过敏性休克(AS)的机制仍未完全了解。钾通道阻断剂4-氨基吡啶(4-AP),胱硫醚γ-裂解酶(ICSE)的抑制剂,dl-炔丙基甘氨酸(DPG)或β-氰基丙氨酸(BCA),和一氧化氮(NO)合酶产生血管收缩,可能是治疗AS的替代方法。这项研究的目的是证明L-NAME的能力,ICSE单独或与4-AP组合以恢复血压(BP)并改善卵清蛋白(OVA)大鼠AS的存活。实验组包括未致敏的Wistar大鼠(n=6);AS(n=6);用4-AP(AS4-AP)静脉注射治疗的AS(每组n=10),肾上腺素(AS+EPI),AS+DPG,AS+BCA,或使用L-NAME(AS+L-NAME);或使用4-AP+DPG药物组合治疗的AS,4-AP+BCA,4-AP+L-NAME,或4-AP+EPI。通过静脉内OVA(1mg)诱导AS。在AS诱导后1分钟静脉内施用治疗。平均动脉血压(MAP),心率(HR),和存活监测60分钟。组胺的血浆水平,前列腺素E2(PGE2)和F2(PGF2α),白三烯B4和C4,血管紧张素II,血管加压素,氧化应激标志物,pH值,测量HCO3、PaO2、PaCO2和K+。OVA诱导严重低血压,所有AS大鼠死亡。此外,4-AP,4-AP+EPI,或4-AP+BCA使MAP和HR均恢复正常,并增加生存率。单独用4-AP或用4-AP+BCA处理的所有致敏大鼠均存活。4-AP联合ICSE治疗后,时间积分MAP“曲线下面积”显着升高。代谢性酸中毒未得到抢救,NO,ICSE,和Kv抑制剂不同地改变氧化应激和过敏性介质的血浆水平。AS诱导的血清血管紧张素II水平的降低可通过单独的4-AP治疗或与其他药物联合使用来预防。Further,4-AP治疗联合EPI或BCA也增加了血清PGF2α,而只有4-AP+EPI组合增加血清LTB4。单独或与其他药物联合使用4-AP治疗可提高血清加压素和血管紧张素II水平。此外,单独使用4-AP并结合抑制胱硫醚γ-裂解酶或EPI使BP正常化,增加血清血管收缩剂水平,并提高了ASWistar大鼠模型的存活率。这些发现提示了研究肾上腺素难治性过敏性休克患者的可能的研究治疗途径。
The mechanism of anaphylactic shock (AS) remains incompletely understood. The potassium channel blocker 4-aminopyridine (4-AP), the inhibitors of cystathionine γ-lyase (ICSE), dl-propargylglycine (DPG) or β-cyanoalanine (BCA), and the nitric oxide (NO) synthase produce vasoconstriction and could be an alternative for the treatment of AS. The aim of this study was to demonstrate the ability of L-NAME, ICSE alone or in combination with 4-AP to restore blood pressure (BP) and improve survival in ovalbumin (OVA) rats AS. Experimental groups included non-sensitized Wistar rats (n = 6); AS (n = 6); AS (n = 10 per group) treated i.v. with 4-AP (AS+4-AP), epinephrine (AS+EPI), AS+DPG, AS+BCA, or with L-NAME (AS+L-NAME); or AS treated with drug combinations 4-AP+DPG, 4-AP+BCA, 4-AP+L-NAME, or 4-AP+EPI. AS was induced by i.v. OVA (1 mg). Treatments were administered i.v. one minute after AS induction. Mean arterial BP (MAP), heart rate (HR), and survival were monitored for 60 min. Plasma levels of histamine, prostaglandin E2 (PGE2) and F2 (PGF2α), leukotriene B4 and C4, angiotensin II, vasopressin, oxidative stress markers, pH, HCO3, PaO2, PaCO2, and K+ were measured. OVA induced severe hypotension and all AS rats died. Moreover, 4-AP, 4-AP+EPI, or 4-AP+BCA normalized both MAP and HR and increased survival. All sensitized rats treated with 4-AP alone or with 4-AP+BCA survived. The time-integrated MAP \"area under the curve\" was significantly higher after combined 4-AP treatment with ICSE. Metabolic acidosis was not rescued and NO, ICSE, and Kv inhibitors differentially alter oxidative stress and plasma levels of anaphylactic mediators. The AS-induced reduction of serum angiotensin II levels was prevented by 4-AP treatment alone or in combination with other drugs. Further, 4-AP treatment combined with EPI or with BCA also increased serum PGF2α, whereas only the 4-AP+EPI combination increased serum LTB4. Serum vasopressin and angiotensin II levels were increased by 4-AP treatment alone or in combination with other drugs. Moreover, 4-AP alone and in combination with inhibition of cystathionine γ-lyase or EPI normalizes BP, increases serum vasoconstrictor levels, and improves survival in the Wistar rat model of AS. These findings suggest possible investigative treatment pathways for research into epinephrine-refractory anaphylactic shock in patients.