抑制诱导型一氧化氮合酶可增强链脲佐菌素诱导的糖尿病模型中去甲肾上腺素的心血管作用。

Inhibition of iNOS augments cardiovascular action of noradrenaline in streptozotocin-induced diabetes.

作者信息

Cheng Xing, Cheng Xiao Shuo, Kuo Kuo-Hsing, Pang Catherine C Y

机构信息

Department of Pharmacology and Therapeutics, The University of British Columbia, 2176 Health Sciences Mall, Vancouver, British Columbia, Canada V6T 1Z3.

出版信息

Cardiovasc Res. 2004 Nov 1;64(2):298-307. doi: 10.1016/j.cardiores.2004.06.023.

DOI:10.1016/j.cardiores.2004.06.023

PMID:15485689

Abstract

OBJECTIVE

The aim was to determine if inducible nitric oxide synthase (iNOS) contributes to depressed cardiovascular function at the acute phase of streptozotocin-induced diabetes.

METHODS

Male Wistar rats were injected with streptozotocin [60 mg/kg, intravenously (i.v.)] or the vehicle (0.9% NaCl) and were studied 3 weeks later.

RESULTS

The diabetic and control rats had similar mean arterial pressure (MAP) and total peripheral resistance (TPR). Noradrenaline (NA) increased in vivo left ventricular contractility (LV +dP/dt), MAP and TPR in both groups; however, the responses were markedly less in the diabetic than control rats. Acute administration of 1400W (selective inhibitor of iNOS; 3 mg/kg followed by 3 mg/kg/h, i.v.) did not alter responses to NA in the control rats, but augmented the influence of NA on MAP, TPR and LV +dP/dt in the diabetic rats. At this time, reverse transcription-polymerase chain reaction (RT-PCR) products (RNA) of iNOS were present in the hearts of the diabetic but not control rats. The activity of iNOS was threefold higher in the hearts of the diabetic rats relative to the controls, and the increase was inhibited by 1400W. Furthermore, immunostaining (proteins) of iNOS and nitrotyrosine (NT; marker of peroxynitrite) were identified in the hearts of the diabetic but not control rats. In contrast, the RT-PCR products of eNOS, activity of eNOS and immunostaining of eNOS were of similar intensity in the hearts of both groups.

CONCLUSIONS

Activation of iNOS contributes to depressed cardiovascular contractile function to NA at the acute phase of streptozotocin-induced diabetes. Selective inhibition of iNOS partially restored cardiovascular responses to NA.

摘要

目的

旨在确定诱导型一氧化氮合酶（iNOS）是否在链脲佐菌素诱导的糖尿病急性期导致心血管功能抑制。

方法

给雄性Wistar大鼠静脉注射链脲佐菌素[60mg/kg]或赋形剂（0.9%氯化钠），3周后进行研究。

结果

糖尿病大鼠和对照大鼠的平均动脉压（MAP）和总外周阻力（TPR）相似。去甲肾上腺素（NA）使两组大鼠的体内左心室收缩力（LV +dP/dt）、MAP和TPR均增加；然而，糖尿病大鼠的反应明显低于对照大鼠。急性给予1400W（iNOS的选择性抑制剂；3mg/kg静脉注射，随后以3mg/kg/h静脉注射）对对照大鼠对NA的反应无影响，但增强了NA对糖尿病大鼠MAP、TPR和LV +dP/dt的影响。此时，iNOS的逆转录-聚合酶链反应（RT-PCR）产物（RNA）存在于糖尿病大鼠的心脏中，而对照大鼠心脏中未出现。糖尿病大鼠心脏中iNOS的活性相对于对照大鼠高出三倍，且这种增加被1400W抑制。此外，在糖尿病大鼠的心脏中鉴定出iNOS和硝基酪氨酸（NT；过氧亚硝酸盐的标志物）的免疫染色（蛋白质），而对照大鼠心脏中未出现。相反，两组大鼠心脏中内皮型一氧化氮合酶（eNOS）的RT-PCR产物、eNOS的活性和eNOS的免疫染色强度相似。