Protective Effect of Nicardipine Treatment on Renal Microanatomical Changes in Spontaneously Hypertensive Rats

The effects of nicardipine administration on kidney morphology were studied in spontaneously hypertensive rats (SHR). Male 12-week-old SHR received an oral dose of 1 mg/Kg/day of nicardipine or vehicle for 8 weeks. Age-matched Wistar-Kyoto rats were used as normotensive reference animals. At 20 weeks, the non treated SHR exhibited hypertension, albuminuria, decreased urinary sodium excretion and renal microanatomical changes. These changes were characterized by vascular alterations consisting in hypertrophy of the tunica media accompanied by a decrease of luminal surface. Glomerular changes consisting primarily in signs of glomerulosclerosis of varying degrees were noticeable in the kidneys of SHR. Treatment with nicardipine significantly reduced blood pressure and albuminuria and increased urinary sodium excretion.     

Central Actions of Agmatine in Conscious Spontaneously Hypertensive Rats

Agmatine (decarboxylated arginine) is an endogenous ligand at alpha-2 adrenergic and imidazoline nonadrenergic receptors. In conscious spontaneously hypertensive rats (SHRs), we have studied its central effects on cardiovascular function and its interaction with the second generation centrally acting antihypertensive agent, rilmenidine, and the reference imidazoline, clonidine, which are mixed alpha-2 adrenoceptor/imidazoline receptor agonists. Agmatine, when administered in low doses (30–100 µg/kg) into the fourth ventricle had no effect on blood pressure and caused an increase in heart rate. A higher dose of 1000 µg/kg produced an adverse reaction in conscious SHRs and a marked and long-lasting increase in blood pressure. The effects of fourth ventricular rilmenidine (300 µg/kg) and clonidine (10 µg/kg) were equihypotensive and equibradycardic. The antihypertensive and bradycardic effects of rilmenidine were not reversed by cumulative intracisternal doses (30-100-300 µg/kg) of agmatine. The bradycardia obtained 20 min after intracisternal administration of clonidine in the fourth ventricle was reversed by 30 µg/kg agmatine. Only the highest dose of agmatine (1000 µg/kg) did reverse the antihypertensive effects of rilmenidine and clonidine. Agmatine neither did mimic nor block the antihypertensive response to rilmenidine and clonidine at well-tolerated doses. Yet agmatine produced a small tachycardia at relatively low doses and was able to reverse the bradycardia induced by clonidine. Therefore, its affinity for alpha-2 adrenoceptors in vitro might partially explain its cardiovascular effects in vivo.     

拉西地平对高血压大鼠的降压作用

目的：观察新的钙拮抗剂拉西地平的降压作用。方法：急性降压实验：将５个月龄雄性卒中型自发性高血压大鼠（ＳＨＲｓｐ）随机分为Ａ、Ｂ、Ｃ（分别经管饲给药１次，拉西地平剂量１ｍｇ／ｋｇ，０．５ｍｇ／ｋｇ，０．２５ｍｇ／ｋｇ）、Ｄ（尼群地平１０ｍｇ／ｋｇ）、Ｅ（溶媒对照）组，每组１１只，于用药后１、３、５、９、１２、２４小时各测１次收缩压及心率（尾套法）。慢性降压实验：将３个月龄ＳＨＲｓｐ分为Ａ、Ｂ、Ｄ、Ｅ组（剂量同急性降压实验），每组１０只，治疗１４天，于治疗后第２、４、６、８、１０、１２、１４天各测１次收缩压及心率。结果：拉西地平１ｍｇ／ｋｇ和０．５ｍｇ／ｋｇ均可显著降低ＳＨＲｓｐ血压，降压作用分别持续１２～２４小时和９～１２小时，降压作用均强于尼群地平１０ｍｇ／ｋｇ，仅轻度增加了心率。结论：拉西地平对ＳＨＲｓｐ降压作用明确，持续时间长。     

Comparative Analysis of Renal Protein Expression in Spontaneously Hypertensive Rat

Objective. Molecular mechanisms of nephrosclerosis caused by hypertension are not well known. Understanding changes in renal protein expression in hypertension may provide further information on how hypertension caused renal injury. Methods and Results. In the present study, we showed the protein expression profiles of the kidney in spontaneously hypertensive rats and Wistar-Kyoto rats using two-dimensional gel electrophoresis (2-DE). Differentially expressed protein spots were excised, underwent in-gel tryptic digestion, and were analyzed by MALDI-TOF MS. Eleven spots were identified. Of these identified spots, four spots were newly appeared, five spots up-regulated, and two spots down-regulated. The identified spots were mainly involved in energy metabolism, lipid transferring between membranes, and cell proliferation. Conclusions. The expression of many proteins have changed significantly in the kidney of spontaneously hypertensive rat. NADP⁺-dependent isocitrate dehydrogenase may be a candidate for further investigation of pathophysiological mechanisms of renal injury in hypertension.     

Antihypertensive Action of Melatonin in the Spontaneously Hypertensive Rat

The effects of melatonin on blood pressure and heart rate were studied in 23-week-old male spontaneously hypertensive rats. Melatonin infused i.p. at a dose of 6 mg/rat per day for 5 days using an osmotic minipump produced a significant reduction of blood pressure and a slight but significant decrease of heart rate in the conscious and unrestrained state. These cardiovascular effects of melatonin developed gradually. Plasma renin concentration tended to decrease after melatonin treatment. These results demonstrate that melatonin has an antihypertensive action. The mechanism of the antihypertensive action of melatonin requires further study.     

Comparison of Simultaneous Measurements of Blood Pressure by Tail-Cuff and Carotid Arterial Methods in Conscious Spontaneously Hypertensive and Wistar-Kyoto Rats

We determined the validity of systolic blood pressure (SBP) measured by tail-cuff blood pressure (TCBP) with direct intra-arterial measurements. In conscious, restrained Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHR), carotid artery (CA) BP and TCBP were simultaneously measured. In both WKY and SHR strains, highly significant correlations between CABP and TCBP were found and Bland-Altman analyses showed no bias when the two methods were compared. The limits of agreement between CABP and TCBP in WKY and SHR were wide and reproducibility of pressure measurements by either technique was poor, with some evidence for strain-dependent differences. Pressure measurements made over short time frames, however, showed close agreement between CABP and TCBP. Acetylcholine-induced reductions in pressure were equivalently detected by tail-cuff and direct arterial measurement in both strains but angiotensin II-induced pressure elevations were over-estimated by tail-cuff in SHR. Telemetered SBP measurements in conscious rats were highly variable in a strain-dependent manner.     

Effects of Chronic Arachidonate on Blood Pressure of Spontaneously Hypertensive Rats

Three weeks of treatment with arachidonic acid (250 mg/kg/day, s.c.) produced an antihypertensive effect in 16 week-old spontaneously hypertensive rats (SHR) as compared with vehicle treated rats. Indomethacin (4 mg/kg, s.c. B.I.D.), given concurrently with arachidonate, abolished the antihypertensive effect. Plasma catecholamines were not altered by the arachidonate treatment, but blood pressure increments after spinal cord stimulation or after intravenous administration of norepinephrine and angiotensin II in the pithed rat were diminished. Increments in plasma catecholamines in response to spinal cord stimulation were similar in both groups of pithed rats.

These data demonstrate the antihypertensive effect of arachidonic acid in SHR with established hypertension. This beneficial effect seems to be mediated through cyclooxygenase metabolites, and might be related to reduced responsiveness of peripheral blood vessels to pressor stimuli.     

Elevated Plasma Adrenaline in Spontaneously Hypertensive Rats

Having found that circulating adrenaline (AD) is selectively elevated in stroke-prone spontaneously hypertensive rats (SHRSP) compared with Wistar-Kyoto rats (WKY), we extended the comparison to include other normotensive and hypertensive rat strains. Aortic catheters were implanted in young (5-7 weeks) and old (7-9 months) WKY, Black-Hooded Wistar (BHW), Sprague Dawley (SD), spontaneously hypertensive rats (SHR) and SHRSP for repeated measurement of mean arterial pressure (MAP) and blood sampling under conscious resting conditions. In the young SHR and SHRSP, MAP was already significantly higher than in age-matched WKY but MAP in the SD rats was similar. Plasma AD was significantly higher in SHR and lower in SD rats when compared with WKY. There was no difference in plasma noradrenaline (NA) between strains at this age. At the older age, MAP was 40-60 mmHg higher in SHR and SHRSP than in WKY and BHW but was significantly lower in the SD strain. Circulating AD did not differ between the normotensive strains but was 3-4 times higher in the hypertensive strains. Plasma NA was elevated in SHR only. The acute reduction of MAP caused by ganglion blockade (an index of the sympathetically mediated component of resting blood pressure) was greater in SHR and SHRSP than in WKY at the older age only. However, the residual MAP after ganglion blockade was significantly higher in the hypertensive strains at both ages. Regression analysis showed that in the older rats, plasma AD was correlated with resting MAP, the reduction in MAP with ganglion blockade, the residual MAP and plasma NA. In the young rats, however, plasma AD levels were not correlated with either plasma NA or resting MAP. Thus, even though plasma AD is elevated in the hypertensive strains at an early age, it is not clear whether this increase contributes to the pathogenesis of hypertension.     

软脉灵对自发性高血压大鼠心肌纤维化的作用

目的 观察软脉灵对自发性高血压大鼠(SHR)心肌纤维化的影响.方法 选择12周龄雄性SHR 36只,随机分为4组,软脉灵大剂量和小剂量组、空白组、阳性对照组.血压正常的京都Wistar大鼠(WKY)为正常对照组(WKY组).治疗前及治疗12周后用尾袖法测定动脉血压,称重后处死,取心脏,计算左心室重量与体重比(LVM/BW),天狼星红染色,计算心肌胶原容积分数.结果 软脉灵大剂量、小剂量组治疗12周后,收缩压(SBP)均显著低于空白组(P<0.01).与空白组相比,软脉灵大剂量组对SHR心肌外斜层纤维化有明显抑制作用(P<0.01),而软脉灵小剂量组则无影响;与空白组相比,软脉灵大剂量和小剂量组对SHR心肌中环层纤维化及心肌血管周围纤维化均有明显抑制作用(P<0.01).结论 软脉灵可以抑制SHR血压的发展,抑制SHR的心肌纤维化.     

长期芦沙坦治疗对自发性高血压大鼠心肌间质的影响

目的 :确定长期芦沙坦治疗能否逆转自发性高血压大鼠(SHR)心肌纤维化。方法 :本实验选用 33周龄Wistar Kyoto(WKY)大鼠 8只 ,SHR未用药组 6只 ,SHR用药组 6只 (已口服 17周芦沙坦 30mg/kg/d)。大鼠断头处死 ,取出心脏标本进行检测。血压、心脏重量、左心室重量、左心室重量指数测定用常规方法。纤维胶原用左心室心肌组织切片行VanGieson染色 ,图象用真彩色图象分析系统计算左室胶原容积分数 ,进行定量评估。免疫组化染色左心室心肌组织切片Ⅲ型胶原 ,用记分法进行半定量分析。电镜观察左心室心肌间质形态学变化。用 3× 10 0 0放大比例计算每个视野成纤维细胞数 ,每个标本随机取 10个视野 ,比较各组间成纤维细胞数的差异。结果 :与WKY组大鼠相比较 ,SHR存在高血压、心肌肥大、左心室胶原容积分数增加。免疫组化分析左心室Ⅲ型胶原增加 ,电镜观察成纤维细胞数增加 ,有统计学显著性差异。与SHR组相比 ,SHR用药组高血压、左心室重量、左心室胶原容积分数降低。免疫组化分析左心室Ⅲ型胶原减少。但成纤维细胞数无明显变化。结论 :芦沙坦在逆转自发性高血压大鼠心肌肥大 ,同时能减少基质胶原沉积。但电镜形态学观察 ,不能抑制成纤维细胞增殖。     

Interrelationships between Salt and Fish Oil in Stroke-Prone Spontaneously Hypertensive Rat

Vaskonen T, Laakso J, Mervaala E, Sievi E, Karppanen H. Interrelationships between salt and fish oil in stroke-prone spontaneously hypertensive rat.

The cardiovascular effects of a partially purified extract of fish oil, enriched in the n-3 series fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), were studied in stroke-prone spontaneously hypertensive rats (SHR-SP) fed with high- and low-sodium diets during 5 weeks. Addition of salt to the low-salt control diet at a level commonly found in human food items (6% NaCl of the dry weight of the diet) produced a remarkable rise in blood pressure, an increase in left ventricular weight-to-body weight ratio (LVH-index) and an increase in kidney weight-to-body weight ratio (RH-index). Fish oil (20% of the dry weight of the diet) did not significantly influence the blood pressure or LVH-index or RH-index during the low-salt control diet. However, fish oil completely prevented the remarkable rise in blood pressure and clearly antagonized the rise of both LVH- and RH-indices, induced by the high-salt diet. The fish oil supplementation increased the levels of the polyunsaturated fatty acids of the n-3 series and decreased those of the n-6 series in plasma and kidney, irrespective of the salt content of the diet. Fish oil lowered serum thromboxane B₂ concentration by approximately 75%. During the high-salt diet, fish oil markedly decreased water intake and urine volume, and increased urinary sodium concentration by about 60%. Our findings show that, in addition to an antihypertensive effect, fish oil also decreases LVH and RH. These effects appear to be due to an improved ability to excrete sodium and could be explained by the observed changes in the fatty acid composition and metabolism.     

Modulation of the Effect of Endothelin-3 on Blood Pressure by Atrial Natriuretic Peptide in Conscious Spontaneously Hypertensive (SHR) and Normotensive (WKY) Rats

Endothelin (ET) exerts direct vasoconstrictory effects and stimulates release of vasoactive substances. It has been demonstrated that ET stimulates the release of atrial natriuretic peptide (ANP) both under in vitro and in vivo conditions. The present study aimed at elucidating whether the cardiovascular effects of endothelin-3 (ET-3) in normotensive (WKY) and spontaneously hypertensive (SHR) rats are modulated by ANP. The experiments were performed on 17 conscious WKY and 17 SHR rats. The effects of i.v. administration of 1 μg of ET-3 on blood pressure (BP) and heart rate (HR) were investigated under control conditions and during ANP infusion (0.3 μg/kg/min). In both strains ET-3 elicited a transient significant hypotensive effect followed by an increase in BP. BP fall was significantly greater and pressor effect significantly smaller in SHR than in WKY. In WKY, but not in SHR rats, both hypotensive and pressor phases were significantly attenuated during ANP administration. The results are evidence of differential involvement of endogenous blood pressure regulating factors in the cardiovascular effects of ET-3 in WKY and SHR rats during ANP infusion.     

苯那普利对SHR大鼠左心室细胞外基质的影响

目的：探讨苯那普利（一种血管紧张素转换酶抑制剂）是否具有将自发性高血压大鼠（ＳＨＲ）左心室肥厚（ＬＶＨ）时增生的胶原和其它细胞外基质成份恢复到正常水平的作用。方法：６周龄的性ＳＨＲ给予口服苯那普利（１０ｍｇ．ｋｇ＾－１．ｄ＾－１）１６周,性别、年龄配对的ＳＨＲ和Ｗｉｓｔａｒ－Ｋｙｏｔｏ（ＷＫＹ）大鼠作为对照。测量血压、体重、左心室肥厚的指标,采用免疫组化方法作纤维粘连蛋白（ＦＮ）、层粘连蛋白（ＬＮ     

Effect of Long-Term Treatment with Diltiazem on Atrial Natriuretic Peptides in Spontaneously Hypertensive Rats

ABSTRACT

The present study was designed to examine the possible effect of long-term treatment with diltiazem on plasma and atrial concentrations of atrial natriuretic peptides (ANP) in spontaneously hypertensive rats (SHR). Diltiazem treatment reduced blood pressure and ventricular weight in SHR. Plasma ANP concentration in untreated SHR was higher than Wistar-Kyoto rats (WKY). Diltiazem treatment decreased plasma ANP concentration in SHR near to the level of WKY; moreover, plasma ANP concentration was correlated with blood pressure and ventricular weight in treated and untreated SHR. Left atrial ANP concentration in untreated SHR was lower than WKY. Diltiazem treatment increased left atrial ANP concentration in SHR, but this effect was not noted in WKY. These results suggest that the ANP release from the left atrium is chronically stimulated in adult SHR, and that the prevention of an increase in plasma ANP by diltiazem treatment may be, in part, attributed to the improvement of cardiac overload induced by reductions in blood pressure and cardiac hypertrophy.     

Neuropeptide Abnormalities Suggest a Dopaminergic Basis for High Blood Pressure in the Spontaneously Hypertensive Rat

The spontaneously hypertensive rat (SHR) and the stroke-prone substrain (sp-SHR) have been reported to have several abnormalities in levels of peptides both in tissue and in plasma (β- endorphin, prolactin, thyroid stimulating hormone and vasopressin) when compared to the Wistar Kyoto (WKY) normotensive control rat. As the secretion of these peptides is under dopaminergic control and the abnormalities consistently suggest under-activity of the dopaminergic control system in the brain, injections of dopamine (0.4 mg/kg) were given i.c.v. to 10 SHR, 10 renal artery stenosis hypertensive rats (LRAS) and 10 genetically hypertensive rats of the New Zealand strain (GHR). Mean blood pressure fell from 205±6(SEM) mmHg to 128±8 mmHg in the SHR (p<0.001), from 184±7 mmHg to 176±7 mmHg in the LRAS (p>0.05) and from 157±5 mmHg to 138±6 mmHg in the GHR (p<0.02). These effects were unlikely to be due to leakage of dopamine out into the periphery as i.v. dopamine (0.4 mg/kg) increased blood pressure in these animals.     

Exaggerated Hypotensive Responses to Calcium Antagonists in Spontaneously Hypertensive Rats

The hypotensive effects of intravenous injection and infusion of diltiazem, 1- and d-verapamil were investigated in conscious and anaesthetized rats with spontaneous hypertension (SHR) and normal blood pressure (NT-WKY). The inhibitory actions of these calcium-influx blockers on the pressor responses to angiotensin II (AII) and noradrenaline (NA) were also examined in anaesthetized SHR and NT-WKY. The intravenous injections of these three drugs (0.03, 0.1, 0.3, 1.0 mg/kg) lowered mean arterial pressure (MAP) in a dose related manner in conscious NT-WKY and SHR. The small dose of the blockers administered by intravenous infusion (0.02 mg/kg per min) also decreased MAP in both groups. The potency of the antihypertensive action was in the order 1-verapamil>d-verapamil=diltiazem. The fall in blood pressure expressed as percentage of the intial MAP produced by the compounds was significantly enhanced in SHR compared to NT-WKY. The pressor responses to All (0.03, 0.1, 0.3, 1.0 ug/kg i.v.) were suppressed by the intravenous infusinon of 20 ug/kg per min with 1-verapamil but not with d-veramil, diltiazem and vehicle in NT-WKY, while no calcium blocker significantly diminished the vasopressor action of All in SHR. The pressor effects of NA (0.3, 1.0, 10.0 ug/kg i.v.) were inhibited with d-verapamil and vehicle in NT-WKY. Diltiazem reduced the response to NA in SHR but the other compounds (and d-verapamil) did not alter the pressor response to NA in SHR. The pressor responses to arginine vasopressin (3, 10, 30 and 100 mU/kg i.v.) were not altered by diltiazem infusion in either SHR or NT-WKY. It is concluded that these compounds are different in the potency of their hypotensive action and also the inhibition of the pressor responses to All and NA. Calcium entry blockers are more effective antihypertensive agents in SHR than in NT-WKY. It appears that their inhibitory effects on the responses to All and NA do not explain the exaggerated hypotensive responses in SHR.     

自发性高血压大鼠左心室流出道自发性电活动的特征

利用玻璃微电极细胞内记录方法 ,记录了自发性高血压大鼠 (SHR)和Wistar鼠左心室流出道自发性慢电位和自发性快电位的特征。结果发现 ,SHR自发性快电位的动作电位时程 (APD)、复极至 5 0 %时间 (APD50 )和复极至 90 %的时间 (APD90 )均明显长于Wistar鼠 (P <0 0 1) ;SHR的自发放电频率 (RPF)明显慢于Wistar鼠 (P <0 0 5 )。结果提示 :SHR左心室流出道自发性的快电位和慢电位均表现为APD、APD50 和APD90 的延长 ,RPF减慢     

The Role of Calmodulin in Neurotransmitter Release and Vascular Responsiveness in Spontaneously Hypertensive Rats

ABSTRACT

This study was designed to investigate the role of calmodulin in adrenergic transmission in hypertension. In perfused mesenteric vasculature: from spontaneously hypertensive rats(SHR, 7-9 weeks of age) and age-matched Wistar Kyoto rats(WKY), the effects of a specific calmodulin antagonist(W-7) on norepinephrine overflow and vascular responsiveness to endogenous and exogenous norepinephrine were examined.

The vasoconstrictor responses to electrical nerve stimulation and exogenous norepinephrine as well as norepinephrine overflow during electrical nerve stimulation were significantly enhanced in SHR compared with those in age-matched WKY. The calmodulin antagonist, W-7, reduced not only vasoconstrictor responses but also norepinephrine overflow during nerve stimulation. These inhibitory effects of W-7 were significantly greater in SHR than in WKY.

The results demonstrate that norepinephrine overflow from the sympathetic nerve endings and vascular responsiveness were increased in SHR. The marked reduction in norepinephrine overflow and pressor responses by W-7 might suggest the greater calmodulin-dependent adrenergic transmission in this model of hypertension.     

In Vivo Potentiation of Vasopressors By Spontaneously Hypertensive Rat Plasma: Correlation with Blood Pressure and Calcium Uptake

Previous studies have shown that plasma from Spontaneously Hypertensive Rats (SHR) can potentiate the action of various vasopressors. Recently, we described a novel circulating hypertensive factor in the plasma of SHR rats which increases calcium uptake in vascular smooth muscle. In order to determine whether this factor might be responsible for the previously described pressor potentiation, the effect of dialyzed SHR plasma on the in vivo sensitivity of normotensive rats to norepinephrine, angiotensin II and arginine vasopressin was examined. Results of this study showed that SHR plasma potentiated the effects of all three pressor agents with peak potentiation occurring approximately 45-60 min post-plasma injection. The time course of pressor potentiation was similar to those for the hypertensive and cellular calcium effects of the plasma. These results suggest that a single factor may be responsible for the hypertensive, calcemic and pressor-potentiating effects of SHR plasma.     

丹参预防自发性高血压大鼠左心室肥厚

目的　观察丹参对自发性高血压大鼠左室肥厚的作用。方法　 18只 8周龄的自发性高血压大鼠随机分成 3组 :一组于 8周处死 ,另两组分别经腹腔注射丹参和蒸馏水 (1g/kg·d) ,共 10周。测量大鼠尾动脉收缩压 (SBP)及左心室重量指数 (LVMI)。应用HE、VG染色 ,结合计算机图像分析技术 ,检测心肌细胞的直径 (TDM)、面积 (CA)、心肌组织胶原体积比例 (CVF)、血管周围胶原面积和管腔面积比例 (PVCA)。结果　与 8周龄的自发性高血压大鼠相比 ,18周龄大鼠的SBP、LVMI、心肌细胞的直径、面积、CVF、PVCA显著增加 (P <0 0 1) ,丹参治疗组大鼠反映左室肥厚的各项指标上升不明显 (P >0 0 5 ) ,但收缩压仍显著升高 (P <0 0 1)。结论　长期应用丹参治疗可预防自发性高血压大鼠左室肥厚的形成。