[Study on therapeutic effect and its related mechanism of anemoside B4 on ischemia reperfusion injury induced by renal artery and vein ligation in rats].

The aim of this paper was to investigate the effect and mechanism of anemoside B4 on renal ischemia reperfusion injury in rats. A total of 50 rats were randomly divided into the model group(NS) and anemoside B4 low-dose(1.25 mg·kg~(-1)), medium-dose(2.5 mg·kg~(-1)) and high-dose(5 mg·kg~(-1)) groups after the right kidney was removed and the left kidney was ligated to make the ischemia reperfusion model. Another 10 rats were selected as sham operation group only for normal control group(NS, received normal saline). Automatic biochemical analyzer was used to measure serum blood urea nitrogen(BUN), creatinine(Cre), cerebrospinal fluid(CSF) and urinemicroalbumin(mALB) levels after 5 days of tail vein injection treament. Total urine protein and total urinary albu-min were calculated and kidney samples were collected. Histopathological changes of renal tissues were observed by PAS staining. Western blot analysis was performed to detect the protein expressions of TLR4 and NF-κB in renal inflammatory factors related to NLRP3 pathway and TLR4/NF-κB pathway. The results showed that the levels of BUN, Cre, urinary total protein and urinary total albumin in the model group were significantly increased(P<0.01), with severe renal tubule injury was serious, manifested by obvious expansion of renal tubules, more serious tubular proteins, and some tubular epithelial cells were exfoliated. At the same time, the expression of inflammatory factors related to NLRP3 pathway and TLR4/NF-κB pathway increased significantly(P<0.01 or P<0.05). The levels of BUN, Cre were reduced in different doses of anemoside B4(P<0.05). The levels of total urinary protein and total urinary albumin were decreased in the low and high dose groups of anemoside B4.The level of total urinary albumin in the high-dose group of anemoside B4 was significantly reduced(P<0.05).Renal tubular injury was alleviated, tubular epithelial cell exfoliation was reduced, and the expression of related inflammatory factors was reduced in different degrees(P<0.01 or P<0.05). This study showed that anemoside B4 could alleviate renal ischemia-reperfusion injury in rats. And its mechanism may be related to the inhibition of inflammatory factors related to response mediated by NLRP3 pathway and TLR4/NF-κB pathway by anemoside B4.

Embolic effects of Bletilla striata microspheres in renal artery and transplanted VX2 liver tumor model in rabbits.

OBJECTIVES: To evaluate the characteristics of Bletilla striata microspheres (BSMs) and its effects as an embolic agent in a rabbit model. METHODS: BSMs were prepared with an emulsification-cool condensation-chemical cross-linking method. The characteristics of BSMs in vitro were observed. Embolization experiments were performed in renal artery of rabbit and in a rabbit liver VX2 carcinoma model. Seventy-two New Zealand rabbits were divided into 2 groups, and the right renal artery was embolized with BSMs (200 µm in diameter) in the experimental group and with polyvinyl alcohol (PVA) of the same size in the control group. The pathological findings were examined with hematoxylin-eosin and Masson stainings. Liver and renal functions were tested before and after embolization. VX2 tumor was transplanted in 15 New Zealand rabbits, which were randomly divided into 3 groups (n=5). Group A were treated with saline, group B with a mixture of doxorubicin and lipiodol, and group C with hepatic arterial infusion of BSMs (200 µm in diameter). Tumor growth rate was evaluated by magnetic resonance imaging scan. Apoptosis-related factors (bax, bcl-2) and tumor vascular endothelial cell growth factor (VEGF) were evaluated through immunohistochemical staining. RESULTS: The characteristics of BSMs in vitro were in full compliance with the requirements for use in interventional procedures. In the renal artery embolization experiment, after BSMs intervention, it was more difficult to form collateral circulation than that with PVAs, and the kidney manifested atrophy and calcification. There were no significant difference of liver and renal functions in rabbits between groups. In the liver VX2 carcinoma embolization experiment, compared with group A, the growth rate of VX2 liver tumor and Bcl-2 levels was reduced, while apoptosis index, Bax, and VEGF were increased in group B (P<0.05). There were no significant difference between groups B and C (P>0.05). CONCLUSIONS: The characteristics of BSMs in vitro and in vivo meet the requirements for its use as an embolic agent in interventional approaches.

Protective Effects of the Segmental Renal Artery Clamping Technique on Ischemia-Reperfusion Injury in db/db Diabetic Mice.

Renal ischemia-reperfusion (I/R) injury is inevitable in partial nephrectomy and other kidney surgeries, with a higher incidence in patients with renal insufficiency. This study aimed to investigate the protective effects of precise segmental renal artery clamping (SRAC) against renal I/R injury in db/db diabetic mice, compared with conventional renal artery clamping (RAC). Grape seed extract, a powerful free radical scavenger, was administered to diabetic mice for 4 weeks before operation in subgroups (30 mg/kg/d). The unilateral renal pedicle was ligatured, and I/R injury to the contralateral kidney was induced (ischemia for 30 min followed by reperfusion for 24 h). Blood glucose value, creatinine, blood urea nitrogen, and urine microalbumin/urine creatinine ratio increased gradually and showed no preoperative statistical differences among six subgroups. These parameters were significantly lower in the SRAC than in the RAC group 24 h postoperatively. Moreover, the nonischemic area in the SRAC group expressed less KIM-1 and TNF-α mRNA and also revealed minor histopathological damage induced by I/R. These findings suggest that SRAC effectively reduces early renal injury induced by I/R and accelerates the recovery of renal function in diabetic mice. Thus, SRAC may be an ideal technique in partial nephrectomy, especially for patients with diabetic nephropathy and other renal insufficiencies.

Potential of renal pathology on refining syndrome typing of Chinese medicine in IgA nephropathy.

OBJECTIVE: To investigate the potential of renal pathological index as a differential diagnosis factor for Chinese medicine (CM) syndromes typing in IgA nephropathy (IgAN). METHODS: A total of 1,016 patients with IgAN was recruited from November 2001 to November 2004. All the signs and symptoms including picture of the tongue and pulse tracings were collected. All patients were typed according to the CM syndrome typing scheme for chronic primary glomerulopathy. The severity of glomerulus and tubulointerstitial lesions (mild, moderate-severe) were evaluated using lee's grading system and the Katafuchi score system. RESULTS: The syndrome types transform in turn by deficiency of both the Spleen (Pi) and Lung (Fei) qi, deficiency of both qi and yin, deficiency of Liver (Gan) and Kidney (Shen) yin and deficiency of Spleen-Kidney (Shen) yang, with the aggravation of pathogenetic condition and that the manifestation of deficiency of qi clinically showed proliferative lesion of glomerular mesangium, while the glomerular sclerosis pathologically showed the manifestation of yin deficiency. CONCLUSION: Renal pathological findings may be a candidate of objective factors to refine CM syndrome typing process.

Polyarteritis nodosa with multiple aneurysms and renal arteriovenous fistula successfully diagnosed by colour Doppler sonography.

Polyarteritis nodosa (PAN) is a vasculitis that typically affects small- and middle-sized arteries of multiple organs. The kidney is most commonly involved. To date, few cases of PAN involving the celiac artery and no cases of iliac artery or internal carotid artery involvement have been published. The most frequent lesions reported were due to occlusions and aneurysms. Finally, no cases of PAN causing arteriovenous fistula have been reported. Here we present a case of PAN with multiple aneurysms and renal arteriovenous fistula that was successfully diagnosed and followed-up by ultrasound. This case report describes the challenges in diagnosing PAN and highlights the importance of a holistic approach when encountering patients with multiple vascular diseases. Ultrasound should be considered the first-line approach in the diagnosis of PAN.

Pure ethiodized oil as a capillary embolic agent with and without ethanol-ethiodol mixture in the rabbit kidney: embolic efficacy and temporal histopathologic findings.

PURPOSE: To determine the extent of ablation and the temporal histopathologic findings associated with selective arterial injection of pure Ethiodol in the normal rabbit kidney, with or without arterial occlusion of the main renal artery. MATERIALS AND METHODS: In 19 rabbits, 27 kidneys were embolized by injecting 0.6 mL of pure Ethiodol into the main renal artery to achieve capillary stasis. A 9:1 ethanol-ethiodized oil mixture was then injected into 17 of the 27 kidneys until complete arterial stasis was accomplished. Macro- and microscopic evaluation was performed 10 minutes to 6 weeks and 60 minutes to 1 week, respectively, for kidneys with and without arterial occlusion. RESULTS: Ethiodol followed by ethanol-Ethiodol mixture (mean +/- standard deviation, 0.37 mL +/- 0.03) caused complete and permanent arterial stasis in all 17 kidneys. Thrombosis of the large arteries occurred initially. Ischemic coagulative necrosis of renal tubules and damage to glomeruli were detected 2 hours after embolization. Within 24 hours, the glomeruli and most tubules of the cortex and medulla were necrotic. Without arterial occlusion, the arteriocapillary bed of the kidneys was completely patent, with normal contrast medium excretion. Ethiodol was observed in glomeruli and interstitial capillaries from 60 minutes to 1 week and caused mild acute glomerulitis from day 1. The lesions were confined to the glomeruli, and no significant parenchymal changes were observed. CONCLUSIONS: In the rabbit, selective arterial injection of pure Ethiodol produces complete renal ablation within 24 hours if prompt and permanent occlusion of the arterial compartment guarantees its permanent capillary retention.

Tetrahydrobiopterin protects the kidney from ischemia-reperfusion injury.

Tetrahydrobiopterin (BH4) is an essential cofactor for the nitric oxide (NO) synthases and represents a critical determinant of NO production. BH4 depletion during ischemia leads to the uncoupling of the synthases, thus contributing to reperfusion injury due to increased superoxide formation. To examine whether BH4 supplementation attenuates ischemia-reperfusion injury, we clamped the left renal arteries of male Lewis rats immediately following right-side nephrectomy. BH4 tissue levels significantly decreased after 45 min of warm ischemia compared with levels in non-ischemic controls. Histopathology demonstrated significant tubular damage and increased peroxynitrite formation. Intravital fluorescent microscopy found perfusion deficits in the microvasculature and leakage of the capillary mesh. Supplemental BH4 treatment before ischemia significantly reduced ischemia-induced renal dysfunction, and decreased tubular histologic injury scores and peroxynitrite generation. BH4 also significantly improved microcirculatory parameters such as functional capillary density and diameter. These protective effects of BH4 on microvasculature were significantly correlated with its ability to abolish peroxynitrite formation. We suggest that BH4 significantly protects against acute renal failure following ischemia reperfusion. Whether BH4 has a therapeutic potential will require more direct testing in humans.

Correlación arteriográfica en 30 pacientes con patología vascular renal diagnosticada mediante TC multicorte / Arteriographic correlation in 30 patients with renal vascular disease diagnosed with multislice CT

Objetivo. Determinar la utilidad de la tomografía computarizada multicorte (TCMC) en la valoración de la patología arterial renal, tomando como patrón oro la angiografía con sustracción digital (ASD). Material y métodos. Se evalúan 30 pacientes con hipertensión arterial o insuficiencia renal, a los que se había realizado una TCMC para descartar etiología vascular de su padecimiento, y en los que ante sospecha de la misma, se practicó una ASD de confirmación diagnóstica. Las TCMC se realizaron en un equipo de 10 detectores, con administración intravenosa de 80 ml de contraste yodado (300 mg de yodo/ml) a flujo de 5 ml/s. Se valoraron 71 arterias renales, 56 principales y 15 accesorias. Las estenosis arteriales se clasificaron para su evaluación en: grado 0 (arteria normal), grado I (estenosis < 50%), grado II (>= 50%, pero < 70%), grado III (>= 70%), grado IV (oclusión). Las estenosis de grado II o superior se consideraron hemodinámicamente significativas. Resultados. En 56 arterias renales (78,8%) se realizó una valoración idéntica en TCMC y ASD. En 13 casos (18,3%) la TCMC sobrevaloró el grado de estenosis. Todas las estenosis de grado III fueron detectadas con TCMC. En el diagnóstico de las estenosis hemodinámicamente significativas la TCMC demostró sensibilidad del 96,5%, especificidad del 78,5%, exactitud del 85,9%, valor predictivo positivo del 75,6% y negativo del 97%. Conclusiones. La TCMC es un buen método de imagen no invasivo en la evaluación de los vasos renales, y resulta útil en el cribado de los pacientes con patología nefrológica en los que se busca descartar una etiología vascular potencialmente tratable (AU)

Objective. To determine the usefulness of multislice computed tomography (MSCT) in the evaluation of renal vascular disease against a gold standard of digital subtraction angio -graphy (DSA). Material and methods. We evaluated 30 patients with arterial hypertension and/or kidney failure that underwent MSCT to rule out a vascular cause and DSA to confirm a vascular cause suspected at MSCT. MSCT examinations were performed on a 10-detector scanner with intravenous administration of 80 ml of iodinated contrast (300 mg iodine/ml) at a flow rate of 5 ml/s. A total of 71 renal arteries, 56 main and 15 accessory, were evaluated. Arterial stenoses were classified as: grade 0 (normal artery), grade I (stenosis < 50%), grade II (>= 50% and < 70%), grade III (>= 70%), grade IV (occlusion). Stenosis >= grade II was considered hemodynamically significant. Results. The findings at MSCT and DSA were identical in 56 (78.8%) renal arteries; MSCT overestimated the degree of stenosis in 13 (18.3%) cases. All grade III stenoses were detected at MSCT. In the diagnosis of hemodynamically significant stenosis, MSCT had a sensitivity of 96.5%, specificity 78.5%, accuracy 85.9%, positive predictive value 75.6%, and negative predictive value 97%. Conclusions. MSCT is a good noninvasive imaging technique for the evaluation of renal vessels; it is useful for screening patients with kidney disease to rule out potentially treatable vascular causes (AU)

Regional Brazilian diet-induced pre-natal malnutrition in rats is correlated with the proliferation of cultured vascular smooth muscle cells.

OBJECTIVES: Pre-natal malnutrition induces hypertension and insulin resistance, pathologies commonly linked to atherosclerotic disease. The proliferation of vascular smooth muscle cells (SMCs) is important during development of the atherosclerotic plaque. In this work, we investigated whether the serum of pre-natal malnourished Wistar rats could alter the proliferation of aortic and renal artery SMCs in culture. Malnutrition was induced by feeding a basic regional diet available in a rural area of Pernambuco State, Brazil. This diet was rich in carbohydrates and deficient in proteins, lipids, vitamins and minerals, including sodium chloride. METHODS AND RESULTS: Serum was obtained from the blood of 90-day-old control and pre-natal undernourished rats. SMCs from control Wistar rats at the 6th passage were allowed to adhere to plates in Dulbecco's modified Eagle's medium (DMEM) supplemented with fetal calf serum (10%). Subsequently, the SMCs were maintained in DMEM supplemented with rat serum (10%). The number of cells was counted on the 3rd, 6th and 8th days of culture into rat serum. [3H]-thymidine incorporation into SMCs was evaluated after 20 h or 6 days of incubation. The birth weight of male and female undernourished offspring was 25% (p<0.05) and 46% (p<0.05) lower, respectively, than their corresponding control groups. On the 8th day of culture, the number of aortic SMCs in the serum of undernourished male and female rats, as well as renal artery SMCs in the serum of undernourished female rats, was higher than in the serum of control rats. The [3H]-thymidine incorporation was higher in aortic SMCs incubated for 6 days in the serum of undernourished male and female rats. At confluence, the density of aortic SMCs was higher than that of renal artery SMCs. CONCLUSIONS: Pre-natal malnutrition produces serum with altered properties that can affect the proliferation of SMCs and may contribute to atherosclerotic disease.

Cognitive dysfunction in cholesterol embolic disease.

A patient who developed neurological and renal complications following coronary angiogram and coronary artery bypass grafting is reported. Neurological involvement was in the form of fluctuating sensorium and a subcortical pattern of dementia. Renal failure was seen in the form of raised urea and creatinine levels. Renal biopsy revealed the cause of the renal failure to be due to cholesterol embolic disease. While the sensorium often improved following renal replacement therapy (dialysis), the dementia was poorly responsive to therapy. The patient succumbed due to progressive renal failure. Awareness of the protean manifestations and a high index of suspicion are essential for appropriate diagnosis in order to enable the clinician to accurately prognosticate in this often fatal disease.

Ethiodized oil-ethanol capillary embolization in rabbit kidneys: temporal histopathologic findings.

PURPOSE: To determine the temporal histopathologic findings associated with selective arterial injection of a 1:1 ethiodized oil-ethanol mixture (EEM) in normal rabbit kidney followed by administration of pure ethanol into the main renal artery. MATERIALS AND METHODS: In five rabbits, the EEM was injected sequentially into each segmental renal artery of the right kidney until capillary stasis occurred. Pure ethanol was then injected into the main renal artery to achieve complete arterial stasis. Before sacrifice, the left kidney in each animal was acutely (ie, with a short follow-up period) embolized by using the same technique. The 10 kidneys of the five rabbits were evaluated microscopically at 1 (n = 3), 1(1/2) (n = 1), and 3 hours (n = 1) and 1 (n = 1), 3 (n = 1), 5 (n = 1), 7 (n = 1), and 14 days (n = 1) after embolization. RESULTS: Injection of the EEM (mean volume, 0.46 mL +/- 0.14 [SD]) followed by ethanol alone (mean volume, 0.25 mL +/- 0.09) led to complete stasis in all kidneys. There was no recanalization in the chronically (ie, with a longer follow-up period) embolized kidneys. Microscopically, uniform distribution of the EEM was evident in all slices at all time points. From 1 to 3 hours, sloughing of endothelium, formation of thrombi, and deposition of eosinophilic material along the renal, interlobar, and arcuate arteries were observed, without evidence of parenchymal damage. Within 24 hours, complete coagulative necrosis of the entire kidney occurred as a result of an occluding thrombus in the main renal artery. Analysis at subsequent time points revealed liquefaction of necrotic tissue and replacement with granulation tissue. CONCLUSION: In the rabbit, selective renal arterial injection of EEM followed by administration of ethanol produces vascular endothelial damage initiating thrombosis that results in renal infarction and ablation within 24 hours.

Selenium-deficient diet induces renal oxidative stress and injury via TGF-beta1 in normal and diabetic rats.

BACKGROUND: Oxidative stress has been implicated in the pathogenesis of diabetic nephropathy. Although glucose itself can initiate oxidative stress, deficiency of essential trace elements such as selenium (Se) may exacerbate this oxidative stress in diabetic rats. The mechanism by which Se deficiency causes oxidative stress and renal injury is not completely understood. This study tested the hypothesis that Se deficiency induces renal oxidative stress and renal injury via transforming growth factor-beta1 (TGF-beta1). METHODS: Fifty-four male Wistar rats were used. Diabetes was induced in 27 rats by streptozotocin, and the other 27 rats received buffer only. Ten weeks after induction of diabetes, both normal and diabetic rats were killed, their kidneys removed, and glomeruli were isolated. Glomeruli from normal and diabetic rats were incubated in the presence of TGF-beta1 alone or its neutralizing antibody. Antioxidant enzyme (Cu-Zn) superoxide dismutase (Cu-Zn SOD), catalase, and glutathione peroxidase (GSH-Px) activities; total glutathione; and lipid peroxidation were determined. For Se studies, 15 normal and 15 diabetic rats were divided into groups of five each and fed either a regular, Se-deficient, or Se-supplemented diet one week after induction of diabetes. Ten weeks after feeding these diets, rats were killed and glomeruli were isolated. Oxidative stress was examined by determining the mRNA expressions for antioxidant enzymes and also for TGF-beta1. Plasma glucose and albuminuria were determined. Histology of the kidney and interlobular artery was evaluated by light microscopy. RESULTS: In vitro studies showed that TGF-beta1 significantly reduced glomerular catalase and GSH-Px activities as well as total glutathione levels with an increase in lipid peroxidation in both normal and diabetic rats. Antibody to TGF-beta abrogated these changes. There was no effect of TGF-beta1 on Cu-Zn SOD. Like TGF-beta1, a Se-deficient diet caused a significant decrease in glomerular mRNA expression for Cu-Zn SOD, catalase, and GSH-Px, but a significant increase in TGF-beta1 mRNA expression. Also, a Se-deficient diet caused an increase in albuminuria, glomerular sclerosis, and plasma glucose levels in both normal and diabetic rats. The deficient diet caused a decrease in the lumen size of the interlobular artery. Se supplementation to diabetic rats up-regulated mRNA expression for antioxidant enzymes, and significantly reduced but did not normalize that of TGF-beta1. Glomerular sclerosis was normalized and the interlobular artery lumen size was greatly enlarged in diabetic rats by Se supplementation. Also, the tubulointerstitium was preserved by Se supplementation in diabetic rats. CONCLUSIONS: The data show that TGF-beta1 is a pro-oxidant and Se deficiency increases oxidative stress via this growth factor. In addition, Se deficiency may simulate hyperglycemic conditions. Se supplementation to diabetic rats prevents not only oxidative stress but renal structural injury, as well.

Regression of renal vascular fibrosis by endothelin receptor antagonism.

In previous studies, we have observed that endothelin participates in the progression of renal vascular and glomerular fibrosis during hypertension by activating collagen I gene synthesis. The present study investigated whether administration of endothelin receptor antagonists leads to the regression of renal sclerotic lesions. Experiments were performed in transgenic mice harboring the luciferase gene under the control of the collagen I-alpha2 chain promoter. Hypertension was induced by long-term inhibition of nitric oxide synthesis by N(G)-nitro-L-arginine methyl ester (L-NAME); systolic pressure gradually increased, reaching a plateau of 165 mm Hg after 10 weeks of hypertensive treatment. At the same time, collagen I gene expression was increased 2- and 5-fold compared with control animals in afferent arterioles and glomeruli, respectively (P<0.01). This increase was accompanied by the appearance of sclerotic lesions within the renal vasculature. When renal vascular lesions had been established (20 weeks of L-NAME), animals were divided into 2 subgroups: the one continued to receive L-NAME, whereas in the other, bosentan, a dual endothelin antagonist, was coadministered with L-NAME for an additional period of 10 weeks. Bosentan coadministration did not alter the increased systolic pressure at 30 weeks; in contrast, collagen I gene activity returned almost to control levels in renal vessels and glomeruli. In this subgroup of animals, renal vascular lesions (collagen and/or extracellular matrix deposition) and mortality rates were substantially reduced compared with untreated mice. These data indicate that endothelin participates in the mechanism(s) of renal vascular fibrosis by activating collagen I gene. Treatment with an endothelin antagonist normalizes expression of collagen I gene and leads to the regression of renal vascular fibrosis and to the improvement of survival, thus providing a complementary curative approach against renal fibrotic complications associated with hypertension.

Hypertension and endothelial dysfunction in apolipoprotein E knockout mice.

Mice lacking ApoE (Apoe(-/-)) develop initially hypercholesterolemia and lastly atherosclerosis. This study examined hemodynamics and endothelial function in 6-week-old Apoe(-/-) mice with hypercholesterolemia only, 7.5-months-old Apoe(-/-) mice with both hypercholesterolemia and atherosclerosis, and age matched controls. One day after implantation of catheters into the carotid artery, arterial pressure was measured in conscious, unrestrained mice. Compared with the respective controls, there was a significant increase in arterial pressure and the ratio of left ventricular weight to body weight in 7.5-month-old Apoe(-/-) mice but not in 6-week-old Apoe(-/-) mice. Histopathological analysis demonstrated significant renal artery disease in the form of extensive atheromatous plaques only in 7.5-month-old Apoe(-/-) mice, whereas no atherosclerotic lesions were found in 6-week-old Apoe(-/-) mice. For evaluation of endothelial function, a laser Doppler perfusion imager with a computer-controlled optical scanner was used to measure cutaneous blood perfusion on the dorsal side of one hind paw before and after topical application of mustard oil, which is known to induce nitric oxide-mediated vasodilation. The mustard oil treatment elicited a substantial increase in blood perfusion (P<0.01), which was similar between 6-week-old Apoe(-/-) mice and controls but significantly blunted in 7.5-month-old Apoe(-/-) mice versus control mice, suggesting nitric oxide-mediated vasodilation is diminished in 7.5-month-old Apoe(-/-) mice but not in 6-week-old Apoe(-/-) mice. In contrast, the increase in blood perfusion induced by topical administration of cilostazol, which induces vasodilation via cyclic adenosine monophosphate, was not different between 7.5-month-old Apoe(-/-) mice and controls. Thus hypertension and endothelial dysfunction observed in 7.5-month-old Apoe(-/-) mice may be due mainly to atherosclerosis.

Effect of AT1 angiotensin-receptor blockade on structure and function of small arteries in SHR.

The structure and function of small arteries of different vascular beds in spontaneously hypertensive rats (SHRs) are altered relative to Wistar-Kyoto (WKY) control rats, and these differences may be blunted under treatment with angiotensin-converting enzyme inhibitors. To determine whether this effect of angiotensin-converting enzyme inhibitors was caused by the interruption of the renin-angiotensin system, our experiments were conducted with an AT1 angiotensin-receptor antagonist to evaluate its ability to induce regression of hypertrophy of resistance arteries in SHRs. The result of treatment of SHRs with losartan, an orally active selective angiotensin AT1 receptor antagonist was examined at a low (20 mg/kg/day) and a high (60 mg/kg/day) oral dose in SHRs once blood pressure had been elevated for some time. SHRs were treated for 12 weeks with losartan. Blood pressure was significantly reduced by losartan treatment from 210 +/- 2 mm Hg in untreated SHRs to 181 +/- 1 mm Hg (low dose) and 156 +/- 4 mm Hg (high dose) (p < 0.01). Cardiac and aortic hypertrophy were dose-dependently reduced in treated SHRs. Coronary, renal, mesenteric, and femoral small arteries (luminal diameter, 200-250 microm) studied on an isometric wire myograph and pressurized mesenteric small arteries examined under isobaric conditions exhibited significant hypertrophy and inward remodeling in SHRs in comparison to WKY rats. Losartan treatment resulted in a dose-dependent reduction in the media thickness and mediato-lumen ratio in small arteries from the four vascular beds studied on the wire myograph and in pressurized mesenteric small arteries. Endothelium-dependent relaxation studied in pressurized arteries was enhanced, and acetylcholine-induced endothelium-dependent contractions studied on the wire myograph were abolished in losartan-treated SHRs relative to untreated SHRs. In WKY rats, treatment had no effect. These results demonstrate that treatment with the selective angiotensin II receptor antagonist losartan, even at doses that reduce blood pressure only moderately, induces regression of cardiovascular hypertrophy and of endothelial dysfunction in genetic hypertension in the rat.

[Captopril in improving vascular structure and lowering blood pressure].

SHRs were given captopril 20 mg/kg/day (group A, n = 13) and 100 mg/kg/day (group B, n = 17) from intrauterus period to 16 weeks of age, then the treatment was removed. Experiments were carried out at 40 weeks. SBP, left ventricular mass/body weight ratio, wall/lumen ratio of branch III mesenteric and renal artery were determined. The perfusion pressure response to alpha 1 adrenergic agonist (phenylephrine) of resistance blood vessels in a hindquarter model in the presence of Nw-nitro-1-arginine-methyl ester (LNAME) or L-arginine were examined. Untreated SHR (n = 16) and untreated WKY (n = 17) served as controls. Both doses of captopril treatment completely prevented hypertrophy of vascular vessels to some extent comparable to that of the untreated WKY. But their SBP was still significantly higher than that of the untreated WKY. The curves of perfusion pressure responding to incremental doses of phenylephrine shifted rightward in the captopril treatment groups in a dose dependent manner. The curves of high dose group were almost identical to those of WKY, markedly different from that of the untreated SHR. Captopril decreased the over enhanced vasoconstrictor effect of LNAME in SHR. The attenuated vasoconstrictor effect by L-arginine was greatly augmented by captopril, suggesting that captopril improves the function of resistance of vessels by mediating endothelial cells. Captopril-induced alteration in vascular structure and function may be separated from its hypotensive effect. Clinically, continuing administration of captopril may be beneficial to the improvement of the vascular system in those blood pressure unresponsive patients.

The influence of antihypertensive treatment on the renal arterial structure in spontaneously hypertensive rats. A morphometric study.

Spontaneously hypertensive rats (SHR) and stroke-prone spontaneously hypertensive rats (SHRSP) were treated with a combination of a beta 1-blocker (metoprolol) and a Ca++-antagonist (felodipine) from 1 to 4 months or 4 to 6 months of age. The renal arterial trunks as well as more distal parts of the renal arterial bed were fixed by immersion and embedded in plastic. The media cross-sectional area and the length of the internal elastic membrane were measured on cross-sectioned arteries. The media thickness, luminal radius and the ratio between media thickness and luminal radius (m/r ratio) were then calculated for a standardized condition, assuming a smooth and circular internal elastic membrane, in which the arteries were compared. The m/r ratio was markedly reduced in the most proximal as well as in more distal arterial segments of the treated animals when compared with untreated rats of corresponding age and category. The quotient was somewhat reduced also when compared with normotensive controls (WKY) although the systolic blood pressure in younger treated rats was not fully normalized. The results may suggest that the present treatment influences the arterial walls not only by reducing the pressure load but also through pressure-independent mechanisms.

Spontaneous arterial lesions involving breaks in the internal elastic lamina in the rat: effects of beta-aminopropionitrile and familial distribution.

We have studied the effects of beta-aminopropionitrile (BAPN) administration on the formation of spontaneous arterial lesions, characterized principally by a rupture in the internal elastic lamina (IEL) in the caudal and renal arteries of the Wistar rat. Treatment with BAPN (an inhibitor of lysyl oxidase) increased the formation of these lesions in rats up to 12 weeks of age but had differential effects on the caudal and renal artery in older rats. Administration of the nitrile to weanling rats led to the premature formation of lesions in caudal arteries of both male and female rats which morphologically resemble lesions which form spontaneously later in life. Dietary supplements of copper or pyridoxine were without effect on the formation of spontaneous caudal artery lesions when given from 5 wks of age but a copper supplement from midgestation slightly inhibited lesion formation only in male rats. This suggests that if copper deficiency is involved in spontaneous lesion formation, it is only a contributory factor. Quantification of either caudal or renal artery lesions within different litters of Wistar rats showed that there exists a familial aggregation in the frequency of spontaneous lesion formation, certain litters showing significantly higher levels of lesions than others. Adult Sprague-Dawley rats also appear to be more susceptible to the development of renal artery IEL defects than Wistar rats. The possibility of a hereditary disorder leading to a minor defect in elastic fibre structure which could be responsible for the spontaneous lesions is discussed.

Renal trauma. Treatment by angiographic injection of autologous clot.

The safety of treatment of renal hemorrhage from trauma with angiographic injection of autologous clot was investigated in rats by demonstrating the effect of various sizes of clot emboli on renal survivial. A large amount of clot injected into the entire distal part of the renal arterial tree (equivalent to 20 cu cm in the human) was required to produce a 15% infarction. This large safety range is possibly due to the endogenous fibrinolytic capability of normal vascular endothelium.