| Objective:The purpose of this study is to investigate the antihypertensive effects and mechanisms of indapamide in SHR.Methods:The SHRs and WKYs were randomly divided into three groups, respectively (n=15each group):the IDP-treated SHRs and WKYs (indapamide), the HCTZ-treated SHRs and WKYs (hydrochlorothiazide), and the saline-treated SHRs and WKYs. The IDP-, HCTZ-, and saline-treated groups received the drug by gastric gavage in daily dose of lmg/kg (indapamide),20mg/kg (HCTZ) and equal volume of indapamide-treatment (saline) for8weeks, respectively. Systolic blood pressures were measured every two weeks for8weeks by a tail-cuff plethysmography system.Results:Blood pressure began to decrease from the second week in IDP-treated SHR group, compared with the saline-treated SHR group (161.8±2.3mmHg and163.3±3.9mmHg, respectively vs.178.7±1.9mmHg in saline-treatment), which lasted until the eighth week (162.2±2.7mmHg and163.4±3.0mmHg vs.195.5±3.7mmHg in saline-treated SHR), but no significant change in blood pressure was observed among WKY groups. Furthermore, measurement of14,15-DHET (stable metabolite of14,15-epoxyeicosatrienoic acids, EETs) and20-HETE showed that indapamide treatment rather than hydrochlorothiazide significantly increased14,15-EET levels and EET:DHET ratio in urine, but did not alter20-HETE levels. Indapamide increased EET, cAMP activity and PKA associated with vasodilatory effect in isolated renal microvessels in SHRs and ameliorated oxidative stress and inflammation in renal cortex by down-regulating expression of p47phox, NF-κB, TGF-β1and p-MAPK. In vitro, p47phox upregulated by Angiotensin Ⅱ was suppressed by CYP2C23induced by indapamide in HBZY-1cells. These results highlight that the P450epoxygenase-EET system may be involved in the hypotensive effect of indapamide in SHR.Conclusion:We first put forward that indapamide lowers blood pressure by increasing renal EET, whose characteristics of Anti-inflammation and Antioxidative may mediate blood pressure-lowering. |
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