Effects Of Nisoldipine And Olmesartan On Endothelial Function And Its Influencing Factors In Essential Hypertensive Patients

Background:More and more evidences show that endothelial dysfunction plays a pivotal role in essential hypertension and arteriosclerosis. If anti-hypertensive drugs are able to not only decrease blood pressure but also improve endothelial dysfunction, it will be beneficial for improving symptoms and long-term life quality of patients. Many factors contribute to endothelial dysfunction. Oxidative stress and inflammation play important roles in the mechanisms of endothelial dysfunction. Moreover, asymmetric dimethylarginine(ADMA), as an endogenous NO synthase inhibitor, and, therefore, is able to decrease nitric oxide(NO) bioavailability to produce endothelial dysfunction. Nisoldipine is a calcium channel blocker, and olmesartan is an angiotensinⅡreceptor blocker(ARB). Nisoldipine and olmesartan are both common anti-hypertensive drugs in clinic. Animal models and ex-vivo experiments have demonstrated that nisoldipine can mobilize endothelial progenitor cells from morrow to vascular lumen and increase NO availability to improve endothelial dysfunction. However, whether nisoldipine is able to improve endothelial dysfunction in essential hypertensive patients has not yet reported. Effect of olmesartan on endothelial dysfunction has been reported, but the detailed mechanisms in improving endothelial dysfunction are still unclear completely. In this study, biological and functional parameters related to endothelial function (such as NO, endothelin-1(ET-1), flow-mediated vasodilation(FMD)) and the circulating levels of ADMA, hs-CRP (as an inflammatory marker), and 8-isoPGF2a(as an oxidative stress marker), were measured at baseline and eight weeks later, in order to evaluate whether nisoldipine can improve endothelial function in essential hypertensive patients, as well as to explore the potential mechanisms of nisoldipine and olmesartan in influencing endothelial function.Objective:1. To observe whether vascular endothelial dysfunction and oxidative stress, inflammation as well as ADMA levels elevation exist in essential hypertensive patients.2. To observe the effects of nisoldipine on vascular endothelial function, oxidative stress, ADMA as well as inflammation, and to explore the potential mechanisms of it in influencing endothelial function3. To observe the effects of olmesartan on vascular endothelial function, oxidative stress, ADMA as well as inflammation, and to explore the potential mechanisms of it in influencing endothelial function.Methods:GradeⅠorⅡessential hypertension without clinically evident organ damage were recruited if seated arterial blood pressure(after 10 min of rest) was consistently found to be≥140/90mm and<180/110mmHg and they were never treated or reported a history of discontinued pharmacological antihypertensive treatment and withdrawal over 1 weeks at least. According to a randomized, parallel design, fifty-five patients were allocated to nisoldipine(10～20mg/d) or olmesartan (20～40mg/d), the whole treatment was 8-week period.48 patients completed the total study,7 patients failed to complete the study due to lost to follow-up. Sitting blood pressure, plasma ADMA, ET-1, 8-iso-PGF2α, NO and hs-CRP levels were assessed before and after 8-week treatment. In addition, we detected brachial artery FMD and nitroglycerin-mediated vasodilation(NMD) by high-resolution ultrasound in order to evaluate the changes of vascular vasodilation between baseline and 8-week treatment later. Meanwhile,28 normotensive control subjects were evaluated as a control group.Results:The results of the study include two parts:1. Besides high blood pressure, endothelial dysfunction, oxidative stress, inflammatory effect and increasing circulating ADMA levels have become widely recognized in essential hypertensive patients.1.1 Mean patient BP was 148.3/87.8±9.1/9.0mmHg compared to 110.4/70.7±10.5/8.9mmHg in controls(P<0.01).1.2 Plasma levels of ADMA、ET-1、8-iso-PGF2α、hs-CRP were significantly higher compared to normotensive control(P<0.05),whereas NO levels was significantly lower(P<0.01).1.3 FMD was significantly lower in patients compared to controls(10.43±3.91% vsl3.37±5.50%, P<0.05),and NMD was similar in both groups (13.12±6.36% vs14.70±4.86%,P>0.05)2. Effects of nisoldipine and olmesartan on vascular endothelial dysfunction, oxidative stress, inflammation and ADMA levels.2.1 At baseline, blood pressure, ADMA、ET-1、NO,8-iso-PGF2αlevels, FMD, NMD were similar in the two treatment groups(P>0.05), however, baseline CRP levels in nisoldipine group was higher than in olmesartan group(1.90[0.80-4.30] vs0.80[0.45-1.40, P<0.05). 2.2 Clinic sitting blood pressure in both groups decreased significantly after treatments(p<0.01), but heart rate was no change after nisoldipine or olmesartan treatment.2.3 At the end of the treatment, plasma ADMA and ET-1 levels were significantly decreased and FMD increased in patients receiving nisoldipine or olmesartan (P<0.05). Plasma NO and 8-iso-PGF2a were no change in both groups (P>0.05). There was a significant decrease of plasma hs-CRP only in patients receiving nisoldipine (P<0.05). In both groups, the BA dilator response to glyceryl trinitrate was similar at baseline and was not significantly increased after treatment(P>0.05).Conclusions:1. Endothelial dysfunction, oxidative stress, inflammatory effect and increasing circulating ADMA levels have become widely recognized in mild-to-moderate essential hypertensive patients.2. Nisoldipine and olmesartan both can decrease plasma ADMA and ET-1 levels and improve FMD. Moreover, nisoldipine has significantly anti-inflammatory effect. NO and 8-isoPGF2a levels were no change from baseline to eight-week nisoldipine or olmesartan treatment.3. The improvements of FMD in nisoldipine may be related to the reduction in ADMA, ET-1 and inflammation; olmesartan may improve FMD by decreasing the levels of ADMA and ET-1.