Bauer J A, Nolan T, Fung H L
Department of Pharmaceutics, School of Pharmacy, State University of New York, Buffalo, USA.
J Pharmacol Exp Ther. 1997 Jan;280(1):326-31.
Because nitroglycerin (NTG, an organic nitrate) and isoamyl nitrite have similar chemical structures and a common mechanism of vascular relaxation (i.e., conversion to nitric oxide in vascular tissues and activation of guanylyl cyclase), it has often been assumed that organic nitrates and nitrites have identical pharmacologic actions. Because recent studies have shown that the vascular enzymes responsible for nitric oxide generation from organic nitrates and nitrites are distinct, we hypothesized that the in vitro vascular actions, in vivo hemodynamic effects and tolerance properties (both in vitro and in vivo) would be different as well. Isolated blood vessel studies showed that NTG provided more stable relaxation effects than ISAN, was more potent and caused greater in vitro vascular tolerance. Because the mechanism(s) of vascular tolerance in vitro may not be the same as those occurring in vivo, we also compared the left ventricular hemodynamic effects and tolerance properties of NTG vs. isoamyl nitrite and in congestive heart failure rats. Constant NTG infusion (10 micrograms/min) caused initial reductions in left ventricular end-diastolic pressure of 45 to 55%, which returned to baseline within 10 hr (tolerance development). In contrast, isobutyl nitrite and isoamyl nitrite (45 micrograms/min) caused initial reductions in left ventricular end-diastolic pressure similar to NTG (42-58%), but these hemodynamic effects of organic nitrites were maintained even when infusions were carried out to 22 hr. These results show that organic nitrites and organic nitrates are not pharmacologically identical (in vitro or in vivo), and may suggest a therapeutic advantage for organic nitrites in the treatment of some cardiovascular diseases.
由于硝酸甘油（NTG，一种有机硝酸盐）和亚硝酸异戊酯具有相似的化学结构和共同的血管舒张机制（即，在血管组织中转化为一氧化氮并激活鸟苷酸环化酶），人们常常认为有机硝酸盐和亚硝酸盐具有相同的药理作用。然而，最近的研究表明，负责将有机硝酸盐和亚硝酸盐转化为一氧化氮的血管酶是不同的，因此我们推测它们在体外的血管作用、体内的血流动力学效应以及耐受性特性（包括体外和体内）也会有所不同。离体血管研究表明，NTG比亚硝酸异戊酯（ISAN）提供更稳定的舒张作用，效力更强，并且在体外引起更大的血管耐受性。由于体外血管耐受性的机制可能与体内发生的机制不同，我们还比较了NTG与亚硝酸异戊酯在充血性心力衰竭大鼠中的左心室血流动力学效应和耐受性特性。持续输注NTG（10微克/分钟）导致左心室舒张末期压力最初降低45%至55%，但在10小时内恢复到基线水平（耐受性形成）。相比之下，亚硝酸异丁酯和亚硝酸异戊酯（45微克/分钟）引起的左心室舒张末期压力最初降低与NTG相似（42%-58%），但即使输注持续到22小时，这些有机亚硝酸盐的血流动力学效应仍能维持。这些结果表明，有机亚硝酸盐和有机硝酸盐在药理学上并不相同（体外或体内），这可能提示有机亚硝酸盐在治疗某些心血管疾病方面具有治疗优势。
