Sampei Kenji, Ulatowski John A, Asano Yoshio, Kwansa Herman, Bucci Enrico, Koehler Raymond C
Department of Anesthesiology and Critical Care Medicine, The Johns Hopkins Medical Institutions, 600 N. Wolfe St., Blalock 1404, Baltimore, MD 21287, USA.
Am J Physiol Heart Circ Physiol. 2005 Sep;289(3):H1191-201. doi: 10.1152/ajpheart.00251.2005. Epub 2005 May 13.
Modified Hb solutions have been developed as O(2) carrier transfusion fluids, but of concern is the possibility that increased scavenging of nitric oxide (NO) within the plasma will alter vascular reactivity even if the Hb does not readily extravasate. The effect of decreasing hematocrit from approximately 30% to 18% by an exchange transfusion of a 6% sebacyl cross-linked tetrameric Hb solution on the diameter of pial arterioles possessing tight endothelial junctions was examined through a cranial window in anesthetized cats with and without a NO synthase (NOS) inhibitor. Superfusion of a NOS inhibitor decreased diameter, and subsequent Hb transfusion produced additional constriction that was not different from Hb transfusion alone but was different from the dilation observed by exchange transfusion of an albumin solution after NOS inhibition. In contrast, abluminal application of the cross-linked Hb produced constriction that was attenuated by the NOS inhibitor. Neither abluminal nor intraluminal cross-linked Hb interfered with pial arteriolar dilation to cromakalim, an activator of ATP-sensitive potassium channels. Pial vascular reactivity to hypocapnia and hypercapnia was unaffected by Hb transfusion. Microsphere-determined regional blood flow indicated selective decreases in perfusion after Hb transfusion in the kidney, small intestine, and neurohypophysis, which does not have tight endothelial junctions. Administration of a NOS inhibitor to reduce the basal level of NO available for scavenging before Hb transfusion prevented further decreases in blood flow to these regions compared with NOS inhibition alone. In contrast, blood flow to skeletal and left ventricular muscle increased, and cerebral blood flow was unchanged after Hb transfusion. This cross-linked Hb tetramer is known to appear in renal lymph but not in urine. We conclude that cell-free tetrameric Hb does not scavenge sufficient NO in the plasma space to significantly affect baseline tone in vascular beds with tight endothelial junctions but does produce substantial constriction in beds with porous endothelium. The data support increasing the molecular size of Hb by polymerization or conjugation to limit extravasation in all vascular beds to preserve normal vascular reactivity.
改良血红蛋白溶液已被开发用作氧气载体输血液，但令人担忧的是，即使血红蛋白不易渗出，血浆中一氧化氮（NO）清除增加也可能改变血管反应性。通过在有或没有一氧化氮合酶（NOS）抑制剂的麻醉猫的颅窗上，研究了用6%癸二酰交联四聚体血红蛋白溶液进行换血输血，使血细胞比容从约30%降至18%对具有紧密内皮连接的软脑膜小动脉直径的影响。灌注NOS抑制剂会使血管直径减小，随后输注血红蛋白会产生额外的收缩，这与单独输注血红蛋白没有差异，但与在NOS抑制后输注白蛋白溶液进行换血观察到的扩张不同。相比之下，在血管外膜应用交联血红蛋白会产生收缩，而NOS抑制剂可减弱这种收缩。血管外膜和管腔内的交联血红蛋白均不干扰软脑膜小动脉对ATP敏感性钾通道激活剂克罗卡林的舒张反应。血红蛋白输血不影响软脑膜血管对低碳酸血症和高碳酸血症的反应性。微球测定的局部血流表明，在肾脏、小肠和神经垂体（其内皮连接不紧密）中，血红蛋白输血后灌注选择性降低。在输注血红蛋白之前给予NOS抑制剂以降低可供清除的NO基础水平，与单独抑制NOS相比，可防止这些区域的血流进一步减少。相比之下，血红蛋白输血后骨骼肌和左心室肌肉的血流增加，而脑血流未改变。已知这种交联血红蛋白四聚体出现在肾淋巴中而非尿液中。我们得出结论，无细胞四聚体血红蛋白在血浆空间中清除的NO不足以显著影响具有紧密内皮连接的血管床的基线张力，但确实会在具有多孔内皮的血管床中产生显著收缩。这些数据支持通过聚合或结合增加血红蛋白的分子大小，以限制在所有血管床中的渗出，从而保持正常的血管反应性。
