McGee Michelle Y, Ogunsina Ololade, Boshra Sadia N, Gao Xianlong, Majetschak Matthias
Department of Surgery, University of South Florida Morsani College of Medicine, Tampa, FL 33612, USA.
Department of Chemistry, University of South Florida, Tampa, FL 33612, USA.
Biomedicines. 2024 Aug 9;12(8):1813. doi: 10.3390/biomedicines12081813.
β-adrenoceptor (β-AR) agonists are known to antagonize thrombin-induced impairment (TII) of bovine and ovine lung endothelial barrier function. The effects of adrenoceptor agonists and other vasoactive agents on human lung microvascular endothelial cell (HULEC-5a) barrier function upon thrombin exposure have not been studied. Furthermore, it is unknown whether the in vitro effects of adrenoceptor agonists translate to lung protective effects in vivo. We observed that epinephrine, norepinephrine, and phenylephrine enhanced normal and prevented TII of HULEC-5a barrier function. Arginine vasopressin and angiotensin II were ineffective. α-, α-, and β-ARs were detectable in HULEC-5a by RT-PCR. Propranolol but not doxazosin blocked the effects of all adrenoceptor agonists. Phenylephrine stimulated β-AR-mediated Gαs activation with 13-fold lower potency than epinephrine. The EC to inhibit TII of HULEC-5a barrier function was 1.8 ± 1.9 nM for epinephrine and >100 nM for phenylephrine. After hemorrhagic shock and fluid resuscitation in rats, Evans blue extravasation into the lung increased threefold ( < 0.01 vs. sham). Single low-dose (1.8 μg/kg) epinephrine administration at the beginning of resuscitation had no effects on blood pressure and reduced Evans blue extravasation by 60% ( < 0.05 vs. vehicle). Our findings confirm the effects of β-adrenoceptor agonists in HULEC-5a and suggest that low-dose β-adrenoceptor agonist treatment protects lung vascular barrier function after traumatic hemorrhagic shock.
已知β-肾上腺素能受体（β-AR）激动剂可拮抗凝血酶诱导的牛和羊肺内皮屏障功能损伤（TII）。尚未研究肾上腺素能受体激动剂和其他血管活性药物对凝血酶暴露后人肺微血管内皮细胞（HULEC-5a）屏障功能的影响。此外，肾上腺素能受体激动剂的体外作用是否能转化为体内的肺保护作用尚不清楚。我们观察到，肾上腺素、去甲肾上腺素和去氧肾上腺素可增强HULEC-5a屏障功能的正常状态并预防TII。精氨酸加压素和血管紧张素II无效。通过RT-PCR在HULEC-5a中可检测到α-、α-和β-AR。普萘洛尔而非多沙唑嗪可阻断所有肾上腺素能受体激动剂的作用。去氧肾上腺素刺激β-AR介导的Gαs激活，其效力比肾上腺素低13倍。抑制HULEC-5a屏障功能TII的肾上腺素的EC为1.8±1.9 nM，去氧肾上腺素则>100 nM。大鼠失血性休克和液体复苏后，伊文思蓝向肺内的渗出增加了三倍（与假手术组相比，<0.01）。复苏开始时单次低剂量（1.8μg/kg）肾上腺素给药对血压无影响，并使伊文思蓝渗出减少60%（与载体组相比，<0.05）。我们的研究结果证实了β-肾上腺素能受体激动剂在HULEC-5a中的作用，并表明低剂量β-肾上腺素能受体激动剂治疗可保护创伤性失血性休克后的肺血管屏障功能。
