Curzen N P, Mitchell J A, Jourdan K B, Griffiths M J, Evans T W
Unit of Critical Care, Royal Brompton Hospital, London, UK.
Crit Care Med. 1996 Dec;24(12):2007-13. doi: 10.1097/00003246-199612000-00013.
Sepsis is characterized by systemic vasodilation and hyporesponsiveness to constrictor agents, at a time when the pulmonary circulation exhibits varying degrees of vasoconstriction. Plasma endothelin-1 concentrations are increased, but the role of this potent vasoconstrictor peptide in modulating the vascular response to sepsis is unknown. Therefore, we assessed the effect of endothelin-A receptor antagonism in the response of pulmonary arteries from rats treated with lipopolysaccharide to endothelin-1, and determined the vasomotor role of the endothelin-B receptors that are known to be located on rat pulmonary artery smooth muscle and endothelium.
Prospective, controlled study.
Animal research laboratory.
Male Wistar rats (275 to 300 g).
Animals were injected with either lipopolysaccharide (20 mg/kg i.p.) or saline (1 mL i.p.) 4 hrs before being killed. The main pulmonary arteries were cut into 2-mm rings, and suspended in an organ bath. In the first set of experiments, half of the rings underwent a procedure that removed the endothelium, and the contractile response to cumulative doses of endothelin-1 (10(-11) to 10(-6) M) was measured. Half of the rings were pretreated with the endothelin-A receptor antagonist, BQ123 (10(-5) M or 10(-6) M), and the other half of the rings were treated with vehicle. In a separate group of experiments, the contractile response to cumulative concentrations of the selective endothelin-B agonist, sarafotoxin S6c (10(-11) to 10(-6) M), was measured in rings at baseline tension. Second, the possible dilator effect of endothelin-B receptor activation was tested by the administration of sarafotoxin S6c (10(-7) to 10(-6) M) to rings preconstricted by 10(-6) M of U46619, a thromboxane receptor agonist, either in the presence or absence of the nitric oxide synthase inhibitor, N omega-nitro-L-arginine-methylester (10(-4) M). Acetylcholine-induced (10(-4) M), endothelium-dependent vasodilation was also measured.
BQ123 (10(-5) or 10(-6) M) caused consecutive rightward shifts in the endothelin-1 concentration-contraction curves for all ring types, including the intact rings from endotoxemic animals. Sarafotoxin S6c failed to induce any direct constriction in rings from sham-treated or lipopolysaccharide-treated rats. However, sarafotoxin S6c induced transient vasodilation at the initial dose in rings from sham-treated rats but not lipopolysaccharide-treated rats-an effect that was attenuated by N omega-nitro-L-arginine-methylester. Acetylcholine induced an N omega-nitro-L-arginine-methylester-sensitive vasodilation that was reduced in rings from endotoxin-treated rats.
Endothelin-A receptor blockade is an effective means of attenuating endothelin-1-induced contraction of isolated pulmonary artery rings, even from rats rendered endotoxemic. Endothelin-B receptors on the pulmonary artery cause vasodilation via the release of nitric oxide, and have no constrictor component. The functional effects of endothelin-B receptors on tone are lost after lipopolysaccharide treatment. The endothelium is involved in both the constrictor and dilator effects of endothelin in rat pulmonary artery, confirming a pivotal role for endothelial cells in the vascular response to sepsis.
脓毒症的特征为全身血管舒张以及对血管收缩剂反应性降低，而此时肺循环呈现不同程度的血管收缩。血浆内皮素-1浓度升高，但这种强效血管收缩肽在调节脓毒症时血管反应中的作用尚不清楚。因此，我们评估了内皮素A受体拮抗作用对脂多糖处理大鼠肺动脉对内皮素-1反应的影响，并确定了已知位于大鼠肺动脉平滑肌和内皮上的内皮素B受体的血管舒缩作用。
前瞻性对照研究。
动物研究实验室。
雄性Wistar大鼠（275至300克）。
在处死动物前4小时，给动物腹腔注射脂多糖（20毫克/千克）或生理盐水（1毫升）。将主肺动脉切成2毫米的环，悬挂于器官浴槽中。在第一组实验中，一半的环进行去除内皮的操作，然后测量对内皮素-1累积剂量（10⁻¹¹至10⁻⁶摩尔/升）的收缩反应。一半的环用内皮素A受体拮抗剂BQ123（10⁻⁵摩尔/升或10⁻⁶摩尔/升）预处理，另一半用溶剂处理。在另一组实验中，测量在基线张力下环对选择性内皮素B激动剂沙拉新（10⁻¹¹至10⁻⁶摩尔/升）累积浓度的收缩反应。其次，通过给预先用血栓素受体激动剂U46619（10⁻⁶摩尔/升）预收缩的环给予沙拉新（10⁻⁷至10⁻⁶摩尔/升）来测试内皮素B受体激活可能的舒张作用，无论是否存在一氧化氮合酶抑制剂Nω-硝基-L-精氨酸甲酯（10⁻⁴摩尔/升）。还测量了乙酰胆碱（10⁻⁴摩尔/升）诱导的、内皮依赖性血管舒张。
BQ123（10⁻⁵或10⁻⁶摩尔/升）使所有环型（包括来自内毒素血症动物的完整环）的内皮素-1浓度-收缩曲线连续右移。沙拉新未能在假手术处理或脂多糖处理大鼠的环中诱导任何直接收缩。然而，沙拉新在假手术处理大鼠的环中初始剂量时诱导短暂血管舒张，但在脂多糖处理大鼠的环中未出现——这种作用被Nω-硝基-L-精氨酸甲酯减弱。乙酰胆碱诱导的Nω-硝基-L-精氨酸甲酯敏感的血管舒张在脂多糖处理大鼠的环中降低。
内皮素A受体阻断是减弱内皮素-1诱导的离体肺动脉环收缩的有效手段，即使是来自内毒素血症大鼠。肺动脉上的内皮素B受体通过释放一氧化氮引起血管舒张，且无收缩成分。脂多糖处理后内皮素B受体对张力的功能作用丧失。内皮参与了内皮素在大鼠肺动脉的收缩和舒张作用，证实了内皮细胞在脓毒症血管反应中的关键作用。
