Role Of Inducible Nitric Oxide Synthase In The Regulation Of Arterial Pressure And Expression Of HO-1 In Renovascular Hypertensive Rats

Objective: The goal of this study is to clarify the relationship between inducible nitric oxide synthase/nitric oxide (iNOS/NO) pathway and heme oxygenase-1 expression in renovascular hypertension.Methods: Thirty-two Spraugue Dawley (SD) rats were randomly divided into four groups: Sham+NaCl group (n=8), Sham+ aminoguanidin (Sham+AG) group (n=8), renovascular hypertension+NaCl (RH+ NaCl) group (n=8) and renovascular hypertension+aminoguanidin (RH+AG) group (n=8). The renovascular hypertension was induced by renal artiery stenosis. Aminoguanidin (AG), the specific inhibitor of inducible nitric oxide synthase, was used in control groups (including Sham and RH group). AG was administrated intraperitoneally at a dose of 150mg/kg two times a day. The arterial pressure was monitored and the NO2- /NO3- (UNOx ) , heme oxygenase-1 mRNA and protein were assayed by Greiss reaction, reverse transcription polymerase chain reaction (RT-PCR) and Western blot, respectively.Results: The arterial pressure of rats in RH+ NaCl group increased significantly. Four weeks after operation, it increased to 132.±3.1mmHg from 104.1 ±3.7mmHg before operation. The hypertensive effect of renal artery stenosis was greatly amplified by co-administration of AG In the group of RH+AG, the arterial pressure was 142.8+ 1.9mmHg 4 weeks after operation, which was significantly higher than that in RH+ NaCl group, but Sham+AG and Sham+NaCl groups had no hemodynamic response to AG. In RH+ NaCl group, UNOx, an index of the NO production of the whole body, increased significantly, for example, 1 week after operation (P<0.01), it increased to 21.98?.30|imol/24h from 9.76?.91 |imol/24h before operation. The aminoguanidin obviously inhibited the production of NO. In the group of RH+AG, the UNOx was 16.17±5.85 μmol/24h in 4 weeks after operation, which was significantly lower than 28.54±8.21 μmol/24h, the UNOx produced by control group (RH+ NaCl group). However, the AG had not effect on the Sham group. In RH+NaCl and RH+AG groups, the expression of heme oxygenase-1 mRNA in aorta was upregulated significantly, compared with Sham groups'. RT-PCR showed HO-1 mRNA expression in RH+AG group was lower than that in RH+NaCl group,but higher than that in Sham groups. Western blot demonstrated HO-1 protein increased obviously in RH+NaCl group compared with RH+AG group. AG markedly suppressed HO-1 protein expression that caused by renal artery stenosis, but AG did not change the HO-1 protein expression in Sham group.Conclusions: 1. iNOS/NO pathway is activated by renovascular hypertension. 2.The hypertensive effect of renal artery stenosis is greatly amplified by co-administration of AG 3. Renovascular hypertension upregulate the expression of HO-1 mRNA and protein. It may play an important role in regulation of arterial pressure. 4.HO-1 is activated and regulated in renovascular hypertension by iNOS/NO pathway.