老年大鼠血管α1肾上腺素受体及其亚型的改变

本工作用离体与整体实验方法,研究了老年(18月龄)与年轻(3月龄)大鼠血管中 α_1肾上腺素受体储备和 α_1(?)与 α_(1b)亚型比值的差别。在离体实验中用机械方法分离血管,用 Krebs 溶液灌流,在灌流液中加入 α_2和 β肾上腺素受体拮抗剂,然后用去甲肾上腺素(NE)激动 α_1受体。结果显示;老年大鼠主动脉、肾动脉和肠系膜动脉由去甲肾上腺素(NE)引起的最大收缩反应与年轻大鼠无显著差别,但浓度-效应曲线显著右移,功能性解离常数 K_A 值不变,而 K_A 与EC_(50)的比值减小。此外,在老年大鼠主动脉和肠系膜动脉血管,选择性 α_(1b)亚型拮抗剂 CEC对 NE 引起的缩血管效应的阻断作用显著减弱,硝苯吡啶(选择性阻断 α_(1a) 亚型的效应)对 NE 缩血管效应的阻断作用显著增强。整体实验显示老年大鼠硝苯吡啶的降血压作用比年轻大鼠增强,在用硝苯吡啶的基础上给予苯肾上腺素升血压作用减弱。上述结果提示:与年轻大鼠相比较,老年大鼠 α_(1-) 肾上腺素受体储备减少,α_(1a) 亚型相对 α_(1b)亚型的比率增高。     

α1A-肾上腺素受体参与大鼠外周血压的调节

采用大鼠整体灌流模型,同时测定灌流大鼠后肢血管床灌流压和全身平均动脉压,通过动态观察,比较多种α_1-肾上腺素受体(α_1-AR)亚型选择性拮抗剂对两者影响的异同,初步探讨α_1-AR亚型在大鼠整体血压调节中的作用。结果表明:α_1-AR选择性拮抗剂(prazosin组13.5±3.6vs 15.1±4.3,n=11)和α_1-AR亚型选择性拮抗剂(5-mithyl-urapidil组2.4±0.9vs 3.7±2.3,n=12;RS-17053组3.2±1.6vs 4.4±3.3,n=12)均对正常大鼠苯肾上腺素引起后肢血管床升压反应曲线和平均动脉压升压反应曲线的右移程度(dose ratio,Dr)无明显影响,α_1-AR亚型选择性拮抗剂(BMY 7378组1.9±0.9vs 2.2±0.8,n=8)对正常大鼠两者苯肾上腺素加压反应也无差别;自发性高血压大鼠(RS-17053组3.4±0.6vs 4.3±0.9,n=5;BMY 7378组1.7±0.5vs 1.7±0.5,n=8)的反应同正常大鼠相似。提示介导苯肾上腺素引起麻醉大鼠全身动脉加压效应的α_1-AR与引起大鼠后肢血管床收缩的α_1-AR可能是同一种亚型,即α_1-AR。     

缺氧与复氧对不同血管α_1肾上腺素受体收缩效应的影响

本实验观察离体大鼠肾动脉(含α_(1V)亚型)、主动脉(含α_(1B)亚型)和肺动脉(含α_(1V)和α_(1B)亚型)在缺氧与复氧时由α_1肾上腺素受体激动所致收缩效应的改变。结果显示肾动脉在缺氧时pD值增大,最大收缩效应降低,复氧时pD值恢复;主动脉在缺氧时pD值减小,最大收缩效应不变,复氧时pD值不恢复:而肺动脉的改变为上述两者的综合。提示σ_1受体不同亚型在缺氧与复氧时发生的变化不同,这可能是不同血管对缺氧、复氧反应不同的机制之一。     

延髓孤束核微量注射可乐宁对自发性高血压大鼠血压和心房钠尿因子的影响

将卒中型自发性高血压大鼠(SHR_(sp))和正常血压对照大鼠(WKY)随机分为可乐宁、α_1受体拮抗剂育亨宾加可乐宁及对照组,进行孤束核(NTS)内微量注射。实验观察到,在SHR_(sp)中,可乐宁的降压效应及外周 ANF 释放减少的效应比 WKY 大鼠更明显。阻断α_2受体后,在 WKY 大鼠中,可乐宁的降压效应被完全阻断,而在 SHR_(sp)仅部分被阻断;两种大鼠的外周 ANF 与对照组相比无明显差异。可乐宁组两种大鼠的血浆儿茶酚胺水平明显降低,育亨宾可阻断该反应。以上结果提示,ANF 未参与 NTS 内微量注射可乐宁引起的降压效应,在 SHR_(sp),ANF 释放的减少可能为血压依赖的代偿反应;可乐宁通过α_2受体介导抑制外周儿茶酚胺的释放。     

大鼠左心房α1受体及其亚型对β受体正性变力效应的影响

本文用放射配体结合实验研究了α１－肾上腺素受体（α１－ＡＲ）及亚型在大鼠左心房的分布。结果表明,大鼠左心房α１－ＡＲ有α１Ａ与α１Ｂ两种亚型,α１Ａ亚型约占１／３,α１Ｂ亚型占２／３。离体灌流左心房功能实验结果表明,α１－ＡＲ不同亚型对β肾上腺素受体（β－ＡＲ）所介导的正性变力反应具有不同性质的协同作用。当酚妥拉明１０μｍｏｌ／Ｌ同时阻断α１Ａ与α１Ｂ亚型时,ＮＥ（同时激动α１－与β－ＡＲ）的剂量－收缩效应曲线显著左移,当用ＣＥＣ２０μｍｏｌ／Ｌ预处理以阻断α１Ｂ亚型时,ＮＥ的剂量－收缩效应曲线则显著右移,而用ＷＢ４１０１１ｎｍｏｌ／Ｌ阻断α１Ａ亚型后,ＮＥ的剂量－收缩效应曲线出现左移;此外,当用苯肾上腺素激动α１－ＡＲ时,异丙肾上腺素的剂量－收缩效应曲线亦显著右移。提示α１Ａ亚型可抑制β－ＡＲ介导的正性变力效应,而α１Ｂ亚型则可增强β－ＡＲ所介导的反应,但当α１－ＡＲ的上述两种亚型同时激动时,则以α１Ａ亚型的调节作用为主。     

静脉平滑肌上的α-受体宜分类为突触后α_2-受体

大量实验证明,肾上腺素能神经-效应器接点突触前膜和突触后膜上的α-受体性质不同,Langers首先提出,将调节效应器官反应的突触后α-受体命名为α_1-受体,而将突触前膜上调节NA释放的α-受体命名为α_2-受体。一些药物可选择性地激动或阻断突触前、后两种不同的α-受体。例如,甲氧胺、新福林选择性地激动α_1-受体;可乐宁(clonidine)、托马唑啉(tramazoline)选择性地激动α_2-受体。哌唑嗪(prazosin)主要阻断α_1-受体;育亨宾(yohimbine)主要阻断α_2-受体。在大多数血管,NA激活突触后α-受体,使血管平滑肌收缩,并因此使血管收缩。但并非所有血管平滑肌细胞上的α-受体均属同一亚型。多数离体动脉平滑肌对A、甲氧胺、NA新福林等α-激动剂发生收缩反应,但对可乐宁和托马唑啉相     

α1A-肾上腺素受体参与大鼠外周血压的调节

采用大鼠整体灌流模型, 同时测定灌流大鼠后肢血管床灌流压和全身平均动脉压, 通过动态观察, 比较多种α₁--肾上腺素受体(α₁-AR)亚型选择性拮抗剂对两者影响的异同, 初步探讨α₁-AR亚型在大鼠整体血压调节中的作用. 结果表明: α₁-AR选择性拮抗剂(prazosin组13.5±3.6 vs 15.1±4.3, n = 11)和α_1A-AR亚型选择性拮抗剂(5-methyl-urapidil组2.4±0.9 vs 3.7±2.3, n = 12; RS-17053组3.2±1.6 vs 4.4±3.3, n = 12)均对正常大鼠苯肾上腺素引起后肢血管床升压反应曲线和平均动脉压升压反应曲线的右移程度(dose ratio, Dr)无明显影响, α_1D-AR亚型选择性拮抗剂(BMY 7378组1.9±0.9 vs 2.2±0.8, n = 8)对正常大鼠两者苯肾上腺素加压反应也无差别; 自发性高血压大鼠(RS-17053组3.4±0.6 vs 4.3±0.9, n = 5; BMY 7378组1.7±0.5 vs 1.7±0.5, n = 8)的反应同正常大鼠相似. 提示介导苯肾上腺素引起麻醉大鼠全身动脉加压效应的α₁-AR 与引起大鼠后肢血管床收缩的α_1A-AR可能是同一种亚型, 即α_1A-AR.     

硝苯吡啶对腹腔神经节突触传递的阻断作用

本文应用细胞内记录技术,观察了钙通道阻滞剂硝苯吡啶（nifedipine)对离体豚鼠腹腔神经节突触传递的影响,硝苯吡啶（0.1-10umol/L)不影响所检细胞的静息膜电位,膜电阻及细胞内刺激引起的动作电位,但能显著阻断N-型胆碱能的突触传递,并且这种作用可被低钙模拟、高钙拮抗,硝苯吡啶（10umol/L)也不影响突触后膜对乙酰胆碱（ACh)的敏感性;但在高钾克氏液中,能减少微小兴奋性突触后电位（mEPSPs)的频率;在低钙和高镁克氏液中,能减少量子含量,而对量子大小无影响。结果表明,治疗量的硝苯吡啶(0.1umol/L)通过阻滞突触前膜钙内流及ACh的量子性释放,产生突触阻断作用。这可能是硝苯吡啶降压机理的一个组成部分。     

硝苯吡啶抑制豚鼠交感神经元的钙依赖性电位

应用细胞内记录技术观察了钙通道阻滞剂硝苯吡啶(nifedlpine)对离体豚鼠腹腔神经节细胞三种钙依赖性电位的可逆性作用。硝苯吡啶(0.1—1mmol/L)可剂量依赖式地抑制动作电位后超极化、强直后膜电位的变化,在无钠高钙加 TEA 溶液中,硝苯吡啶(0.1μmol/L)能抑制钙锋电位。结果表明,大剂量的硝苯吡啶可继发性抑制钙依赖性钾电导,临床治疗剂量的硝苯吡啶还直接减少钙电导。以上作用是硝苯吡啶调节交感节后神经元的兴奋性,阻滞突触前膜 ACh 的量子性释放的基础。     

α2-肾上腺素受体介导大鼠主动脉收缩的特性

为阐明功能性α2-肾上腺素受体(α2-AR)的特性及其与α2-AR的相互关系,以离体大鼠主动脉为模型,进行收缩功能实验.发现在大鼠主动脉中,α2-AR和α2-AR均可介导其收缩效应并以α1-AR的作用为主.α1-AR可增强α2-AR介导的收缩效应,而α2-AR则对α1-AR介导的收缩效应无影响.在不可逆阻断α1-AR而保留α2-AR的条件下,α2-AR介导的缩血管效应消失,仅在阈值浓度的KCl在下才能显示,且收缩幅度较对照显著降低.结果表明,在离体大鼠主动脉中存在功能性α2-AR,α2-AR的缩血管作用依赖于α1-AR的激动,其最大收缩反应远远小于α1-AR.     

Effect of nifedipine on calcium-induced contractions to potassium in the aorta and mesenteric arteries of spontaneously hypertensive and normotensive rats

Graded contractions to cumulative additions of calcium in the presence of KCl were obtained in strips of aorta and mesenteric arteries of normotensive (WKY) and spontaneously hypertensive (SHR) rats. In calcium-free medium, a maximally effective concentration of KCl produced a response that was larger in the mesenteric arteries (43-51% of control) than in the aorta (12-14% of control). The calcium channel blocker nifedipine (NFD, up to 10(-7) M) did not significantly alter these calcium-insensitive responses. The Ca2+-induced responses were inhibited by NFD, in a concentration-dependent fashion, in both vessel types of WKY and SHR rats. The aortic responses were more sensitive to inhibition by NFD than the responses of mesenteric arteries. Moreover, the aortic responses of WKY were inhibited to a greater extent than those of the SHR. The results suggest: (a) a differential calcium dependence of contractions to KCl in the vessels studied; (b) that aortic responses are dependent on NFD-sensitive voltage-sensitive Ca2+ channels to a greater extent than the responses of mesenteric arteries; and (c) that hypertension results in a decreased sensitivity of the aorta Ca2+ channels to NFD.     

Increased sympathetic innervation in the cerebral and mesenteric arteries of hypertensive rats

The density of catecholamine-containing nerve fibers was studied in the cerebral and mesenteric arteries from normotensive Wistar-Kyoto rats (WKY), spontaneously hypertensive rats (SHR), and stroke-prone SHR (SHRSP) in the growing (SHR, WKY) and adult (SHR, SHRSP, WKY) animals. Cerebral arteries from SHR showed an increased adrenergic innervation from day 1. The nerve plexuses reached an adult pattern earlier in SHR than in WKY. The arteries from adult SHR and SHRSP (22 weeks old) showed a markedly higher nerve density than WKY. There was a positive linear correlation between blood pressure and nerve density for four cerebral arteries. The mesenteric arteries were not innervated at birth. However, hyperinnervation of these arteries in the SHR was already present at 10 days of age as compared with WKY. Sympathectomy with anti-nerve growth factor and guanethidine caused a complete disappearance of fluorescent fibers in the mesenteric arteries from SHR and WKY, and in the cerebral arteries of WKY. The same procedure caused only partial denervation of the cerebral arteries from hypertensive animals. We postulate that the increase in nerve density in the cerebral arteries from the hypertensive rats may contribute to the development of arterial hypertrophy in chronic hypertension through the trophic effect of the sympathetic innervation on vascular structure.     

Inhibition of NOS enhances pulmonary vascular changes in stroke-prone spontaneously hypertensive rats

To determine the effects of chronic nitric oxide (NO) blockade on the pulmonary vasculature, 58-day-old spontaneously hypertensive rats of the stroke-prone substrain (SHRSP) and Wistar-Kyoto rats (WKY) received N(omega)-nitro-L-arginine (L-NNA; 15 mg. kg(-1). day(-1) orally for 8 days). Relaxation to acetylcholine (ACh) in hilar pulmonary arteries (PAs), the ratio of right ventricular (RV) to body weight (RV/BW) to assess RV hypertrophy (RVH), and the percent medial wall thickness (WT) of resistance PAs were examined. L-NNA did not alter the PA relaxation, RV/BW, or WT in WKY. Although the PA relaxation and RV/BW in control SHRSP were comparable to those in WKY, the WT was increased (31 +/- 2 vs. 19 +/- 1%). L-NNA-treated SHRSP showed two patterns: in one group, the relaxation, RV/BW, and WT were comparable to those in the control SHRSP; in the other, impaired relaxation (36 +/- 7 vs. 88 +/- 4% for WKY) was associated with an increase in WT (37 +/- 1%) and RV/BW (0. 76 +/- 0.05). Thus the abnormal pulmonary vasculature in SHRSP at <10 wk of age is not accompanied by impaired relaxation in PAs or RVH; however, impaired relaxation is associated with increased WT and RVH.     

Nifedipine-sensitive vascular reactivity of femoral arteries in WKY: the effects of pertussis toxin pretreatment and endothelium removal

Maintenance of norepinephrine (NE)-induced contraction is dependent on Ca(2+) influx through L-type voltage-dependent Ca(2+) channels (VDCC), which is opposed by nitric oxide. Adrenergic receptors are coupled with different G proteins, including inhibitory G proteins (Gi) that can be inactivated by pertussis toxin (PTX). Our study was aimed to investigate the effects of endothelium removal, PTX pretreatment and acute VDCC blockade by nifedipine on the contractions of femoral arteries stimulated by norepinephrine. We used 12-week-old male WKY, half of the rats being injected with PTX (10 microg/kg i.v., 48 h before the experiment), which considerably reduced their blood pressure (BP). Contractions of isolated arteries were measured using Mulvany-Halpern myograph. NE dose-response curves determined in femoral arteries from PTX-treated WKY rats were shifted to the right compared to those from control WKY. On the contrary, removal of endothelium augmented NE dose-response curves shifting them to the left. Acute VDCC blockade by nifedipine (10(-7) M) abolished all differences in NE dose-response curves which were dependent on the presence of either intact endothelium or functional Gi proteins because all NE dose-response curves were identical to the curve seen in vessels with intact endothelium from PTX-treated animals. We can conclude that BP reduction after PTX injection is accompanied by the attenuation of NE-induced contraction of femoral arteries irrespective of endothelium presence. Moreover, our data indicate that both vasodilator action of endothelium and Gi-dependent vasoconstrictor effect of norepinephrine operate via the control of Ca(2+) influx through VDCC.     

Elevated production of 20-HETE in the cerebral vasculature contributes to severity of ischemic stroke and oxidative stress in spontaneously hypertensive rats

Hypertension is a major risk factor for stroke, but the factors that contribute to the increased incidence and severity of ischemic stroke in hypertension remain to be determined. 20-hydroxyeicosatetraenoic acid (20-HETE) has been reported to be a potent constrictor of cerebral arteries, and inhibitors of 20-HETE formation reduce infarct size following cerebral ischemia. The present study examined whether elevated production of 20-HETE in the cerebral vasculature could contribute to the larger infarct size previously reported after transient middle cerebral artery occlusion (MCAO) in hypertensive strains of rat [spontaneously hypertensive rat (SHR) and spontaneously hypertensive stroke-prone rat (SHRSP)]. The synthesis of 20-HETE in the cerebral vasculature of SHRSP measured by liquid chromatography-tandem mass spectrometry was about twice that seen in Wistar-Kyoto (WKY) rats. This was associated with the elevated expression of cytochrome P-450 (CYP)4A protein and CYP4A1 and CYP4A8 mRNA. Infarct volume after transient MCAO was greater in SHRSP (36+/-4% of hemisphere volume) than in SHR (19+/-5%) or WKY rats (5+/-2%). This was associated with a significantly greater reduction in regional cerebral blood flow (rCBF) in SHR and SHRSP than in WKY rats during the ischemic period (78% vs. 62%). In WKY rats, rCBF returned to 75% of control following reperfusion. In contrast, SHR and SHRSP exhibited a large (166+/-18% of baseline) and sustained (1 h) postischemic hyperperfusion. Acute blockade of the synthesis of 20-HETE with N-hydroxy-N'-(4-butyl-2-methylphenyl)-formamidine (HET0016; 1 mg/kg) reduced infarct size by 59% in SHR and 87% in SHRSP. HET0016 had no effect on the fall in rCBF during MCAO but eliminated the hyperemic response. HET0016 also attenuated vascular O2*- formation and restored endothelium-dependent dilation in cerebral arteries of SHRSP. These results indicate the production of 20-HETE is elevated in the cerebral vasculature of SHRSP and contributes to oxidative stress, endothelial dysfunction, and the enhanced sensitivity to ischemic stroke in this hypertensive model.     

Insulin resistance in spontaneously hypertensive rats is associated with endothelial dysfunction characterized by imbalance between NO and ET-1 production

Insulin stimulates production of NO in vascular endothelium via activation of phosphatidylinositol (PI) 3-kinase, Akt, and endothelial NO synthase. We hypothesized that insulin resistance may cause imbalance between endothelial vasodilators and vasoconstrictors (e.g., NO and ET-1), leading to hypertension. Twelve-week-old male spontaneously hypertensive rats (SHR) were hypertensive and insulin resistant compared with control Wistar-Kyoto (WKY) rats (systolic blood pressure 202 +/- 11 vs. 132 +/- 10 mmHg; fasting plasma insulin 5 +/- 1 vs. 0.9 +/- 0.1 ng/ml; P < 0.001). In WKY rats, insulin stimulated dose-dependent relaxation of mesenteric arteries precontracted with norepinephrine (NE) ex vivo. This depended on intact endothelium and was blocked by genistein, wortmannin, or N(omega)-nitro-l-arginine methyl ester (inhibitors of tyrosine kinase, PI3-kinase, and NO synthases, respectively). Vasodilation in response to insulin (but not ACh) was impaired by 20% in SHR (vs. WKY, P < 0.005). Preincubation of arteries with insulin significantly reduced the contractile effect of NE by 20% in WKY but not SHR rats. In SHR, the effect of insulin to reduce NE-mediated vasoconstriction became evident when insulin pretreatment was accompanied by ET-1 receptor blockade (BQ-123, BQ-788). Similar results were observed during treatment with the MEK inhibitor PD-98059. In addition, insulin-stimulated secretion of ET-1 from primary endothelial cells was significantly reduced by pretreatment of cells with PD-98059 (but not wortmannin). We conclude that insulin resistance in SHR is accompanied by endothelial dysfunction in mesenteric vessels with impaired PI3-kinase-dependent NO production and enhanced MAPK-dependent ET-1 secretion. These results may reflect pathophysiology in other vascular beds that directly contribute to elevated peripheral vascular resistance and hypertension.     

自发性高血压大鼠中枢血管紧张素Ⅱ的变化对中枢肾上腺素...

The content of norepinephrine (NE) and epinephrine (E) in the brain of spontaneously hypertensive rats has proved abnormal, but the cause remained unknown. It was shown in the recent work that NE content in pons, posterior hypothalamus, nucleus caudatus and E concentration in medulla oblongata, anterior and posterior hypothalamus of 12-week old stroke-prone spontaneously hypertensive rats (SHRSP) were much higher than those of age-matched Wister-Kyoto rats (WKY). SHRSP also showed higher levels of systolic blood pressure (SBP) and brain angiotensin II (A II) than WKY. Intracerebroventricular (icv) perfusion of angiotensin-converting enzyme inhibitor captopril (20 micrograms for each time and three times for each day for four weeks) inhibited the synthesis of brain A II and reduced SBP and NE, E contents in all examined brain areas in SHRSP and WKY. However, the effects of chronically perfused captopril on SBP and brain NE, E levels in SHRSP were much more significant than in WKY. The results indicate that the modulatory effects of central renin-angiotensin system (RAS) on central adrenergic and noradrenergic system might be overactivated in SHRSP, which might partially responsible for the abnormally high levels of NE, E in some of the brain areas of SHRSP.     

Decreased content in left atrium and increased plasma concentration of atrial natriuretic polypeptide in spontaneously hypertensive rats (SHR) and SHR stroke-prone

The atrial contents and concentrations, and the plasma concentrations of atrial natriuretic polypeptide (ANP) in spontaneously hypertensive rats (SHR) and SHR stroke-prone (SHRSP) were measured and compared with those of age-matched Wistar Kyoto rats (WKY) using a specific radioimmunoassay (RIA) for alpha-rat ANP (alpha-rANP). The contents of alpha-rANP-LI in the atria of SHR (19.0 +/- 0.9 micrograms, mean +/- SEM) and SHRSP (19.3 +/- 0.6 micrograms) were significantly lower than that of WKY (22.8 +/- 1.4 micrograms) (p less than 0.05). The atrial concentration of alpha-rANP-LI was also significantly lower in SHR (248.2 +/- 11.3 ng/mg, p less than 0.05) and tended to be lower in SHRSP (272.2 +/- 12.4 ng/mg) than that of WKY (300.0 +/- 14.2 ng/mg). Furthermore, the concentrations in the left auricles of SHR and SHRSP were significantly lower than that of WKY (p less than 0.01 and p less than 0.05, respectively). In contrast, no significant difference was observed in the alpha-rANP-LI concentrations in the right auricles of WKY, SHR and SHRSP. Gel filtration studies coupled with RIA showed that gel filtration profiles of the extracts from the right and left auricles of WKY, SHR and SHRSP were essentially identical. The plasma alpha-rANP-LI levels in SHR (260 +/- 34 pg/ml) and SHRSP (319 +/- 19 pg/ml) were significantly higher than that in WKY (170 +/- 17 pg/ml) (p less than 0.05 and p less than 0.01, respectively). These results suggest that the secretion of ANP from the heart is increased in SHR and SHRSP compared with WKY.     

ChREBP regulates Pdx-1 and other glucose-sensitive genes in pancreatic β-cells

The Na⁺-K⁺-2Cl⁻ cotransporter 1 (NKCC1) is one of several transporters that have been implicated for development of hypertension since NKCC1 activity is elevated in hypertensive aorta and vascular contractions are inhibited by bumetanide, an inhibitor of NKCC1. We hypothesized that promoter hypomethylation upregulates the NKCC1 in spontaneously hypertensive rats (SHR). Thoracic aortae and mesenteric arteries were excised, cut into rings, mounted in organ baths and subjected to vascular contraction. The expression levels of nkcc1 mRNA and protein in aortae and heart tissues were measured by real-time PCR and Western blot, respectively. The methylation status of nkcc1 promoter region was analyzed by combined bisulfite restriction assay (COBRA) and bisulfite sequencing. Phenylephrine-induced vascular contraction in a dose-dependent manner, which was inhibited by bumetanide. The inhibition of dose-response curves by bumetanide was much greater in SHR than in Wistar Kyoto (WKY) normotensive rats. The expression levels of nkcc1 mRNA and of NKCC1 protein in aortae and heart tissues were higher in SHR than in WKY. Nkcc1 gene promoter was hypomethylated in aortae and heart than those of WKY. These results suggest that promoter hypomethylation upregulates the NKCC1 expression in aortae and heart of SHR.