Laursen J B, Mülsch A, Boesgaard S, Mordvintcev P, Trautner S, Gruhn N, Nielsen-Kudsk J E, Busse R, Aldershvile J
Medical Department B, Rigshospitalet, University of Copenhagen, Denmark.
Circulation. 1996 Nov 1;94(9):2241-7. doi: 10.1161/01.cir.94.9.2241.
In vitro data suggest that reduced bioconversion of nitroglycerin (NTG) to nitric oxide (NO) contributes to the development of vascular and hemodynamic tolerance to NTG. We examined the in vivo validity of this hypothesis by measuring NTG-derived NO formation by in vivo spin-trapping of NO in vascular tissues from nitrate-tolerant and -nontolerant rats.
Five groups (n = 6 to 8 each) of conscious chronically catheterized rats received NTG (0.2 or 1 mg/h IV) for 72 hours (nitrate-tolerant groups). Four other groups received either NTG vehicle (placebo, for 72 hours) or were left untreated (control). Nitrate tolerance was substantiated by a reduced (55% to 85%) hypotensive response to NTG in vivo and a reduced relaxation to NTG in isolated aortic rings. NTG-derived NO formation in aorta, vena cava, heart, and liver was measured as NOFe(DETC)2 and NO-heme complexes formed in vivo during 35 minutes combined with ex vivo cryogenic electron spin resonance spectroscopy. NO formation was significantly (P < .05) increased in all tissues in nitrate-tolerant rats in an NTG dose-dependent manner. Furthermore, the amount of NO formed from a bolus dose of NTG (6.5 mg/kg over 20 minutes) was similar in nitrate-tolerant and -nontolerant rats.
The results suggest that vascular and hemodynamic NTG tolerance occurs despite high and similar rates of NO formation by NTG in tolerant and nontolerant target tissues. This finding is compatible with the assumption that reduced biological activity of NO, rather than reduced bioconversion of NTG to NO, contributes to in vivo development of nitrate tolerance.
体外数据表明，硝酸甘油（NTG）向一氧化氮（NO）的生物转化减少会导致对NTG的血管和血流动力学耐受性的发展。我们通过在体内自旋捕获耐硝酸盐和不耐硝酸盐大鼠血管组织中的NO来测量NTG衍生的NO形成，从而检验该假设在体内的有效性。
五组（每组n = 6至8只）清醒的慢性插管大鼠接受NTG（0.2或1 mg/h静脉注射）72小时（耐硝酸盐组）。另外四组接受NTG载体（安慰剂，72小时）或不接受治疗（对照组）。体内对NTG的降压反应降低（55%至85%）以及离体主动脉环对NTG的舒张反应降低，证实了硝酸盐耐受性。通过在35分钟内体内形成并结合离体低温电子自旋共振光谱法测量的NOFe(DETC)2和NO-血红素复合物，来测定主动脉、腔静脉、心脏和肝脏中NTG衍生的NO形成。在耐硝酸盐大鼠的所有组织中，NO形成均以NTG剂量依赖性方式显著增加（P <.05）。此外，耐硝酸盐和不耐硝酸盐大鼠中，大剂量NTG（20分钟内6.5 mg/kg）形成的NO量相似。
结果表明，尽管在耐受和不耐受的靶组织中NTG产生NO的速率高且相似，但仍会出现血管和血流动力学NTG耐受性。这一发现与以下假设相符，即NO的生物活性降低而非NTG向NO的生物转化减少，有助于硝酸盐耐受性在体内的发展。
