Restoration of diabetes-induced abnormal local Ca2+ release in cardiomyocytes by angiotensin II receptor blockade

2007 ◽  
Vol 292 (2) ◽  
pp. H912-H920 ◽  
Author(s):  
Nazmi Yaras ◽  
Ayca Bilginoglu ◽  
Guy Vassort ◽  
Belma Turan
Keyword(s):  
Renin Angiotensin System ◽  
Diabetic Rats ◽  
Diabetic Rat ◽  
Receptor Blockade ◽  
Angiotensin Ii Receptor ◽  
Rat Cardiomyocytes ◽  
Fk506 Binding Protein ◽  
Protein Levels ◽  
Release Mechanisms

Stimulation of local renin-angiotensin system and increased levels of oxidants characterize the diabetic heart. Downregulation of ANG II type 1 receptors (AT1) and enhancement in PKC activity in the heart point out the role of AT1 blockers in diabetes. The purpose of this study was to evaluate a potential role of an AT1 blocker, candesartan, on abnormal Ca2+ release mechanisms and its relationship with PKC in the cardiomyocytes from streptozotocin-induced diabetic rats. Cardiomyocytes were isolated enzymatically and then incubated with either candesartan or a nonspecific PKC inhibitor bisindolylmaleimide I (BIM) for 6–8 h at 37°C. Both candesartan and BIM applied on diabetic cardiomyocytes significantly restored the altered kinetic parameters of Ca2+ transients, as well as depressed Ca2+ loading of sarcoplasmic reticulum, basal Ca2+ level, and spatiotemporal properties of the Ca2+ sparks. In addition, candesartan and BIM significantly antagonized the hyperphosphorylation of cardiac ryanodine receptor (RyR2) and restored the depleted protein levels of both RyR2 and FK506 binding protein 12.6 (FKBP12.6). Furthermore, candesartan and BIM also reduced the increased PKC levels and oxidized protein thiol level in membrane fraction of diabetic rat cardiomyocytes. Taken together, these data demonstrate that AT1 receptor blockade protects cardiomyocytes from development of cellular alterations typically associated with Ca2+ release mechanisms in diabetes mellitus. Prevention of these alterations by candesartan may present a useful pharmacological strategy for the treatment of diabetic cardiomyopathy.

A novel mechanism for angiotensin II formation in streptozotocin-diabetic rat glomeruli

2005 ◽  
Vol 288 (6) ◽  
pp. F1183-F1190 ◽  
Author(s):  
Rekha Singh ◽  
Ashok K. Singh ◽  
David J. Leehey
Keyword(s):  
Angiotensin Ii ◽  
Renin Angiotensin System ◽  
Diabetic Rats ◽  
Diabetic Rat ◽  
Ang Ii ◽  
Sprague Dawley ◽  
New Information ◽  
Sprague Dawley Rats ◽  
And Control

Recent evidence suggests that the intrarenal renin-angiotensin system (RAS) may play an important role in the development of glomerular changes associated with diabetic nephropathy. In this study, the glomerular RAS was examined in male Sprague-Dawley rats made diabetic with streptozotocin (STZ), and the findings compared with those obtained in control nondiabetic rats. In diabetic rat glomerular extracts, angiotensinogen and angiotensin II (ANG II) levels were increased significantly by 2.2- and 1.9-fold, respectively, compared with nondiabetic controls. No significant differences in ANG I and angiotensin-converting enzyme (ACE) levels were observed between these groups. The HPLC analysis of the glomerular extracts demonstrated that exogenous ANG I was converted into various ANG peptides including ANG II, ANG(1–9), and ANG(1–7). A significant increase in formation of ANG II from exogenous ANG I was observed in STZ rats compared with control rats. Preincubation of glomerular extracts with captopril resulted in a 20–30% decrease in ANG II conversion from exogenous ANG I in diabetic and control rats. The possible role of ANG(1–9) in formation of ANG II was examined by HPLC. Exogenous ANG(1–9) in glomerular extracts was converted into ANG II, this conversion being significantly higher in STZ rats than in control rats. These findings provide new information that ANG(1–9) is produced in rat glomerular extracts, can be converted to ANG II, and that this conversion is also stimulated in diabetic rat glomeruli. Thus this study demonstrates that in diabetic rats, glomerular ANG II levels are increased due to an increase in angiotensinogen and an increase in the formation of ANG II.

scholarly journals Candesartan augments compensatory changes in medullary transport proteins in the diabetic rat kidney

2008 ◽  
Vol 294 (6) ◽  
pp. F1448-F1452 ◽  
Author(s):  
Mitsi A. Blount ◽  
Jeff M. Sands ◽  
Kimilia J. Kent ◽  
Tekla D. Smith ◽  
S. Russ Price ◽  
...  
Keyword(s):  
Rat Kidney ◽  
Renin Angiotensin System ◽  
Transport Proteins ◽  
Diabetic Rat ◽  
Angiotensin Ii Receptor ◽  
Volume Depletion ◽  
Angiotensin System ◽  
Uncontrolled Diabetes ◽  
Receptor Blockers

Volume depletion due to persistent glucosuria-induced osmotic diuresis is a significant problem in uncontrolled diabetes mellitus (DM). Angiotensin II receptor blockers (ARBs), such as candesartan, slow the progression of chronic kidney disease in patients with DM. However, mice with genetic knockout of components of the renin-angiotensin system have urine concentrating defects, suggesting that ARBs may exacerbate the volume depletion. Therefore, the effect of candesartan on UT-A1, UT-A3, NKCC2, and aquaporin-2 (AQP2) protein abundances was determined in control and 3-wk DM rats. Aldosterone levels in control rats (0.36 ± 0.06 nM) and candesartan-treated rats (0.34 ± 0.14 nM) were the same. DM rats had higher aldosterone levels (1.48 ± 0.37 nM) that were decreased by candesartan (0.97 ± 0.26 nM). Western analysis showed that UT-A1 expression was increased in DM rats compared with controls in inner medullary (IM) tip (158 ± 13%) and base (120 ± 25%). UT-A3 abundance was increased in IM tip (123 ± 11%) and base (146 ± 17%) of DM rats vs. controls. UT-A3 was unchanged in candesartan-treated control rats. In candesartan-treated DM rats, UT-A3 increased in IM tip (160 ± 14%) and base (210 ± 19%). Candesartan-treated DM rats had slightly higher AQP2 in IM (46%, P < 0.05) vs. control rats. NKCC2/BSC1 was increased 145 ± 10% in outer medulla of DM vs. control rats. We conclude that candesartan augments compensatory changes in medullary transport proteins, reducing the losses of solute and water during uncontrolled DM. These changes may represent a previously unrecognized beneficial effect of type 1 ARBs in DM.

Abstract P153: Downregulation of Neuronal Nitric Oxide Synthase Within the Paraventricular Nucleus in Insulin Dependent Diabetic Akita Mice

Hypertension ◽  
2016 ◽  
Vol 68 (suppl_1) ◽  
Author(s):  
Neeru M Sharma ◽  
Paras K Mishra ◽  
Kaushik P Patel
Keyword(s):  
Nitric Oxide ◽  
Paraventricular Nucleus ◽  
Renin Angiotensin System ◽  
Diabetic Rats ◽  
Ang Ii ◽  
Protein Levels ◽  
Catalytically Active ◽  
Insulin Dependent ◽  
Insulin Dependent Diabetic ◽  
Akita Mice

Activation of both renin-angiotensin- system (RAS) and sympathetic system are the primary etiologic events in the development of hypertension in diabetes mellitus (DM). However, the precise mechanisms for sympathetic activation in DM have not been elucidated. Our previous studies have demonstrated that neuronal nitric oxide (nNOS) expression and nitric oxide (NO) mediated inhibition of sympathetic nerve activity (SNA) is markedly reduced in the paraventricular nucleus (PVN) of streptozotocin-induced diabetic rats. We have further demonstrated that Angiotensin II (Ang II) via Ang II type 1 receptors (AT 1 R) modulates the expression of nNOS in the PVN, which augments sympathetic outflow. Here we hypothesized that DM-linked hypertension and cardiovascular dysregulation is due to the reduction in nNOS with the PVN. To test the hypothesis, we used Ins2 +/- Akita (a spontaneous, insulin dependent genetic diabetic murine model) which showed an increase in systolic blood pressure at the age of 14 weeks compared to corresponding C57BL/6J (WT) mice with concomitant decreased expression of nNOS (0.75±0.05 WT vs. 0.43±0.11* Akita) in the PVN. Further, Akita mice had increased expression of ACE (angiotensin converting enzyme) (WT 0.34±0.04 vs. Akita 0.58±0.05*) and AT 1 R (WT 0.29±0.09 vs. Akita 0.49±0.03*) and decreased expression of ACE2 (0.27±0.03 WT vs. 0.17±0.05* Akita) and Mas receptor (WT 0.77±0.07 vs. Akita 0.46±0.02*), suggesting an imbalance in the excitatory and protective arms of RAS. Moreover, we found increased protein levels of PIN (a protein inhibitor of nNOS, known to dissociate catalytically active nNOS dimers to monomers) (WT 0.71±0.09 vs. Akita 1.75±0.08) with 72 percent decrease in dimer/monomer ratio of nNOS (WT 0.19±0.0 vs. Akita 0.11±0.04) in the PVN of Akita mice. Taken together, our studies suggest that accumulation of PIN, mediated by activation of the excitatory arm of RAS, leads to a decrease in the active dimeric form of nNOS resulting in reduced NO causing an over-activation of the sympathetic drive, leading to hypertension in DM. 1

Higher Angiotensin II type 1 receptor (AT1R) levels and activity in the post-mortem brains of older persons with Alzheimer's disease

2021 ◽  
Author(s):  
Caglar Cosarderelioglu ◽  
Lolita S Nidadavolu ◽  
Claudene J George ◽  
Ruth Marx ◽  
Laura Powell ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Angiotensin Ii ◽  
Amyloid Β ◽  
Renin Angiotensin System ◽  
Angiotensin Receptors ◽  
Post Mortem ◽  
Protein Levels ◽  
Normal Individuals ◽  
Markers Of Oxidative Stress

Abstract Aging is a key risk factor in Alzheimer's dementia (AD) development and progression. The primary dementia-protective benefits of Angiotensin II subtype 1 receptor (AT1R) blockers are believed to arise from systemic effects on blood pressure. However, a brain-specific renin-angiotensin system (b-RAS) exists, which can be altered by AT1R blockers. Brain RAS acts mainly through three angiotensin receptors: AT1R, AT2R, and AT4R. Changes in these brain angiotensin receptors may accelerate the progression of AD. Using post-mortem frontal cortex brain samples of age- and sex-matched cognitively normal individuals (n = 30) and AD patients (n = 30), we sought to dissect the b-RAS changes associated with AD and assess how these changes correlate with brain markers of oxidative stress, inflammation, and mitochondrial dysfunction as well as amyloid-β and paired helical filament tau pathologies. Our results show higher protein levels of the pro-inflammatory AT1R and phospho-ERK (pERK) in the brains of AD participants. Brain AT1R levels and pERK correlated with higher oxidative stress, lower cognitive performance, and higher tangle and amyloid-β scores. This study identifies molecular changes in b-RAS and offers insight into the role of b-RAS in AD-related brain pathology.

scholarly journals Facilitated Ca2+ homeostasis and attenuated myocardial autophagy contribute to alleviation of diabetic cardiomyopathy after bariatric surgery

2018 ◽  
Vol 315 (5) ◽  
pp. H1258-H1268 ◽  
Author(s):  
Xin Huang ◽  
Shaozhuang Liu ◽  
Dong Wu ◽  
Yugang Cheng ◽  
Haifeng Han ◽  
...  
Keyword(s):  
Bariatric Surgery ◽  
Diabetic Cardiomyopathy ◽  
Ventricular Myocytes ◽  
Mammalian Target Of Rapamycin ◽  
Diabetic Rats ◽  
Diabetic Rat ◽  
Autophagic Flux ◽  
Fk506 Binding Protein ◽  
Plasmic Reticulum ◽  
Chloroquine Treatment

Bariatric surgery has been reported to relieve diabetic cardiomyopathy (DCM) effectively. However, the mechanisms remain largely unknown. To determine the effects of bariatric surgery on DCM via modulation of myocardial Ca2+ homeostasis and autophagy, sleeve gastrectomy (SG), duodenal-jejunal bypass (DJB), and sham surgeries were performed in diabetic rats induced by high-fat diet and a low dose of streptozotocin. Cardiac remodeling was assessed by a series of morphometric and histological analyses. Transthoracic echocardiography and hemodynamic measurements were performed to determine cardiac function. Ca2+ homeostasis was evaluated by measuring Ca2+ transients with fura-2 AM in isolated ventricular myocytes along with detection of the abundance of Ca2+ regulatory proteins in the myocardium. Myocardial autophagic flux was determined by expression of autophagy-related proteins in the absence and presence of chloroquine. Both SG and DJB surgery alleviated DCM morphologically and functionally. Ca2+ transients exhibited a significantly higher amplitude and faster decay after SG and DJB, which could be partially explained by increased expression of ryanodine receptor 2, sarco(endo)plasmic reticulum Ca2+-2ATPase, 12.6-kDa FK506-binding protein, and hyperphosphorylation of phospholamban. In addition, a lower level of light chain 3B and higher level of p62 were detected after both SG and DJB, which was not reversed by chloroquine treatment and associated with activated mammalian target of rapamycin and attenuated AMP-activated protein kinase signaling pathway. Collectively, these results provided evidence that bariatric surgery could alleviate DCM effectively, which may result, at least in part, from facilitated Ca2+ homeostasis and attenuated autophagy, suggesting a potential choice for treatment of DCM when properly implemented. NEW & NOTEWORTHY The present study is the first to investigate the modulation of myocardial Ca2+ homeostasis and autophagy after bariatric surgery and to examine its effects on diabetic cardiomyopathy. Bariatric surgery could facilitate myocardial Ca2+ homeostasis and attenuate myocardial autophagy, contributing to the alleviation of cardiomyopathy morphologically and functionally in a diabetic rat model.

Sexual dysfunction in the diabetic BB/WOR rat: a role of central neuropathy

1997 ◽  
Vol 272 (1) ◽  
pp. R259-R267 ◽  
Author(s):  
K. T. McVary ◽  
C. H. Rathnau ◽  
K. E. McKenna
Keyword(s):  
Sexual Function ◽  
Diabetic Rats ◽  
Nerve Fibers ◽  
Diabetic Rat ◽  
Penile Erections ◽  
Reflex Testing ◽  
Diabetic Impotence ◽  
Central Neuropathy ◽  
Sexual Reflexes

The pathophysiological mechanisms of diabetic impotence remain obscure. We have presented an analysis of sexual function in a diabetic rat (BB/WOR) model characterized by diffuse neuropathic changes without a confounding vasculopathy that allows us to define the neural components of erectile failure. Copulatory behavioral testing demonstrated that diabetic males were severely impaired: the controls mounted three times more than the diabetics and had about one-half the latency to first mount. The diabetics had about one-fourth the number of intromissions and took nearly twice as long to achieve first ejaculation. The number of ejaculations was drastically reduced as well. We examined sexual reflexes in the anesthetized acutely spinalized rat. These experiments tested the integrity of spinal circuits controlling sexual function. Reflex testing demonstrated that spinal sexual reflexes were also severely impaired: the onset latency of reflexes was more than doubled, and the duration of reflexes was less than one-half. More than one-half of the diabetic rats showed no penile erections. Neural studies showed even more derangement in reflex measures in rats, without erection. Nerve conduction velocity experiments suggested a peripheral neuropathic change in hypogastric nerve and motor pudendal nerve fibers. These dysfunctional findings were seen without any androgen deficiency. These results indicate that diabetic impotence in this model reflects central and peripheral neuropathic disease processes.

Studies on regulatory mechanisms of heme biosynthesis in hepatocytes from normal and experimental-diabetic rats. Role of insulin

1990 ◽  
Vol 68 (6) ◽  
pp. 914-921 ◽  
Author(s):  
Eduardo T. Cánepa ◽  
Elena B. C. Llambías ◽  
Moisés Grinstein
Keyword(s):  
Aminolevulinic Acid ◽  
Rat Hepatocytes ◽  
Isolated Hepatocytes ◽  
Inhibitory Effect ◽  
Diabetic Rats ◽  
Significant Inhibition ◽  
Diabetic Rat ◽  
Experimental Conditions ◽  
Cytochrome P 450

In the present work we demonstrate that insulin decreases the phenobarbital-induced activities of δ-aminolevulinic acid synthase and ferrochelatase in isolated hepatocytes from normal and experimental-diabetic rats. Insulin concentrations required to produce significant inhibition in diabetic hepatocytes were higher than in normal cells. Under similar experimental conditions, insulin decreased the basal activities of δ-aminolevulinic acid synthase and ferrochelatase in hepatocytes from normal rats; no inhibitory effect was observed on the basal activity of δ-aminolevulinic acid synthase in hepatocytes from diabetic rats. Cytochrome P-450 content of both normal and diabetic cells was not affected by insulin in absence or presence of phenobarbital. The inhibitory action of insulin was exerted even when effective concentrations of glucagon, dexamethasone, or 8-(p-chlorophenylthio)-cAMP were present.Key words: δ-aminolevulinic acid synthase, ferrochelatase, cAMP, insulin, diabetic rat hepatocytes.

Increased expression of cyclooxygenase-1 and -2 in the diabetic rat renal medulla

2003 ◽  
Vol 285 (6) ◽  
pp. F1068-F1077 ◽  
Author(s):  
Rania Nasrallah ◽  
Anne Landry ◽  
Sonia Singh ◽  
Monika Sklepowicz ◽  
Richard L. Hébert
Keyword(s):  
Collecting Duct ◽  
Renal Medulla ◽  
Immunohistochemical Analysis ◽  
Diabetic Rats ◽  
Diabetic Rat ◽  
Fourfold Increase ◽  
Protein Levels ◽  
Cyclooxygenase 1 ◽  
Streptozotocin Diabetic Rats ◽  
Medullary Collecting Duct

Alterations in renal prostaglandins (PGs) may contribute to some of the renal manifestations in diabetes leading to nephropathy. PG production is dependent on the activity of cyclooxygenases (COX-1 AND -2) and PG synthases. Our present study investigated levels of these enzymes in streptozotocin-diabetic rats at 2, 4, 6, and 8 wk of diabetes. Immunohistochemical analysis revealed an increase in COX signal in the inner and outer medulla of diabetic rats. This was confirmed by Western blotting, showing up to a fourfold increase in both COX isoforms at 4–6 wk of diabetes. Also, Western blot analysis revealed a sixfold increase in PGE2 synthase expression in the outer medullary region of 6-wk diabetic rats but no difference in the inner medulla. In cultured rat inner medullary collecting duct (IMCD), levels of COX were increased two- to threefold in cells exposed for 4 days to 37.5 mM glucose compared with control of 17.5 mM. While no change in PGE2 synthase levels was noted, PGE2 synthesis was increased. Furthermore, levels of EP1 and EP4 mRNA were increased, as well as a twofold increase in EP4 protein levels. Future studies will determine which COX isoform is contributing to the majority of PGE2 produced in the diabetic IMCD and the significance of these findings to disturbances in IMCD function and to the progression of diabetic nephropathy.

Role of adrenal renin-angiotensin system in the control of aldosterone secretion in sodium-restricted rats

2000 ◽  
Vol 278 (6) ◽  
pp. E1027-E1030 ◽  
Author(s):  
Giuseppina Mazzocchi ◽  
Ludwik K. Malendowicz ◽  
Anna Markowska ◽  
Giovanna Albertin ◽  
Gastone G. Nussdorfer
Keyword(s):  
Enzyme Inhibitor ◽  
Renin Angiotensin System ◽  
Zona Glomerulosa ◽  
Normal Diet ◽  
Angiotensin Ii Receptor ◽  
Aldosterone Secretion ◽  
Angiotensin System ◽  
Renin Angiotensin

This study examined the effect of the pharmacological manipulation of adrenal renin-angiotensin system (RAS) on aldosterone secretion from in situ perfused adrenals of rats kept on a normal diet and sodium restricted for 14 days. Neither the angiotensin-converting enzyme inhibitor captopril nor the nonselective angiotensin II receptor antagonist saralasin and the AT1 receptor-selective antagonist losartan affected basal aldosterone output in normally fed rats. In contrast, they concentration dependently decreased aldosterone secretion in sodium-restricted animals, with maximal effective concentration ranging from 10− 7 to 10− 6 M. Captopril (10− 6 M), saralasin (10− 6 M), and losartan (10− 7 M) counteracted aldosterone response to 10 mM K+ in sodium-restricted rats but not in normally fed animals. Collectively, these findings provide evidence that adrenal RAS plays a role in the regulation of aldosterone secretion, but only under conditions of prolonged stimulation of zona glomerulosa probably leading to overexpression of adrenal RAS.

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