg/mL. Blood flow in the collateral zone was less (0.74 mL.min-1.g-1) than in the normal zone (P < .05) and did not increase at an ET-1 dose of 10 ng/min. MBF in the normal and collateral zones significantly decreased when ET-1 was increased to 100 ng/min, corresponding to a coronary sinus concentration of 175 +/- 45 pg/mL (P < .05). ET-1 produced dose-related increases in aortic and coronary sinus 6-keto-prostaglandin F1 alpha and the transcoronary difference (P < .05). To assess the importance of prostacyclin in opposing the vasoconstriction produced by ET-1, additional studies were performed after cyclooxygenase blockade with indomethacin. After indomethacin administration, ET-1 (10 ng/min) caused a 120 +/- 23% increase in collateral vascular resistance (P < .05) and abolished the vasodilation that this dose produced in the normal zone.
Blood flow to normal myocardium is increased at moderate plasma elevations of ET-1, whereas collateral blood flow is unchanged. Only at significantly elevated plasma concentrations of ET-1 is blood flow to normal and collateral-dependent myocardium impaired. Coronary endothelial production of prostacyclin in response to increasing concentrations of ET-1 represents an important means of blunting the vasoconstrictor properties of ET-1 in the canine coronary circulation. Coronary collateral vessels demonstrate a much greater dependence on prostacyclin production in blunting the vasoconstrictor properties of ET-1.
内皮素-1（ET-1）的血浆水平在缺血期间升高，可能会导致心肌血流量（MBF）受损。由于侧支血管对某些血管收缩剂的反应性增强，流向依赖侧支循环的心肌的血流量可能对ET-1水平的升高特别敏感。
对13只犬进行了研究，在研究前4至6周通过荧光透视引导下用空心栓塞物栓塞左前降支冠状动脉中段来促进侧支血管形成。在基线时以及向左主冠状动脉内输注ET-1（1、10和100 ng/min）30分钟期间，用放射性微球测量MBF。由于ET-1刺激内皮前列环素释放，在每次输注结束时测量主动脉和冠状窦中ET-1和6-酮-前列腺素F1α的水平。ET-1使MBF从基线时的0.82 mL·min⁻¹·g⁻¹增加到10 ng/min时的0.92 mL·min⁻¹·g⁻¹（P<.05），这相当于冠状动脉血浆浓度为73±16 pg/mL。侧支循环区域的血流量（0.74 mL·min⁻¹·g⁻¹）低于正常区域（P<.05），并且在ET-1剂量为10 ng/min时未增加。当ET-1增加到100 ng/min时，正常区域和侧支循环区域的MBF均显著降低，相当于冠状窦浓度为175±45 pg/mL（P<.05）。ET-1使主动脉和冠状窦中6-酮-前列腺素F1α以及跨冠状动脉差值呈剂量相关增加（P<.05）。为了评估前列环素在对抗ET-1引起的血管收缩中的重要性，在用吲哚美辛阻断环氧化酶后进行了额外的研究。给予吲哚美辛后，ET-1（10 ng/min）使侧支血管阻力增加120±23%（P<.05），并消除了该剂量在正常区域产生的血管舒张作用。
在ET-1血浆水平适度升高时，正常心肌的血流量增加，而侧支循环血流量不变。只有在血浆ET-1浓度显著升高时，正常心肌和依赖侧支循环的心肌的血流量才会受损。冠状动脉内皮对ET-1浓度升高产生的前列环素生成是减轻ET-1在犬冠状动脉循环中血管收缩特性的重要手段。冠状动脉侧支血管在减轻ET-1血管收缩特性方面对前列环素生成的依赖性更强。
