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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

During the past decade, experimental and clinical evidence has indicated an important role for the renin-angiotensin system in the progressive destruction of nephrons in a wide variety of chronic renal diseases. Studies have indicated that in the subtotally nephrectomized rat model of progressive glomerulosclerosis, in experimental diabetes mellitus, in the chronic phase of puromycin aminonucleoside-induced nephrotic syndrome and in Heymann's nephritis, angiotensin-converting enzyme (ACE) inhibitors dramatically preserve both nephron structure and function. Clinical studies have similarly noted that chronic administration of ACE inhibitors inhibits progression of renal failure in type I diabetes and type II diabetes as well as primary glomerulopathies, sickle cell nephropathy, systemic lupus erythematosis, chronic pyelonephritis and adult polycystic kidney disease. Current evidence suggests that the beneficial effect of ACE inhibitors is primarily due to inhibition of angiotensin II production, and there is strong suggestive evidence for increases in local intrarenal activation of the renin-angiotensin system in these conditions. In obstructive uropathy, activation of the renin-angiotensin system has also been shown to be an important aspect of the early functional changes and may be of importance in the subsequent generation of interstitial fibrosis. In the obstructed kidney, renin and angiotensinogen production increase and type I angiotensin receptors decrease. Inhibitors of angiotensin II production and angiotensin II action partially reverse the vasoconstriction and the reduced renal blood flow, and abolish the changes in expression of AT1 MRNA induced by obstruction. Studies suggest that the angiotensin-mediated increases in tubulointerstitial fibrosis may be mediated by increased production of transforming growth factor-beta.
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PMID:Angiotensin II-mediated renal injury. 756 81

Effects of the angiotensin II AT1 receptor antagonist ZD-7155 on nerve function, blood flow, capillarization, oxygenation, and regenerative capacity after injury were studied in streptozocin-diabetic rats. Deficits in saphenous sensory and sciatic motor conduction velocity measured after 1 or 2 mo of diabetes in anesthetized rats were prevented and corrected by ZD-7155. Sciatic resistance to hypoxic conduction failure, which was increased by 71% by 2 mo of diabetes, was attenuated by 39% with ZD-7155. Endoneurial capillary density, which was unaffected by diabetes, was increased by 34% with 2 mo of ZD-7155 treatment. Sciatic nutritive endoneurial blood flow, which was reduced by 45% by 2 mo of diabetes, remained in the nondiabetic range with ZD-7155. Mean endoneurial O2 tension was reduced 38% by diabetes, which was attenuated by ZD-7155. Punctate freeze damage of sciatic nerve caused complete fiber degeneration. Fourteen days postlesion, there was a 26% deficit in myelinated fiber regeneration distance after 2 mo of diabetes, which was prevented by ZD-7155 treatment from diabetes induction. Thus alterations in the renin-angiotensin system contribute to the neurovascular etiology of nerve dysfunction in experimental diabetes.
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PMID:Nerve function and regeneration in diabetic rats: effects of ZD-7155, an AT1 receptor antagonist. 757 31

1. Angiotensin II (AII) plays a major role in cardiovascular function via direct actions on the vasculature, kidney, adrenal, heart, brain and sympathetic nerves. The cellular effects of AII are extensive and encompass hypertrophy, hyperplasia and the deposition of extracellular matrix. 2. The actions of AII are mediated by the AT1 and AT2 membrane receptor subtypes, and additional forms of each subtype. Evidence is emerging that selective changes in AII receptor subtypes occur in cardiovascular diseases. 3. Thyroid dysfunction increased cardiac, liver and kidney AII receptor density but decreased adrenal gland receptor density. In the heart, there was a selective increase in AT2 receptor density. 4. Diabetes increased cardiac, liver and adrenal gland AII receptor densities but decreased kidney receptor density. 5. Hypertension increased AII receptor density in the heart and kidney. A corresponding increase in receptor mRNA was prevented by selective AT1 receptor antagonists. 6. The human heart contained AII receptors in all chambers; right atrial receptor density was increased in coronary artery bypass graft patients. 7. The presence of AII receptor changes in these models of cardiac hypertrophy and hypertension raises the possibility of using orally active, subtype-selective agonists and antagonists to treat particular forms of cardiovascular diseases.
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PMID:Angiotensin receptors in cardiovascular diseases. 786 32

In this article, we have discussed the localization of components of the renal renin-angiotensin system, as well as the existing information on the regulation of this axis and the effects of Ang II on renal function. All the components of the renin-angiotensin system are present in both fetal and adult kidney. In the adult kidney, renin is principally localized to jg cells of the distal afferent arteriole, where release is stimulated by increases in intracellular cAMP and inhibited by increases in cytosolic calcium. Four distinct stimuli mediating renin release are (1) NaCl sensed at the macula densa, (2) the sympathetic nervous system, (3) humoral factors, with Ang II, vasopressin, endothelin, and adenosine inhibiting renin release, and (4) changes in intrarenal blood pressure. Alterations in renal renin gene expression have been reported in pathophysiological states, such as salt depletion, diabetes mellitus, ureteral obstruction, Bartter's syndrome, and with high protein feeding. The highest renal concentrations of mRNA for the renin substrate angiotensinogen are found in the PT, where the protein is localized to subapical granules. Both salt depletion and androgens upregulate renal angiotensinogen mRNA. Of interest, renal angiotensinogen mRNA levels are lower in SHR than in normotensive WKY rats. As with angiotensinogen, renal ACE is mainly localized to the PT, with highest concentration on the brush border. The mechanisms of regulation of both renal angiotensinogen and ACE require further study. Using recently developed specific nonpeptide Ang II receptor antagonists, it appears that adult renal Ang II receptors are principally of the AT1 class, whereas fetal kidney Ang II receptors are of the AT2 subtype. By binding to AT1 receptors, Ang II exerts constrictive effects on both afferent and efferent arterioles, with increased effect reported on efferent arterioles. Glomerular Ang II receptors are localized to mesangial cells, mediating contractile responses resulting in changes in glomerular surface area and Kf, and potentially regulating mesangial sieving and phagocytosis. These receptors are reduced with salt restriction or in experimental diabetes. The highest concentrations of tubular Ang II receptors are found in PT, on both brush border and basolateral membranes.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:The intrarenal renin-angiotensin system. 843 83

In the past decade there have been considerable advances in basic knowledge of the renin-angiotensin system (RAS). The most important new development has been the appreciation of a tissue based RAS that can be independently regulated from the renal and vascular RAS. Greater insight into the mechanism by which angiotension-II (AII) exerts its action has been achieved through the study of molecular biology and pharmacological characterization of multiple receptor subtypes. This review summarises the features and distribution of several binding subtypes that may mediate the diverse functions of AII. Of these AT1 subtype is the most well known receptor which preferentially binds AII and AIII. The AT1 receptor site appears to mediate the classic angiotensin responses concerned with the body water balance and the maintenance of blood pressure. Less is known about the AT2 sites which also bind AII and AIII and may play a role in vascular growth. Recently, an AT3 has been discovered in cultured neuroblastoma cells and an AT4 site which preferentially binds AIV. It has been implicated in memory aquisition and retrieval and in the regulation of blood flow. Another important aspect covered is the primary and secondary messengers involved during the signal transduction after the binding of AII with receptors. A stress has also been given on the regulation of density and affinity of AII receptors by various physiological parametres as they affect the responses of RAS. Autoregulation by RAS, salt intake, development and aging and some of the hormones are important variables which could affect the AII receptors. Interactions of AII with various neuroeffector transmission involved in the regulation of water-electrolyte balance and BP regulation play an important role in the maintenance of the homeostasis. AII has been suggested to increase the NAergic transmission by enhancing synthesis, release, inhibiting reuptake by the presynaptic nerve terminals as well as enhancing cell responsiveness to the transmitter. The finding of existence of AII receptors in vagal afferent nerve terminals suggests that its baroreflex inhibitory effect is mediated by inhibiting neurotransmitter release at NTS in the baroreflex arc. Moreover, AII acts on the central receptors to stimulate AVP and ACTH secretion, drinking and peripherally increase synthesis and secretion of aldosterone. Interactions of RAS with kallikrein-kinin system and prostaglandins strongly support the existence of a balance between renal depressor and pressor substances. AII is now considered a growth promotor in cardiovascular tissues and the resultant vascular hypertrophy could contribute in the maintenance of hypertension. AII also plays a role in the kidney, not only as a regulator of hemodynamics but also in the structural changes occurring in a variety of renal disorders. In addition to the more well studied functions of RAS in RVH the review also highlights the potential contribution by the RAS to other clinically relevant syndromes such as aortoarterities induced RVH, hyperaldosteronism, heavy metal induced cardiovascular effects, diabetes mellitus and thyroid dysfunction. Although the receptor subtypes involved in these pathological states have not been definitely identified, research efforts in this direction are ongoing.
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PMID:Angiotensin II--receptor subtypes characterization and pathophysiological implications. 864 21

The aims of this study were to assess whether high-dose treatment with an endothelin 1 (ET1) ETA antagonist could correct deficits in peripheral nerve conduction and blood flow in streptozotocin-diabetic rats and to examine interactions between ET1 and the renin-angiotensin system using low-dose single and combined treatments with ETA and AT1 antagonists. After B wk of diabetes, sciatic motor nerve conduction velocity (NCV) was approximately 20% reduced. High-dose ETA antagonist treatment for 2 wk corrected NCV to the extent of 84%. A approximately 48% diabetic deficit in nutritive endoneurial blood flow was also 88% corrected by the ETA antagonist. Combined treatment with low-doses of ETA and AT1 antagonists, selected to give approximately 20% amelioration of diabetic NCV deficits on their own, resulted in 66% correction. This was greater than expected for a simple additive effect between the antagonists, demonstrating a synergistic interaction. From NCV dose-response curves, the combined treatment effect was equivalent to a 4.2- to 8.9-fold dose increase for the individual antagonists. In parallel, joint treatment markedly improved sciatic nutritive endoneurial perfusion. Thus, the data strongly implicate ET1, acting via ETA receptors in the etiology of neurovascular dysfunction in experimental diabetic neuropathy. Furthermore, they demonstrate synergistic interactions between ET1 and renin-angiotensin systems that, if present in neuropathic patients, could potentially be used to obtain a therapeutic advantage.
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PMID:Effects of a nonpeptide endothelin-1 ETA antagonist on neurovascular function in diabetic rats: interaction with the renin-angiotensin system. 881 10

Hypertension is one of the most important cardiovascular risk factors. Without therapy hypertension leads to stroke, coronary heart disease with angina pectoris and myocardial infarction, kidney failure and/or peripheral vascular disease. The association between blood pressure and these cardiovascular complications can be demonstrated over the entire blood pressure range. The risk of stroke, myocardial infarction, renal failure or peripheral vascular disease increases with increasing blood pressure. Additional cardiovascular risk factors such as hyperlipidemia, smoking and diabetes involve a further increase in risk. Today hypertension can be effectively treated. To that end, diuretics, betablockers, ACE-inhibitors or calcium antagonists can be used. Alpha receptor antagonists and angiotensin AT1 receptor antagonists are also of value. The antihypertensive effectiveness of these drugs is comparable but may vary in individual patients. During antihypertensive therapy, a reduction in cerebrovascular and cardiac complications has been demonstrated for alpha methyldopa, diuretics and betablockers. In these studies, fatal and non-fatal strokes were reduced by 42%, while the reduction in cardiac events was less pronounced (14%). The reasons for this greater efficacy of antihypertensive therapy in the cerebral circulation are not clear. Other risk factors may be particularly important in the pathogenesis of coronary artery disease (e.g. genetic factors, hyperlipidemia and others) or hypertensive vascular changes in the coronary circulation may not be as reversible as they are in the cerebral circulation. The well documented correlation between stroke, myocardial infarction and hypertension, as well as the proven efficacy of antihypertensive therapy in preventing cardiovascular events, underscores the importance of effective and sustained blood pressure control in these patients.
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PMID:[Heart, brain and hypertension]. 884 9

The aim of this study was to compare the effects of angiotensin converting enzyme (ACE) inhibition, angiotensin II (AII) AT1-receptor blockade, and dihydropyridine calcium antagonism on hypertrophy and on vascular albumin permeability in kidney, heart, and mesenteric artery in a model combining genetic hypertension and diabetes mellitus. Diabetes mellitus was induced by streptozotocin in 8-week-old spontaneously hypertensive rats. The animals were randomized to receive no treatment, the angiotensin converting enzyme inhibitor ramipril, the AII AT1-receptor blocker valsartan, or the dihydropyridine calcium antagonist lacidipine for 3 weeks. Vascular albumin permeability was measured as the tissue content of intravenously injected Evans blue dye (EB) in kidney, heart, and mesenteric artery and the tissue/plasma EB ratio was calculated. Systolic blood pressure was reduced by all three antihypertensive regimens. Glycemic control was similar in all diabetic groups. Kidney hypertrophy was not affected by any of the antihypertensive drugs. Hypertrophy of the mesenteric artery was enhanced by lacidipine but was not affected by ramipril or valsartan. Relative heart weight was also increased by lacidipine. Vascular albumin permeability, expressed as EB content in micrograms/gram dry weight or as tissue/plasma EB ratio, was higher in the kidneys of lacidipine-treated rats than in any other group of diabetic rats. There was a positive correlation between kidney weight/body weight and kidney/plasma EB ratio in the diabetic rats. These findings indicate that the dihydropyridine calcium antagonist lacidipine is associated with an unfavorable effect on vascular hypertrophy and on vascular albumin permeability in the kidneys in rats with hypertension and diabetes mellitus. Furthermore, there seems to be a coupling in the diabetic kidney between hypertrophy and increased vascular albumin permeability.
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PMID:Vascular hypertrophy and albumin permeability in a rat model combining hypertension and diabetes mellitus. Effects of calcium antagonism, angiotensin converting enzyme inhibition, and angiotensin II-AT1-receptor blockade. 887 46

The present study examined vascular reactivity to angiotensin II in blood-perfused kidneys of diabetic normotensive Wistar-Kyoto (WKY) and diabetic spontaneously hypertensive rats (SHR). In addition, the effect of the angiotensin AT1 receptor antagonist, CV-11974 (2-ethoxy-l-[[2'-(1 H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1 H-benzimidazole-7-carboxylic acid), on angiotensin II responses was examined. Dose-response curves to angiotensin II (0.1-30 micrograms/kg, i.a.) were obtained in kidneys of control- and diabetic-WKY rats and -SHR rats, either in the absence or presence of CV-11974 (3 micrograms/kg, i.v.). In all four treatment groups, angiotensin II produced dose-dependent increases in renal perfusion pressure with the order or reactivity: control-SHR > control-WKY = diabetic-SHR > diabetic-WKY. In the presence of CV-11974 (3 micrograms/kg, i.v.), dose-response curves to angiotensin II were significantly inhibited in kidneys of control-SHR and -WKY rats. However, CV-11974 (3 micrograms/kg, i.v.) had no significant effect on angiotensin II responses in kidneys of diabetic-SHR or -WKY rats. These results suggest that diabetes in normotensive rats is associated with impaired renal responsiveness to angiotensin II, while hypertension augments renal responsiveness to angiotensin II. However, the combination of diabetes and hypertension has largely offset the opposite effects on angiotensin II responses seen separately. Importantly, the lack of effect of CV-11974 in diabetic rats, with or without hypertension, has been identified. While the reasons for these alterations have yet to be determined, they may involve changes in angiotensin II receptor mechanisms (e.g. density and/or affinity).
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PMID:Vascular reactivity to angiotensin II in blood-perfused kidneys of hypertensive diabetic rats. 888 15

After a 4-week placebo baseline period, 29 Chinese elderly hypertensive patients were randomized, double-blind, to 12 weeks of treatment with either losartan potassium (n = 19), an angiotensin II antagonist at the AT1 receptor, or felodipine (n = 10), a calcium channel blocking agent. Of these 29 patients 12 had coexisting non-insulin-dependent diabetes mellitus. At week 12, the mean reductions (95% confidence intervals) in mean arterial pressure were similar in both groups: losartan -18 (range -22 to -14) mm Hg; felodipine -19 (range -25 to -11) mm Hg. In the whole group, the 24-hour urinary albumin excretion was reduced by 27% with losartan as compared with no change in the felodipine-treated group (p = 0.03; analysis of variance). In the diabetic group, losartan treatment reduced the urinary albumin excretion by 24% as compared with 11% in the felodipine-treated group. In the non-diabetic patients, the urinary albumin excretion fell by 29% in the losartan-treated group, but increased by 14% in the felodipine-treated group (p < 0.001; repeated-measures analysis of variance). Plasma sodium increased to a similar extent in both groups. The fasting plasma triglyceride level declined by 25% (p < 0.001 within group) with losartan, but was not significantly reduced in the felodipine-treated group. For comparable reductions in blood pressure, a greater reduction in albuminuria was seen with losartan than with felodipine treatment in Chinese hypertensive patients with or without non-insulin-dependent diabetes mellitus. Long-term studies are required to examine whether these antiproteinuric effects of losartan can be translated to renoprotection.
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PMID:Antihypertensive and anti-albuminuric effects of losartan potassium and felodipine in Chinese elderly hypertensive patients with or without non-insulin-dependent diabetes mellitus. 905 57


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