| Summary: | 博士 === 國防醫學院 === 生命科學研究所 === 86 === A lot of studies have demonstrated that nitric oxide (NO) is an important multifunctional modulator in maintenance of blood pressure homeostasis, contraction of myocyte, inhibition of platelet aggregation and prevention of the adhesion of platelets and neutrophils to the endothelium as well as inhibition of prolifera-tion of vascular smooth muscle. The aims of this study were to investigate whether the activity and protein e-xpression of endothelial nitric oxide synthase (eNOS) and inducible NOS (iNOS) are changed during the development of hypertension in spontaneously hypertensiverats (SHR) and further clarify the relationship between hypertension and the ch-anges of NOS expression in SHR. Another approach is to compare the plasma concen-tration of asymmetrical dimethylarginine (ADMA), an endogenous inhibitor of NOS,and L-arginine in SHR and WKY at 14 weeks of age. In the meantime, we compared the nitrite production and L-arginine uptake rate in vascular smooth muscle cells(VSMC) between SHR and WKY. Our results showed that at 14-17 and 63 weeks, the basal activity and protein expression of eNOS in the aorta of SHR were significantly lower than those in WKY. In addition, the aged WKY exhibited lower eNOS activity than that of adult WKYbut this change was not found in SHR. Interestingly, the basal activity and pro-tein expression of iNOS were only observed in SHR of the 14-17 weeks group and in SHR 63-week group. Thesis differences of iNOS were further enhance by treat-ment with lipopolysaccharide (LPS). The basal and LPS-induced plasma NO2-/NO3- and TNF-α level were also significantly higher in SHR except the 4-week group. After antihypertensive treatment with angiotensin converting enzyme inhibitor, quinapril, the basal and LPS-induced expression of iNOS in SHR were significant-ly attenuated. The plasma concentrations of L-arginine of SHR was significantly lower than that in WKY, whereas the plasma ADMA of SHR was significantly higher than that in WKY leading to a decrease of L-arginine/ADMA ratio. The level of symmetricaldimethylarginine (SDMA) was similar in SHR and WKY. In addition, the nitrite pr-oduction and L-arginine uptake of VSMC in SHR induced by LPS (100 ug/ml) or the combination with LPS and IFN-γ (100 u/ml) were also significantly higher than in WKY. In conclusion, our results demonstrated that alterations of activity and pro-tein expression of eNOS and iNOS occurred in SHR. In addition, aging may reduce the activity of eNOS in WKY but not in SHR. The decline of eNOS activity and/orexpression may contribute to the development of hypertension, whereas the inc-rease of iNOS expression may be a consequence of pathological state of vessels associated with hypertension in SHR and/or plays a compensatory effect under hypertension. However, the augmented expression of iNOS in SHR was attenuatedby antihypertensive therapy with quinapril, suggesting that the abnormal expre-ssion of iNOS is closely associated with hypertension. We also conclude that thethe elevation of plasma ADMA in SHR may be at least in part accounted for the reduction of NOS activity, which was associated with the hypertension. Further-more, the elevation of L-arginine uptake in VSMC of SHR may provide an another important mechanism in increasing the availability of L-arginine, resulting in producing excess NO and activation of iNOS in SHR.
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