Gerth Klaus, Ehring Thomas, Braendle Marian, Schelling Pierre
Merck KGaA, Darmstadt, Germany.
Clin Toxicol (Phila). 2006;44 Suppl 1:29-36. doi: 10.1080/15563650600811805.
Antidotal doses of hydroxocobalamin are associated with transient increases in blood pressure in some animals and humans. These studies in anesthetized rabbits were undertaken to explore the possible mechanisms underlying the hemodynamic effects of hydroxocobalamin by investigating 1) possible hemodynamic effects of cyanocobalamin, which is formed on a molar-to-molar basis when hydroxocobalamin binds cyanide, and 2) the interference of hydroxocobalamin with the endothelial nitric oxide system.
Study 1 investigated the hemodynamic effects of cyanocobalamin. This study included two treatment arms: 1) cyanocobalamin (75 mg/kg, IV) followed by saline (n = 7) and 2) saline followed by cyanocobalamin (n = 7). Study 2 assessed the hemodynamic effects of hydroxocobalamin (75 mg/kg, IV) in the presence and absence of the nitric oxide synthase inhibitor L-Nomega-nitro-L-arginine methyl ester (L-NAME; 30 mg/kg, IV). Nitric oxide synthase inhibition itself increases blood pressure. Thus, as part of Study 2, the hemodynamic effects of hydroxocobalamin were also investigated in the presence of an equipressor dose of angiotensin II (ANGII; 0.05 microg/kg/min, IV) in order to determine whether elevated blood pressure per se could interfere with hydroxocobalamin's hemodynamic effects. This study included six treatment arms (designated as first treatment + second treatment): saline + saline (n = 5), L-NAME + saline (n = 7), saline + hydroxocobalamin (n = 7), L-NAME + hydroxocobalamin (n = 7), ANGII + hydroxocobalamin (n = 7), and ANGII + saline (n = 7).
In Study 1, the effects of cyanocobalamin on hemodynamic parameters were indistinguishable from those of saline. In Study 2, hydroxocobalamin infusion was associated with moderate hemodynamic effects, including an increase in systemic vascular resistance, an increase in blood pressure, and a decrease in cardiac output. Administration of L-NAME abolished the effects of hydroxocobalamin on all hemodynamic parameters. ANGII at a dose producing a pressor response comparable to that of L-NAME did not influence the hydroxocobalamin-associated hemodynamic changes.
These studies in anesthetized rabbits demonstrate that the moderate pressor effect of hydroxocobalamin is not related to the formation of cyanocobalamin but is very likely related to the scavenging of nitric oxide by hydroxocobalamin.
解毒剂量的羟钴胺素在一些动物和人类中会导致血压短暂升高。在麻醉兔身上进行的这些研究，旨在通过研究以下内容来探索羟钴胺素血流动力学效应的潜在机制：1）氰钴胺素的可能血流动力学效应，当羟钴胺素与氰化物按摩尔比结合时会生成氰钴胺素；2）羟钴胺素对内皮一氧化氮系统的干扰。
研究1调查了氰钴胺素的血流动力学效应。该研究包括两个治疗组：1）氰钴胺素（75毫克/千克，静脉注射）后接生理盐水（n = 7）；2）生理盐水后接氰钴胺素（n = 7）。研究2评估了在存在和不存在一氧化氮合酶抑制剂L-硝基-精氨酸甲酯（L-NAME；30毫克/千克，静脉注射）的情况下羟钴胺素（75毫克/千克，静脉注射）的血流动力学效应。抑制一氧化氮合酶本身会升高血压。因此，作为研究2的一部分，还在存在等升压剂量的血管紧张素II（ANGII；0.05微克/千克/分钟，静脉注射）的情况下研究了羟钴胺素的血流动力学效应，以确定血压升高本身是否会干扰羟钴胺素的血流动力学效应。该研究包括六个治疗组（指定为首次治疗 + 第二次治疗）：生理盐水 + 生理盐水（n = 5）、L-NAME + 生理盐水（n = 7）、生理盐水 + 羟钴胺素（n = 7）、L-NAME + 羟钴胺素（n = 7）、ANGII + 羟钴胺素（n = 7）和ANGII + 生理盐水（n = 7）。
在研究1中，氰钴胺素对血流动力学参数的影响与生理盐水的影响无法区分。在研究2中，输注羟钴胺素与中等程度的血流动力学效应相关，包括全身血管阻力增加、血压升高和心输出量减少。给予L-NAME消除了羟钴胺素对所有血流动力学参数的影响。产生与L-NAME相当的升压反应剂量的ANGII并未影响与羟钴胺素相关的血流动力学变化。
这些在麻醉兔身上进行的研究表明，羟钴胺素的中等升压效应与氰钴胺素的形成无关，很可能与羟钴胺素清除一氧化氮有关。
