Micro-Embolic Renal Ischemia and Hypertension

A new experimental method of causing apparently sustained hypertension of renal origin is described. The method depends on the production of a source of micro-emboli in the thoracic aorta of rabbits by the insertion of magnesium-aluminum wire, covered by a plastic in which notches have been cut. Thrombus, considered to be formed largely of platelets, forms on the exposed areas of the wire and atrophic lesions subsequently occur along the cortical surface of the kidneys. It is probable that the atrophic lesions are due to repeated episodes of platelet micro-embolism. These lesions resemble the marginal zone of infarcts, which has been suggested as the source of a pressor substance. Proximal to the atrophic lesions, arterioles show a prominent intimal thickening resembling that seen in severe hypertension.     

Follow up study of 70 patients with renal artery stenosis treated by percutaneous transluminal dilatation.

Between April 1978 and April 1981, 70 patients with hypertension and renal artery stenosis were treated by percutaneous transluminal arterial dilatation. Selection of the patients was based solely on arteriographic criteria. Arteriography after dilatation showed considerable widening of the stenosed area in all patients. In 65 patients the effect of treatment on the blood pressure was assessed during follow up periods of one to four years. In 14 of these patients the hypertension was cured, in 29 it was improved, and in 22 there was no change. Patients with fibromuscular lesions benefited distinctly more than did those with atheromatous stenosis, only one of the 21 patients with fibromuscular lesions showing no change as compared with 21 of the 44 patients with atheromatous lesions. The only serious complication encountered was microcholesterol emboli, which developed in two patients with severe atheromatous lesions of the aorta. In the atheromatous group age and overall renal function had no influence on the blood pressure response. In the subgroup of patients with a unilateral lesion the renal vein renin ratios and asymmetrical curves obtained by renography had only a very limited predictive value. In experienced hands percutaneous transluminal arterial dilatation is relatively safe, and this study suggests that it should be attempted in all patients with renal artery stenosis. Only in patients with severe atheromatosis of the aorta should the risk associated with the catheterisation be weighed against the 50% or so chance of benefit from the procedure.     

Spontaneous hypertension and its sequelae in woolly monkeys (Lagothrix lagotricha)

Arteriolar nephrosclerosis was observed at necropsy in 26 of 38 woolly monkeys (Lagothrix lagotricha). This lesion is the earliest histologic change associated with hypertension in humans. Seventeen of the monkeys had died of congestive heart failure, renal failure or acute cardiovascular accident, complications similar to those seen in human hypertension. All monkeys known to be over 4 years of age were affected. Direct blood pressure measurements in nine otherwise healthy woolly monkeys revealed systolic pressures of 194 +/- 20 mmHg. Our physiologic, clinical and pathologic studies suggest that woolly monkeys develop hypertension spontaneously and could be a useful model for the study of human hypertension.     

Age-related non-neoplastic lesions in the heart and kidneys of Syrian hamsters of the APA strain

Spontaneous cardiac and renal lesions in APA hamsters were examined histopathologically. Myocardial degeneration, valvular thickening, coronary arterial degeneration and increase in heart weight were common in old hamsters. These changes, which suggest cardiac failure, seem to be related to cardiac thrombosis which predominantly affected the left atrium and was found in over 40% of each sex over 16 months of age. Neither glomerular amyloidosis nor arteriolar nephrosclerosis was detected. In general the histopathology of renal lesions in APA hamsters resembled that of the condition known as glomerulonephrosis in rats. Renal lesions occurred more frequently and more severely and developed more rapidly in females than in males. There was no apparent correlation between cardiac thrombosis and renal disease.     

Arterial hypertension and neurofibromatosis: renal artery stenosis and coarctation of abdominal aorta.

A 10-year-old girl had arterial hypertension, generalized neurofibromatosis, coarctation of the abdominal aorta and multiple stenoses at the origin of each renal artery. After resection of the stenotic areas and reimplantation of the renal arteries in the aorta, her arterial pressure decreased substantially. However, hypertension recurred and radiologic follow-up 4 1/2 years later showed distinct progression of the coarctation and renewed stenosis of all renal arteries at their origin. The stenotic areas showed eccentric intimal proliferation, frequently bulging into the lumen, with small nodular aggregates of smooth muscle cells and proliferation of fibrous tissue containing spindle-shaped nuclei in a palisading pattern. Hypertension associated with neurofibromatotic vascular disease has been described in 47 other patients in the literature. These patients have been young (mean age, 14 years) and predominantly male. In contrast to fibromuscular dysplasia, in which 95% of all stenoses are found in the distal two thirds of the renal arteries, in vascular neurofibromatosis more than 50% of the stenoses are found at the origin.     

Morphological aspects of age-related adaptation of the arterial vessels of the human kidneys in various cardiovascular diseases

The investigation has been performed in 190 normal kidneys and at certain cardiovascular diseases (atherosclerosis of the abdominal aorta, hypertension, chronic ischemic cardiac disease and their combination). Principally similar morphological structures are mobilized in the process of the renal arterial bed adaptation both normal and at the cardio-vascular diseases studied. Transition from certain functional changes to the organic ones in the muscular tunic and in the elastic membranes of large arteries, in correlation of afferent and deferent glomerular arterioles of all cortical layers is stated, as well as adaptive rearrangement of the microvessels and of the juxtamedullary shunt.     

Endothelin-1 in chronic renal failure and hypertension

Investigation into the role of endothelin-1 (ET-1) in renal function has revealed two major direct actions leading to the control of extracellular volume and blood pressure. These are the regulation of renal hemodynamics and glomerular filtration rate and the modulation of sodium and water excretion. In the rat remnant kidney model of chronic renal failure, ET-1 production is increased in blood vessels and renal tissues. These changes are related to an increase in preproET-1 expression and correlate with the rise in blood pressure, the development of cardiovascular hypertrophy, and the degree of renal insufficiency and injury. Selective ETA receptor blockade prevents the progression of hypertension and the vascular and renal damage, supporting a role for ET-1 in chronic renal failure progression. The increase in ET-1 production can be associated with other local mediators, including angiotensin II, transforming growth factor-beta1 and nitric oxide, the local production of which is also altered in chronic renal failure. In human patients with essential hypertension, atherosclerosis, and nephrosclerosis, plasma ET-1 levels are increased compared with patients with uncomplicated essential hypertension. Similarly, plasma ET-1 concentrations are markedly increased in patients with end-stage renal disease undergoing dialysis, and this correlates with blood pressure, suggesting that ET-1 may contribute to hypertension in these patients. The treatment of anemia in patients with renal failure with human recombinant erythropoietin increases blood pressure by accentuating the underlying endothelial dysfunction and the elevated vascular ET-1 production. Overall, these results support a role for ET-1 in hypertension and the end-organ damage associated with chronic renal failure. ETA receptor blockade may then represent a potential target for the management of hypertension and cardiovascular and renal protection.     

The role of prostaglandins in hypertension. I. The release of prostaglandins by aorta strips of renal, DOCA-salt, and spontaneously hypertensive rats

The release of prostaglandin-like (PG-like) material by aorta strips of normotensive and hypertensive rats has been studied in vitro. When incubated in an oxygenated Krebs solution kept at 37 degrees C, aorta strips removed from 8- and 12-week-old spontaneously hypertensive (SH) rats generate 1.2-2.5 times more PG-like material than aorta strips from age-matched normotensive Wistar (NW) rats. The overproduction of PG-like material by aorta strips of SH rats did not precede the development of hypertension in SH rats. Aorta strips derived from renal and DOCA-salt hypertensive rats produced 1.5-3 times more PG-like material than aorta strips from NW rats. The production of PG-like material by aorta strips of renal and DOCA-salt hypertensive rats was largely reduced when hypertension was interrupted in these animals, thus suggesting that the alteration taking place in the arteries of hypertensive rats (namely increased production of PGs) during the development of hypertension was reversible. The production of PG-like material by aorta strips of hypertensive rats was inhibited by indomethacin. Analysis of the PG-like material by bioassays and thin-layer chromatography suggests the presence of PGE2 and PGE1. The possible involvement of these PGs in the pathogenesis of hypertension in rats is discussed.     

Nocturnal blood pressure in normotensive subjects and those with white coat,primary, and secondary hypertension.

OBJECTIVE--To compare the mean nocturnal blood pressure of patients with various forms of renal and endocrine hypertension with that in patients with primary and white coat hypertension, and normal blood pressure. DESIGN--Ambulatory monitoring of blood pressure over 24 hours in a prospective study. SETTING--Two German centres for outpatients with hypertension and kidney diseases. SUBJECTS--176 normotensive subjects, 490 patients with primary hypertension including mild and severe forms, 42 with white coat hypertension, 208 patients with renal and renovascular hypertension, 43 with hypertension and endocrine disorders, and three with coarctation of the aorta. MAIN OUTCOME MEASURES--Fall in nocturnal blood pressure. RESULTS--Blood pressure in normotensive subjects fell by a mean of 14 mm Hg (11%) systolic and 13 mm Hg (17%) diastolic overnight (2200 to 0600). The falls in patients with primary and white coat hypertension were not significantly different. In all patients with renal and renovascular hypertension, however, the fall was significantly reduced (range of fall from 3/3 mm Hg to 7/9 mm Hg). In patients with hypertension and endocrine disorders the pattern of night time blood pressure was not uniform: patients with hyperthyroidism, primary hyperaldosteronism, and Cushing''s syndrome had significantly smaller reductions in blood pressure (6/8, 4/7, 3/6 mm Hg, respectively). In patients with phaeochromocytoma the mean night time blood pressure increased by 4/2 mm Hg. In patients with hypertension, primary hyperparathyroidism, and unoperated coarctation of the aorta the falls in blood pressure were normal. CONCLUSIONS--In normotensive subjects and those with primary hypertension there is usually a reduction in blood pressure at night. In all renal forms of secondary hypertension and in most endocrine forms the reduction in blood pressure is only a third to a half of normal. Patients with primary hyperparathyroidism and unoperated coarctation of the aorta show a normal reduction.     

Preliminary observations, at the ultrastructural level, on the reactivity of cerebral arteries from New Zealand rabbits to combined atherogenic stimuli (hypercholesterol diet and hypertension)

Both in monkeys (Rhesus and Cynomolgus) and in New Zealand rabbits fed an atherogenic diet, a marked delay in the appearance of atherosclerotic lesions of the cerebral arteries in comparison with other arterial districts has been observed. This appearance has been described in monkeys as relatively earlier if hypertension is added to the atherogenic diet. Preliminary observations on a little group of rabbits on a 3 months hypercholesterolic diet, subjected to Goldblatt aortic coarctation, have shown an increase of blood pressure and a severe gross atherosclerotic involvement of aorta, resembling the one obtainable after 6 months of atherogenic diet. Histologically, the aorta predominantly shows lesions of the fatty streaks type with necrotic areas in the deep; the carotid lesions show some lipid in smooth muscle cells disseminated in a sub-endothelial "edematous" space (rich in protein). The cerebral arteries do not show any lesion. At TEM, the aortic lesions look sometimes as advanced plaques with an initial fibrosis at the surface; the carotid lesions are characterized by a granular deposit in the sub-endothelial space in which some smooth muscle cells (with lipid in the cytoplasm) are present; in the cerebral arteries only the presence of collagen fibers among the smooth muscle cells of the media, never observed in the animals fed the atherogenic diet alone, has sometimes been noted.     

Effect of nitrendipine on cardiac and renal lesions and arterial hypertrophy

A low dose of nitrendipine (1 mg/kg twice daily) ameliorated the percent incidence and severity of vascular lesions in the kidney and heart induced by deoxycorticosterone (DOC). Less protection was offered by administration of 1 mg/kg of the calcium antagonist once daily. A lower dose of the antagonist (0.5 mg/kg) administered twice daily produced almost no protection against myocardial scars, but the percent incidence and severity of renal tubular casts and glomerular changes were similar to those following injection of 1 mg/kg of the antagonist twice daily. DOC induced hypertrophy of the media in aorta, coronary artery and renal interlobular artery and renal arteriole. Neither 1 mg/kg once or twice daily nor 0.5 mg twice daily of calcium antagonist modified the hypertrophy of the arterial vasculature in the hypertensive DOC group. We conclude that a low dose of the calcium antagonist dissociates at least in part lesions but not hypertrophy from the increased systolic blood pressure, because the antagonist protects against vascular lesions induced by the hypertension. The antagonist likely acts on the endothelial cell of the vessels alone or combined with an effect on the vascular smooth muscle cells.     

Salt water promotes hypertension in Dahl-S rats.

Hypertension was induced in Dahl-salt-sensitive (Dahl-S) rats by administering salt in drinking water. Control rats receiving tap water did not show a significant change in blood pressure or abnormalities in the kidney. Rats receiving 0.5% NaCl solution developed moderate hypertension and renal lesions. Rats receiving 1.0% NaCl solution showed prominent and increasing hypertension and severe renal damage. This method of salt administration should be simpler than administration in the diet as a means of promoting renal hypertension. The lower concentration salt water caused chronic mild hypertension in Dahl-S rats, and may serve as a useful model for progressive hypertension.     

The Sequence of Events in the Development of Bilateral Renal Cortical Necrosis Accompanying the Generalized Shwartzman Reaction

The generalized Shwartzman reaction, or Shwartzman-like conditions, were induced in a variety of experimental mammalian species by systemic injections of disintegrated cells of Gram negative bacteria, live Salmonella cholerae-suis or Liquoid. A comparative study of the renal lesions showed that the initial step in the development of bilateral cortical necrosis is stagnation and disintegration of red cells in glomerular capillaries. The glomerular “microthrombi” consist mainly of erythrocytic debris, which frequently has staining properties akin to those of fibrin; even wide-spread glomerular “thrombosis” is not accompanied by obvious destruction of renal parenchyma. A second step is necrotic mural lesions in afferent arteries, with ensuing thrombosis. These vascular lesions lead to the formation of individual infarcts which fuse to form total bilateral cortical necrosis in fulminant cases of the generalized Shwartzman reaction.     

Increased Renal Iron Accumulation in Hypertensive Nephropathy of Salt-Loaded Hypertensive Rats

Although iron is reported to be associated with the pathogenesis of chronic kidney disease, it is unknown whether iron participates in the pathophysiology of nephrosclerosis. Here, we investigate whether iron is involved in the development of hypertensive nephropathy and the effects of iron restriction on nephrosclerosis in salt- loaded stroke-prone spontaneously hypertensive rats (SHRSP). SHRSP were given either a normal or high-salt diet for 8 weeks. Another subset of SHRSP were fed a high-salt with iron-restricted diet. SHRSP given a high-salt diet developed severe hypertension and nephrosclerosis. As a result, survival rate was decreased after 8 weeks diet. Importantly, massive iron accumulation and increased iron content were observed in the kidneys of salt-loaded SHRSP, along with increased superoxide production, urinary 8-Hydroxy-2′-deoxyguanosine excretion, and urinary iron excretion; however, these changes were markedly attenuated by iron restriction. Of interest, expression of cellular iron transport proteins, transferrin receptor 1 and divalent metal transporter 1, was increased in the tubules of salt-loaded SHRSP. Notably, iron restriction attenuated the development of severe hypertension and nephrosclerosis, thereby improving survival rate in salt-loaded SHRSP. Taken together, these results suggest a novel mechanism by which iron plays a role in the development of hypertensive nephropathy and establish the effects of iron restriction on salt-induced nephrosclerosis.     

Naturally Occurring Genetic Variants in Human Chromogranin A (CHGA) Associated with Hypertension as well as Hypertensive Renal Disease

Chromogranin A (CHGA) plays a fundamental role in the biogenesis of catecholamine secretory granules. Changes in storage and release of CHGA in clinical and experimental hypertension prompted us to study whether genetic variation at the CHGA locus might contribute to alterations in autonomic function, and hence hypertension and its target organ consequences such as hypertensive renal disease (nephrosclerosis). Systematic polymorphism discovery across the human CHGA locus revealed both common and unusual variants in both the open reading frame and such regulatory regions as the proximal promoter and 30-UTR. In chromaffin cell-transfected CHGA 30-UTR and promoter/luciferase reporter plasmids, the functional consequences of the regulatory/non-coding allelic variants were documented. Variants in both the proximal promoter and the 30-UTR displayed statistical associations with hypertension. Genetic variation in the proximal CHGA promoter predicted glomerular filtration rate in healthy twins. However, for hypertensive renal damage, both end-stage renal disease and rate of progression of earlier disease were best predicted by variants in the 30-UTR. Finally, mechanistic studies were undertaken initiated by the clue that CHGA promoter variation predicted circulating endothelin-1. In cultured endothelial cells, CHGA triggered co-release of not only the vasoconstrictor and pro-fibrotic endothelin-1, but also the pro-coagulant von Willebrand Factor and the pro-angiogenic angiopoietin-2. These findings, coupled with stimulation of endothelin-1 release from glomerular capillary endothelial cells by CHGA, suggest a plausible mechanism whereby genetic variation at the CHGA locus eventuates in alterations in human renal function. These results document the consequences of genetic variation at the CHGA locus for cardiorenal disease and suggest mechanisms whereby such variation achieves functional effects.     

Effect of nitrendipine on cardiac and renal lesions and arterial hypertrophy. Protective effect of a low dose of calcium antagonist in deoxycorticosterone-induced hypertensive rats

A low dose of nitrendipine (1 mg/kg twice daily) ameliorated the percent incidence and severity of vascular lesions in the kidney and heart induced by deoxycorticosterone (DOC). Less protection was offered by administration of 1 mg/kg of the calcium antagonist once daily. A lower dose of the antagonist (0.5 mg/kg) administered twice daily produced almost no protection against myocardial scars, but the percent incidence and severity of renal tubular casts and glomerular changes were similar to those following injection of 1 mg/kg of the antagonist twice daily. DOC induced hypertrophy of the media in aorta, coronary artery and renal interlobular artery and renal arteriole. Neither 1 mg/kg once or twice daily nor 0.5 mg twice daily of calcium antagonist modified the hypertrophy of the arterial vasculature in the hypertensive DOC group. We conclude that a low dose of the calcium antagonist dissociates at least in part lesions but not hypertrophy from the increased systolic blood pressure, because the antagonist protects against vascular lesions induced by the hypertension. The antagonist likely acts on the endothelial cell of the vessels alone or combined with an effect on the vascular smooth muscle cells.     

A review of the biological properties and clinical implications of adrenomedullin and proadrenomedullin N-terminal 20 peptide (PAMP), hypotensive and vasodilating peptides.

Adrenomedullin (AM), identified from pheochromocytoma and having 52 amino acids, elicits a long-lasting vasodilatation and diuresis. AM is mainly mediated by the intracellular adenylate cyclase coupled with cyclic adenosine monophosphate (cAMP) and nitric oxide (NO) -cyclic guanosine monophosphate (cGMP) pathway through its specific receptor. The calcitonin receptor-like receptor (CLCR) and receptor-activity modifying protein (RAMP) 2 or RAMP3 models have been proposed as the candidate receptor. AM is produced mainly in cardiovascular tissues in response to stimuli such as shear stress and stretch, hormonal factors and cytokines. Recently established AM knockout mice lines revealed that AM is essential for development of vitelline vessels of embryo. Plasma AM levels elevate in cardiovascular diseases such as heart failure, hypertension and septic shock, where AM may play protective roles through its characteristic biological activities. Human AM gene delivery improves hypertension, renal function, cardiac hypertrophy and nephrosclerosis in the hypertensive rats. AM decreases cardiac preload and afterload and improves cardiac contractility and diuresis in patients with heart failure and hypertension. Advances in gene engineering and receptor studies may contribute to further understandings of biological implication and therapeutic availability of AM.     

Nephrotoxic Lesions from 5-Aminosalicylic Acid

5-Aminosalicylic acid given to rats as a single intravenous injection led to necrosis of the proximal convoluted tubules and of the renal papilla. These two lesions developed at the same time and the cortical lesions did not appear to be a consequence of the renal papillary necrosis. Since the compound possesses the molecular structure both of a phenacetin derivative and of a salicylate these observations may be relevant to the problem of renal damage incident to abuse of analgesic compounds and suggest the possibility that in this syndrome cortical lesions may develop independently of renal papillary necrosis.     

Gαq／11介导的细胞信号转导在两肾一夹肾性高血压大鼠主动脉中的变化

实验以两肾一夹肾性高血压大鼠为模型,研究主动脉Gαq/11倡导 的细胞信号转导的变化及其意义。制备两肾一夹肾性高血压大鼠模型,分别于术后第1、2、4和8周测定动脉血压,用免疫印迹法检测主动脉组织中Gαq/11亚单位和细胞个信号调节激酶1／2（ERK1／2）含量,测定磷脂酶C（phospholipase C,PLC)活性。结果显示高血压组大鼠于术后第2周血压开始升高;主动脉Gαq/11和ERK1／2含量于术后第1周增加（分别为57.53%和40.16%）,并维持在高水平（P＜0.01）;术后主动脉PLC活性亦增加（P＜0.05）。实验表明,肾素依赖性高血压能引起大鼠主动脉Gαq/11介导的细胞信号转导系统激活,并参与高血压的发生和发展。     

Energy-dependent calcium uptake activity of microsomes from the aorta of normal and hypertensive rats

Energy-dependent calcium uptake activity of microsomes isolated from the rat aorta has been characterized. The microsomes consist of smooth membrane vesicles which in the presence of Mg · ATP as an energy source continuously sequester calcium over a 60-min period. This calcium uptake is greatly stimulated by oxalate anion which serves as a calcium trapping agent. Unlike the calcium uptake of miltochondria this uptake is not inhibited by sodium azide. Sucrose density gradient analysis of the microsomal calcium uptake suggests that the system is associated with the sarcoplasmic reticulum. In presence of 5 mM Mg · ATP and 20μM calcium approximately 38 nmol of calcium per mg of microsormal protein are taken up in 20 min. In the absence of ATP, less than 2 nmol of calcium per mg of protein are taken up in the first 2 min. with no further uptake of calcium in subsequent time periods. When calcium uptake activity is plotted against calcium or ATP concentration of the medium, half maximal activity is calculated for 24.3 μM calcium and for 1.6 mM ATP. The calcium uptake characteristics of the rat aorta microsomes are compatible with a postulated role in the relaxation of the vascular smooth muscle and the provision of an intracellular calcium store for muscle contraction.Aorta microsomes from SHR rats (a genetic strain that is spontaneously hypertensive) have a significantly reduced calcium uptake when compared with the corresponding nonhypertensive control strain. The level of calcium and ATP for half maximal activity of the rat aorta microsomal calcium uptake system is approximately the same in the SHR and the control strain. The rate of release of calcium from rat aorta microsomes is apparently identical in SHR strain and control. The calcium uptake activity of kidney and liver microsomes isolated from the SHR rat appears to be identical to that found in the control strain.Rats were treated with the steroid deoxycorticosterone acetate for ten and thirty days to induce hypertension. After ten days of deoxycorticosterone acetate although hypertension is present, there is no change in calcium uptake activity of aorta microsomes, renal microsomes or renal plasma membranes. After 30 days of deoxycorticosterone acetate treatment calcium uptake activity of renal microsomes is reduced. A variable decrease in calcium uptake activity is observed with aorta microsomes. Renal plasma membrane calcium uptake remains unchanged.