Vascular BDNF expression and oxidative stress during aging and the development of chronic hypertension

Brain-derived neurotrophic factor (BDNF) and TrK receptors play an important role in vascular development and response to injury. In this study, we investigated the participation of the BDNF/TrK pathway and oxidative stress during the development of hypertension in spontaneously hypertensive rats (SHR). In SHR and normotensive rats (WKY) at 6 and 13 weeks of age, we studied (i) plasma antioxidant capacity, (ii) production of superoxide and NAD(P)H oxidase activity in aorta (iii) plasma BDNF and vascular expression of BDNF, TrKB, NAD(P)H oxidase subunits, AT1 receptor, and MCP-1. In 6- and 13-week-old SHR aorta, superoxide level was twice than in WKY aorta. At 13 weeks, when blood pressure in SHR was 60 mmHg higher in SHR than in WKY, an enhancement of NAD(P)H oxidase activity in SHR was associated with an increase in p47phox, AT1, and BDNF expression in vessels. MCP-1 expression increased with blood pressure. Our study demonstrated that in SHR rats, an increase in levels of vascular oxidative stress and in aortic BDNF and TrKB expression occurs prior to the rise in blood pressure, while a reinforcement of vascular and circulating oxidative stress markers is brought about later by hypertension.     

高血压左室肥厚发病中细胞间黏附分子1的表达及丹参酮ⅡA的抑制效应

背景细胞间黏附分子1作为炎症反应的可靠标志物在动脉粥样硬化发病中具有重要的作用.近年来研究认为其介导的慢性炎症反应可能参与高血压左室肥厚的发病过程,但也有报道持相反观点.丹参酮ⅡA是丹参的一种脂溶性提取性,动物实验证明其具有抑制高血压左室肥厚发生的作用.目的探讨细胞间黏附分子1在高血压左室肥厚发生中的作用及丹参酮ⅡA对其表达的影响.设计随机对照观察.单位华中科技大学同济医学院附属同济医院.材料实验于2002-10/2004-01在华中科技大学同济医学院附属同济医院急诊科实验室完成,选用12周龄雄性WKY大鼠10只、自发性高血压SHR大鼠20只,分为对照组(WKY大鼠10只)、高血压组(SHR大鼠10只)、丹参酮ⅡA组(SHR大鼠10只).方法丹参酮ⅡA组经尾静脉注射丹参酮ⅡA 1.5 mg/(kg·d)治疗,其他两组分别注射等量的蒸馏水.12周后断头处死所有大鼠留取心肌标本,应用苏木精-伊红染色、VG染色,免疫组化染色及心肌ED1标记检测心肌巨噬细胞浸润数,心肌细胞间黏附分子1 mRNA及蛋白的表达应用反转录-聚合酶链反应及酶链免疫吸附实验等方法.主要观察指标各组大鼠心肌巨噬细胞浸润数,心肌细胞间黏附分子1mRNA及蛋白表达.结果20只SHR和10只WKY大鼠被纳入实验,并全部进入结果分析,无脱失值.①与对照组比较,高血压组大鼠肥厚心肌中细胞间黏附分子1的mRNA及蛋白表达显著增加(0.176±0.087,0.537±0 195;0.104±0.011,0.173±0.027,P＜0.01或P＜0.05),巨噬细胞浸润明显(0.62±0.07,1.85±0.23,P＜0.01).②与高血压组比较,丹参酮ⅡA组大鼠心肌细胞间黏附分子1的mRNA及蛋白表达水平显著下调(0.537±0.195,0.291±0.106;0.173±0.027,0.125±0.014,P＜0.01或P＜0.05),巨噬细胞浸润数减少(1.85±0.23,1.16±0.17,P＜0.05),心肌细胞肥大和间质纤维化程度明显减轻.结论心肌细胞间黏附分子1的过度表达及其介导的炎性细胞浸润在高血压左室肥厚的发病过程中具有重要作用.丹参酮ⅡA抑制左室肥厚的效应可能与其下调细胞间黏附分子1表达,减少炎性细胞的心肌浸润有关.     

Renal kallikrein activity in rats developing spontaneous hypertension

1. Spontaneously hypertensive rats (SHR) excrete less kallikrein in urine than Wistar-Kyoto rats (WKY) during the developmental phase of hypertension. The present study was designed to examine whether the urinary defect is related to abnormalities in the renal kallikrein content in this hypertensive model. 2. Active and total kallikrein were measured (amidolytic assay) in the renal cortex of newborn and 4-, 8- and 12-week-old SHR and age-matched WKY. Active and total kallikrein were also measured in urine at the same ages, except at birth. 3. Tissue active kallikrein was significantly lower in SHR at birth, representing on average 53% of the values in WKY expressed as content per total cortex weight. Tissue total kallikrein did not differ between newborn SHR and WKY. 4. SHR at 4, 8 and 12 weeks of age had lower urinary active and total kallikrein excretion. Tissue active akllikrein, but not total kallikrein, was higher than in age-matched WKY per g of cortex weight or per mg of protein, whereas both tissue active and total kallikrein were lower in SHR when expressed as content per total cortex weight. At these three ages, active kallikrein represented, on average 86%, while total kallikrein represented 77%, of the values in age-matched WKY. 5. Our results indicate a defect in prokallikrein activation rather than in kallikrein synthesis in the renal cortex of SHR at birth. The reduction in urinary kallikrein excretion during the developmental phase of hypertension in young SHR is similar to the reduction observed in the renal tissue.     

Renal permeability alteration precedes hypertension and involves bradykinin in the spontaneously hypertensive rat.

Vascular permeability disorders have been described in experimental models, as well as in human hypertension. We recently described the fact that vascular permeability to albumin is heterogeneous in the normal rat. In the present study, we examine the contents of Evans blue dye (EB) bound to albumin in selected organs of unanesthetized Wistar Kyoto (WKY) and in spontaneously hypertensive rats (SHR) at various stages of development of hypertension. EB was injected in the caudal vein of paired 4, 8, 12, and 16-wk-old WKY and SHR. Rats were killed 10 min after EB injection and extraction of the marker was measured in selected tissues. In additional 4 and 16-wk-old animals, bradykinin B1 and B2 receptor antagonists (BKA) were also injected with EB. Renal contents of EB bound to albumin were higher in the SHR than in the WKY: 196 +/- 9, 202 +/- 10, 182 +/- 7, and 196 +/- 9, compared with 158 +/- 8, 155 +/- 7, 138 +/- 7, and 118 +/- 6 micrograms/g dry tissue, in the 4, 8, 12, and 16-wk-old rats, respectively. In the 4-wk-old SHR and WKY, blood pressure values were normal and comparable, yet the alteration in EB permeability was already present in the SHR. Both BKA failed to alter the renal EB extravasation in the WKY, but the B2-BKA restored the renal permeability to control levels in the SHR. We conclude that a selective defect in the renal vascular permeability to EB developed in the SHR. Since this finding precedes hypertension and is corrected by a selective B2-BKA, it is suggested that bradykinin is involved at an early stage of the disease in the SHR.     

Calmodulin reduces ouabain-sensitive ATPase of cardiac sarcolemmal membranes: high reduction in spontaneously hypertensive rats

Calmodulin and calcium effects on cardiac ouabain-sensitive adenosine triphosphatase (ATPase) activity were studied in young spontaneously hypertensive rats (SHR) and in their normotensive control Wistar-Kyoto rats (WKY). Cardiac sarcolemmal membranes from SHR showed significantly higher ouabain-sensitive ATPase activity than membranes from WKY rats. This activity was unaffected by calmodulin or calcium alone. However, when both calmodulin and calcium were added, ouabain-sensitive activity was significantly reduced without changes in the total ATPase activity. The calcium-dependent calmodulin effect was dose-dependent and greater in SHR than in WKY membranes. An altered interaction between the calcium-calmodulin system and sodium handling by the plasma membrane in SHR may play a role in the pathogenesis of hypertension.     

声学密度技术评价高龄高血压大鼠心肌间质纤维化

目的 探讨声学密度技术评价高龄高血压大鼠心肌间质纤维化的可靠性。方法 20月龄自发性高血压大鼠(SHR)及Wistar京都(WKY)大鼠各15只，测量室间隔、左室后壁、左室侧壁心肌的超声背向散射参数。将左室后壁校正的背向散射积分(IB％)与光镜、电镜检测的体视学定量结果对比。结果 两组间左心室各部位的背向散射积分(IBS)及室间隔、左室后壁的背向散射积分周期变化幅度(CVIB)差异有显著性意义，左室后壁IB％与光镜、电镜测得的间质胶原纤维体积百分比平均值高度相关。结论 声学密度技术可用于评价高龄高血压大鼠心肌间质纤维化程度，高龄SHR较WKY大鼠心肌间质纤维化加重。     

Enhanced slow-pressor response to angiotensin II in spontaneously hypertensive rats

Rapid-pressor and slow-pressor responses to angiotensin (ANG) II and norepinephrine (NE) in spontaneously hypertensive rats (SHR) and Wistar Kyoto control rats (WKY) were examined. All animals were treated from 4 wk of age with captopril (100 mg/kg/day in drinking water) to prevent development of hypertension so that changes in responsiveness could not be attributed to disparate base-line blood pressures or to hypertension-induced injury of the cardiovascular system. In 11-wk, conscious, unrestrained, captopril-treated rats, ANG II and NE induced rapid-pressor responses (i.e., a rapid increase in arterial blood pressure that reached a maximum within 10 min) that were of similar magnitude in SHR and WKY. In an additional group of 9-wk captopril-treated rats, both ANG II and NE caused slow-pressor responses (i.e., a slow increase in arterial blood pressure over 2 wk). Although the slow-pressor response to NE was similar in SHR versus WKY, the slow-pressor response to ANG II was much greater in SHR compared with WKY. Further studies were conducted in captopril-treated (from 4 wk of age) SHR and WKY to investigate whether the increased slow-pressor response to ANG II in SHR was mediated by an enhanced ability of ANG II to potentiate peripheral sympathetic neurotransmission, contract vascular smooth muscle, increase sympathetic tone to nonadrenal sites, release aldosterone, and/or reduce renal function. No evidence was found that supported a role for the aforementioned nonrenal actions of ANG II. However, 11-wk captopril-treated SHR were 10-fold more sensitive to the antidiuretic, antinatriuretic, and renal vascular effects of intrarenal infusions of ANG II compared with captopril-treated WKY. Also, chronic (1 wk) intrarenal infusions of a very low dose of ANG II (1 ng/min) caused a marked slow-pressor response in 11-wk captopril-treated SHR but did not alter arterial blood pressure in WKY. We conclude that 1) the slow-pressor response to ANG II is greatly enhanced in SHR, 2) this enhancement is specific with respect to type of response (slow not rapid) and pressor agent (ANG II not NE), 3) a genetic defect underlies the increased slow-pressor response to ANG II in SHR, and 4) the enhanced slow-pressor response to ANG II contributes significantly to the pathophysiology of hypertension in SHR. Finally, the current studies are consistent with our working hypothesis that the kidneys mediate the enhanced slow-pressor response to ANG II in SHR.     

Disturbance of acid-base balance in the young spontaneously hypertensive rat

1. The acid-base status of young spontaneously hypertensive rats (SHR) was compared with that of Wistar-Kyoto rats (WKY) in the steady state, after acid loading and after blood pressure had been maintained at normal levels from weaning. Whole blood ionized calcium was measured simultaneously. 2. In the prehypertensive stage (4 weeks of age), plasma bicarbonate was significantly lower in SHR than in WKY, while blood pH did not differ significantly. 3. After 6 weeks of age, blood pH and plasma bicarbonate were significantly lower in both anaesthetized and conscious SHR than in corresponding WKY. After 7 days administration of NH4Cl in the drinking fluid, both parameters decreased significantly in both strains and the difference in pH remained constant (0.05 pH unit, P less than 0.01). 4. In none of the groups investigated did non-pH-adjusted ionized calcium differ significantly between the SHR and WKY. 5. Prevention of the development of hypertension in SHR by hydralazine treatment from weaning did not increase pH or bicarbonate compared with untreated SHR, indicating that the metabolic acidosis in the SHR was not a consequence of raised blood pressure. 6. Disturbance in acid-base balance may be involved in the pathogenesis of raised blood pressure in this animal model of genetic hypertension.     

Hypercholesterolemia does not alter endothelial function in spontaneously hypertensive rats

In humans, hypercholesterolemia and hypertension are associated with endothelial dysfunction. Here, we assess whether hypercholesterolemia induces endothelial dysfunction in rats with pre-existing hypertension. Spontaneously hypertensive rats (SHR) and normotensive controls (WKY) were fed with a high-cholesterol diet for 12 weeks, and endothelial function was assessed in isolated thoracic aortic rings. In SHR and WKY rats, the hypercholesterolemic diet resulted in the elevation of total cholesterol and low-density lipoprotein levels by approximately 2.5- and 4.5-fold, respectively. However, in aorta, the basal nitric oxide (NO) production--as assessed by the magnitude of L-NG-nitroarginine methyl ester-induced vasoconstriction as well as the NO-dependent relaxation induced by acetylcholine or histamine--were not diminished either in SHR or in WKY rats fed with the hypercholesterolemic diet. Interestingly, prostacyclin (PGI2) production in aortic rings from SHR rats was higher than in the aorta from WKY rats. However, the hypercholesterolemic diet had no further effects on PGI2 production in the aorta either of SHR or WKY rats. The monocyte chemoattractant protein 1 level in plasma was slightly elevated in SHR and WKY rats fed with the hypercholesterolemic diet compared with their normocholesterolemic counterparts. In summary, even in the presence of pre-existing hypertension, hypercholesterolemia fails to modify NO-dependent and PGI2-dependent endothelial function in SHR rats; it also does not induce a robust inflammatory response. Both are prerequisites for the development of atherosclerosis.     

自发性高血压大鼠左室心肌细胞FAK-pTyr576磷酸化及其定位

目的探讨黏着斑激酶酪氨酸576(focal adhesion kinase tyrosine 576,FAK-pTyr576)磷酸化在自发性高血压大鼠(spontaneously hypertensive rats,SHR)心肌肥大发生与发展机制中的作用。方法选择2、6和18月龄雄性SHR为SHR组,相同月龄Wistar-Kyoto(WKY)雄性大鼠作为正常血压对照组(WKY组),每个月龄段大鼠6只。乙醚麻醉,于胸骨剑突下肋骨侧缘剪开,取适量左心室组织,通过免疫荧光标记、共聚焦显微镜及蛋白质印迹(Western blotting,WB)等方法,检测2组不同月龄大鼠心肌细胞中FAK-pTyr576的表达和定位的变化。结果 HE染色发现,与WKY组相比,SHR组左心室心肌细胞不同程度增大。WB检测结果显示:FAK-pTyr576的表达SHR组随大鼠月龄的增加而增强(P0.05),而WKY组不同月龄大鼠间无统计学意义(P0.05);与WKY组比较,SHR组6月龄、18月龄大鼠FAK-pTyr576的表达明显增强(P0.01)。免疫荧光染色结果显示:WKY组不同月龄大鼠心肌细胞FAKpTyr576的表达相似,无明显变化;而SHR组6月龄及18月龄大鼠出现了定位变化。结论 SHR的心肌细胞中存在FAK-pTyr576磷酸化,这可能是高血压致左心室失代偿肥大时心肌细胞黏着斑激酶信号转导通路活化的重要一环。     

Effect of acute and chronic treatment of tin on blood pressure in spontaneously hypertensive rats.

Cytochrome P450-dependent metabolites of arachidonic acid (AA) are increased in the kidneys of spontaneously hypertensive rats (SHR) as compared to control rats (WKY) in the period of rapid elevation of blood pressure (BP) from 5 to 13 weeks. We treated rats with stannous chloride (SnCl2) (10 mg/100 g body weight/day for 4 days) to decrease selectively renal cytochrome P450 content through increasing renal heme oxygenase activity. A decrease in renal cytochrome P450-dependent AA metabolites was associated with decreased BP and increased urinary Na+ excretion in 7- but not in 20-week-old SHR rats. Chronic treatment with SnCl2 (10 mg/100 g body weight twice a week) from 5 to 20 weeks prevented the elevation of BP in SHR rats. Further, the antihypertensive effects of tin persisted for 7 weeks beyond its discontinuation. BP in WKY rats was unaffected by tin. Both the acute and chronic treatment with tin are the first studies to demonstrate amelioration of hypertension in SHR by an intervention which is targeted at a single enzyme system.     

Genetic co-segregation of renal haemodynamics and blood pressure in the spontaneously hypertensive rat

1. To determine the relevance of renal circulatory abnormalities found in the immature spontaneously hypertensive rat (SHR) to the genetic hypertensive process, glomerular filtration rate and renal blood flow were measured in conscious F2 rats, derived from cross-breeding SHR and normotensive Wistar-Kyoto rats (WKY), at 4, 11 and 16 weeks of age by determining the renal clearances of 51Cr-ethylenediaminetetra-acetate and 125I-hippuran respectively. Plasma renin activity was measured at 11 and 16 weeks of age. 2. Mean arterial pressure, glomerular filtration rate and renal blood flow increased between 4 and 11 weeks of age. Between 11 and 16 weeks the mean glomerular filtration rate and renal blood flow did not alter, although the mean arterial pressure rose significantly. At 11 weeks of age, during the developmental phase of hypertension, a significant negative correlation between mean arterial pressure and both glomerular filtration rate and renal blood flow was noted. However, by 16 weeks when the manifestations of genetic hypertension were more fully expressed, no correlation between mean arterial pressure and renal blood flow or glomerular filtration rate was observed. Plasma renin activity was negatively correlated with both glomerular filtration rate and renal blood flow, but the relationship was stronger at 11 than at 16 weeks of age. 3. These results suggest that the reduction in renal blood flow and glomerular filtration rate, found in immature SHR, is genetically linked to the hypertension and may be of primary pathogenetic importance. It is proposed that the increased renal vascular resistance in these young animals stimulates the rise of systemic arterial pressure which returns renal blood flow and glomerular filtration rate to normal.     

Haemodynamic response following a 10% topload infusion of HemolinkTM in conscious, anaesthetized and treated spontaneously hypertensive rats

HemolinkTM (HLK), a haemoglobin-based oxygen carrier (HBOC), is currently undergoing Phase II/III clinical trials in surgical patients. It causes some blood pressure rise in animal and human tests. This study was designed to investigate the systemic haemodynamic response to HemolinkTM in spontaneously hypertensive rats (SHR rats). Conscious or anaesthetized SHR rats and control Wistar Kyoto rats (WKY rats) received either HemolinkTM or homologous plasma as a 10% topload infusion. Some awake animals were pretreated with nifedipine and followed by HLK infusion. In the conscious animal study, HLK induced a greater pressure rise and less bradycardia in SHR rats than in WKY rats. In the anaesthetized animal experiment, HLK-induced pressure rise and bradycardia were similar in both strains and less pronounced than in the conscious animals. In the nifedipine pretreated SHR rats, HLK-induced pressure rise was significantly smaller than that observed in nontreated SHR rats and was not different from that of nontreated WKY rats. The HLK-induced bradycardia was significantly smaller in nifedipine-treated animals than in the nontreated SHR or WKY rats. This study suggests that the pressor effect of HemolinkTM can be attenuated in hypertensive animals with general anaesthesia or treatment with antihypertensive agents.     

高血压大鼠肾脏ACE2的表达及其与内皮素的关系

目的探讨自发性高血压大鼠的肾脏中ACE2的表达情况并对其与血浆中内皮素水平做相关分析。方法实验分为对照组和自发高血压组,采用反转录．聚合酶链式反应（RT—PCR）法测定肾脏中ACE2mRNA表达水平,放射免疫法同批检测大鼠血浆中内皮素的含量。结果自发性高血压大鼠和正常对照大鼠相比,肾脏组织中ACE2蛋白的表达下降（P〈0．05）,血清中内皮素的水平升高（P〈0．05）,与ACE2蛋白的表达呈负相关（r=-0．632,P〈0．05）,与血压水平呈正相关（r=0．615,P〈0．05）。结论ACE2在肾脏的表达不同可能是引发高血压病发病的一个重要因素,且其影响血压的机制可能与缩血管物质有关。     

MCP-1、RANTES在慢性移植肾失功肾组织中的表达及意义

目的 探讨单核细胞趋化蛋白-1(MCP-1)和RANTES在慢性移植肾失功(CRAD)患者移植肾组织中的表达及意义.方法 用免疫组织化学技术和计算机真彩色图像分析系统半定量检测32例慢性移植肾失功患者移植肾组织中MCP-1和RANTES的表达,分析与移植肾间质纤维化/小管萎缩程度及炎性细胞浸润程度之间的关系.结果 慢性移植肾失功患者的移植肾组织中MCP-1和RANTES的表达较正常肾组织中明显增加,并随着间质纤维化/小管萎缩及炎症细胞浸润程度而递增.结论 移植肾组织中MCP-1和RANTES的表达升高与慢性移植肾失功的进展有关.     

Time course of changes in the norepinephrine content of tissues from spontaneously hypertensive and Wistar Kyoto rats

The change in norepinephrine (NE) content with age (from 2 days to 17 weeks old) was examined in a variety of tissues from spontaneously hypertensive rats (SHR) and normotensive Wistar Kyoto (WKY) rats. NE content was determined by either a catechol-O-methyltransferase-based radioenzymatic assay or high performance liquid chromatography with electrochemical detection. Regardless of the age of the animal, NE content per gram of tissue was significantly greater in mesenteric arteries and kidneys from SHR compared to WKY tissues, whereas NE content per whole kidney was similar between the two rat strains. The time course of enhanced NE content in caudal arteries and aortas from SHR followed the development of hypertension. In the spleen, NE content per gram of tissue was elevated in young SHR; however, in adult rats NE content was not significantly different between the two rat strains. Because spleens from WKY rats were substantially larger, total NE content per spleen was significantly greater in tissues from WKY rats. Cardiac contents of NE were similar in SHR and WKY rats at all ages examined. Adrenal epinephrine concentrations were similar in SHR and WKY rats, whereas NE content was elevated in the SHR at 46 and 81 days of age. The results of the present study demonstrate that the appearance of increased NE levels in some SHR tissues occurs before the development of hypertension in this model. If NE content is a valid index of sympathetic innervation, enhanced innervation may contribute to the vascular medial hypertrophy observed in young SHR and the elevation of blood pressure in these rats.     

Trace elements during the development of hypertension in the spontaneously hypertensive rat

Total plasma concentrations of bromine, copper, rubidium, selenium and zinc were measured in spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY) of 5-20 weeks of age, using an X-ray fluorescence spectrometry technique. Although plasma levels of bromine, rubidium, selenium and zinc varied at different ages when comparing SHR and WKY, their general evolution was similar. Copper levels increased more in SHR than in WKY. These perturbations in trace element levels could perhaps participate in the establishment of hypertension in SHR, but could also be due to genetic differences between the strains, unrelated to the development of hypertension.     

Decreased Adrenal Responsiveness to Angiotensin II: A Defect Present in Spontaneously Hypertensive Rats: A POSSIBLE MODEL OF HUMAN ESSENTIAL HYPERTENSION

30% of patients with essential hypertension have a decreased adrenal response to angiotensin II (A II) on a low but not a high sodium intake. They also have a compensatory increase in the activity of the renin-angiotensin system best documented in a sodium-restricted state.To assess whether such a mechanism could account for the hypertension in genetically hypertensive rats, adrenal responsiveness to A II was determined in three groups of rats; spontaneously hypertensive rats (SHR), normotensive Wistar rats (WKY), and normotensive Sprague-Dawley rats (SDR). Animals in each group were placed on either a low or high sodium diet for 14 d with balance assessed by sodium excretion. The animals were then decapitated, blood was obtained for plasma renin activity (PRA), A II and aldosterone and adrenals isolated for the preparation of purified glomerulosa cells. The cells were incubated in Krebs-Ringer bicarbonate solution, containing bovine serum albumin, for 60 min in the absence and presence of increasing concentrations of A II.The PRA, basal aldosterone output, and adrenal sensitivity to A II were similar in the three groups of rats on the high sodium diet. On the low sodium diet the SHR had a significantly (P < 0.01) higher PRA (25+/-7 ng/ml per h) than either the WKY (12+/-2 ng/ml per h) or the SDR (7+/-1 ng/ml per h) and lower basal aldosterone output (68+/-17 vs. 154+/-43 and 197+/-21 ng/10(6) cells per h, respectively). In addition, the slope of the A II dose response curve was more shallow (P < 0.01) in the cells from the SHR than those obtained from the WKY and SDR.Thus, the SHR PRA and aldosterone responses to sodium restriction and aldosterone response to A II were similar to that previously described in a subgroup of patients with essential hypertension suggesting that the SHR will serve as a model for exploring the mechanism(s) responsible for the hypertension in these patients.     

Endothelial regulation of cyclic GMP and vascular responses in hypertension

The mechanism whereby endothelial modulation of drug-induced vascular responses might change during hypertension was examined. Acetylcholine (ACh) (1 microM) induced maximal relaxation of aortic ring segments with intact endothelium from both Wistar-Kyoto, normotensive rats (WKY) and spontaneously hypertensive rats (SHR) at 5 to 6 weeks of age. At 15 to 18 weeks of age the relaxation response to ACh was reduced in rings from both SHR and WKY (to a greater extent in SHR) and was attenuated even more in the deoxycorticosterone acetate (DOCA)-salt hypertensive rat. The contractile responses of aortic preparations to norepinephrine (NE) (0.1 microM) were similar between 5-6-week-old and 15-18-week-old WKY, but were increased in 15-18-week-old SHR compared to 5-6-week-old SHR. Endothelial cell removal increased contractile responses to NE to a greater extent in WKY than SHR but this did not affect that seen in DOCA-salt hypertensive rats. Methylene blue treatment increased contractions of aortic rings with intact endothelium from 15-18-week-old WKY and SHR to the level detected in rubbed arteries, but it did not affect the NE-induced constriction of intact aortic rings from DOCA-salt hypertensive rats. Basal cyclic GMP concentrations in intact aortic rings were not different between SHR and WKY at 5 to 6 weeks of age. The basal aortic cyclic GMP was unchanged in WKY at 15 to 18 weeks of age, but decreased in SHR and in DOCA-salt hypertensive rats of the same age.(ABSTRACT TRUNCATED AT 250 WORDS)     

Glomerular injury in uninephrectomized spontaneously hypertensive rats. A consequence of glomerular capillary hypertension.

Micropuncture and/or morphologic studies were performed in intact Wistar-Kyoto rats (WKY) (group 0), intact spontaneously hypertensive rats (SHR) (groups 1 and 5), uninephrectomized (UNX) WKY (groups 2 and 6), and UNX SHR (groups 3 and 4, 7 and 8). UNX was performed when rats were 5 wk of age. Groups 0-4 were observed for 34 wk after which whole kidney clearance and morphologic studies were performed. Groups 5-8 underwent micropuncture study at 10 wk of age. Groups 4 and 8 were fed a diet containing 6% protein. All other rats ingested standard laboratory diet. 5 wk after UNX, normotensive group 6 had higher single nephron glomerular filtration rate (SNGFR) and initial glomerular plasma flow rate (QA) than intact, hypertensive group 5. Glomerular transcapillary hydraulic pressure difference (delta P) was similar in these two groups. Hypertensive group 7 exhibited less elevation in SNGFR and QA than group 6, but delta P was significantly increased. The presence of glomerular capillary hypertension in UNX SHR at 10 wk was associated with the development of significant proteinuria and an increased incidence of mesangial expansion and glomerular sclerosis at 7 mo (group 3) as compared with groups 0, 1, and 2. Protein restriction prevented the development of increased delta P in UNX SHR (group 8) and also conferred long-term protection from increased urinary protein excretion and glomerular injury (group 4). These studies suggest that glomerular capillary hypertension predisposes to glomerular injury in this model of hypertension with reduced renal mass.