Biomedical subjects

Alejandro R Chade

Publications and source records attributed to Alejandro R Chade.

At least 19 recordsLinked to original sources

PubMed2006

Endothelin-a receptor blockade improves renal microvascular architecture and function in experimental hypercholesterolemia.

Hypercholesterolemia (HC) may trigger early renal injury, partly by impairing the function or the structure of renal microvessels (MV). The endothelin (ET) system is upregulated in HC and can have an impact on the renal microcirculation by regulating MV tone, growth factors, and remodeling. It was hypothesized that ET-A blockade would protect the HC kidney by improving the function and attenuating the damage of intrarenal MV. Single-kidney function and hemodynamic responses to endothelium-dependent challenge were assessed in pigs after 12 wk of experimental HC, HC and chronic supplementation with the ET receptor A blocker ABT-627 (HC+ET-A, 0.75 mg/kg per d), and normal controls. Renal MV architecture then was studied ex vivo using three-dimensional microcomputed tomography imaging, and growth factors and remodeling pathways were explored in renal tissue. The HC kidney showed increased MV density compared with normal (77.68 +/- 5.1 versus 62.9 +/- 4.8 vessels/cm(2); P = 0.04) but blunted endothelial function. Chronic ET-A blockade in HC upregulated renal vascular growth factors, further increased renal MV density (139.9 +/- 8.4 vessels/cm(2); P = 0.001 versus normal and HC), and decreased renal tissue and MV remodeling. Furthermore, ET-A blockade in HC decreased MV tortuosity and improved MV endothelial function, suggesting accelerated stabilization and maturation of neo-vessels. Modulation of renal MV architecture and function in HC is mediated partly by the endogenous ET system. Notably, ET-A blockade enhanced the proliferation and facilitated the maturation of renal MV in the HC kidney and improved renal MV remodeling and function. This study suggests novel renoprotective effects of ET-A blockers and supports further exploration of strategies that target the ET pathway in HC and atherosclerosis.

Animals↗

PubMed2006

Early experimental obesity is associated with coronary endothelial dysfunction and oxidative stress.

Obesity is independently associated with increased cardiovascular risk. However, since established obesity clusters with various cardiovascular risk factors, configuring the metabolic syndrome, the early effects of obesity on vascular function are still poorly understood. The current study was designed to evaluate the effect of early obesity on coronary endothelial function in a new animal model of swine obesity. As to method, juvenile domestic crossbred pigs were randomized to either high-fat/high-calorie diet (HF) or normal chow diet for 12 wk. Coronary microvascular permeability and abdominal wall fat were determined by using electron beam computerized tomography. Epicardial endothelial function and oxidative stress were measured in vitro. Systemic oxidative stress, renin-angiotensin activity, leptin levels, and parameters of insulin sensitivity were evaluated. As a result, HF pigs were characterized by abdominal obesity, hypertension, and elevated plasma lysophosphatidylcholine and leptin in the presence of increased insulin sensitivity. Coronary endothelium-dependent vasorelaxation was reduced in HF pigs and myocardial microvascular permeability increased compared with those values in normal pigs. Systemic redox status in HF pigs was similar to that in normal pigs, whereas the coronary endothelium demonstrated higher content of superoxide anions, nitrotyrosine, and NADPH-oxidase subunits, indicating increased tissue oxidative stress. In conclusion, the current study shows that early obesity is characterized by increased vascular oxidative stress and endothelial dysfunction in association with increased levels of leptin and before the development of insulin resistance and systemic oxidative stress. Vascular dysfunction is therefore an early manifestation of obesity and might contribute to the increased cardiovascular risk, independently of insulin resistance.

Animals↗

PubMed2006

Redox-sensitive myocardial remodeling and dysfunction in swine diet-induced experimental hypercholesterolemia.

OBJECTIVES: The effects of hypercholesterolemia (HC) on the myocardium and the underlying mechanisms are unclear. We tested the hypothesis that diet-induced HC-induced myocardial fibrosis by regulating the transforming growth factor (TGF)-beta pathway and apoptosis through increased oxidative stress, and that these would be functionally consequential. METHODS: Three groups of pigs (n=6 each) were studied after 12 weeks of normal or 2% HC diet, or HC+antioxidant supplementation. Cardiac function was evaluated by electron beam computed tomography, while fibrogenic mechanisms and apoptosis were evaluated in myocardial tissue. RESULTS: HC-induced myocardial fibrosis was accompanied by increased ratio of interstitial collagen I/III (1.4+/-0.3 versus 0.5+/-0.1 in normal, p<0.05), expression of TGF-beta1 and its downstream smad mediators, as well as myocyte apoptosis. These alterations were also associated with a decrease in diastolic filling rate compared to normal (134.0+/-10.6 ml/s versus 70.3+/-14.3 ml/s, p<0.05), but were attenuated in HC animals chronically supplemented with antioxidants. CONCLUSIONS: Myocardial injury elicited by experimental HC includes redox-sensitive increases in TGF-beta1 expression and apoptosis, which are associated with diastolic dysfunction. These observations underscore a role of increased oxidative stress in modulating myocardial tissue remodeling and dysfunction in vivo in HC.

Animals↗

PubMed2006

The porcine remnant kidney model of chronic renal insufficiency.

BACKGROUND: The purpose of the present study was to develop and characterize a porcine model of chronic renal insufficiency created by renal artery embolization. METHODS: The model was created using 42 castrated juvenile male pigs (7-8 months old) in two parts (pilot (N = 10) group, definitive (N = 26) group, and control group (N = 6). In the pilot group, the embolization procedure was optimized with respect to the size of polyvinyl acrylide (PVA) particles, coils, and amount of kidney embolized. The animals were followed serially for 4 weeks after the embolization procedure to determine the renal function and hypertensive response. In the definitive group, these results were extended to later time points and a left total nephrectomy and a right partial nephrectomy (remnant) were performed and these animals were followed for 28 to 84 days. RESULTS: The kidney function after the embolization was characterized by acute deterioration in renal function, followed by improvement, and "stable" chronic renal insufficiency with statistically significant elevation in creatinine and BUN being observed until day 42. The mean arterial blood pressure remained significantly elevated until day 7 after which it began to decrease to pre-embolization value. The remnant kidney developed fibrosis in the tublointerstitial compartment as it hypertrophied and increased its weight which remained significantly elevated after embolization. CONCLUSIONS: A reproducible remnant kidney model of chronic renal insufficiency in pigs was developed. In this model, stable renal insufficiency develops by 4 weeks that lasts until 12 weeks.

Angiography↗

PubMed2006

Simvastatin promotes angiogenesis and prevents microvascular remodeling in chronic renal ischemia.

We tested the hypothesis that statins would decrease renal injury in renal artery stenosis (RAS) by restoring angiogenesis and attenuating intrarenal microvascular (IMV) remodeling. Single-kidney hemodynamics and function were quantified using electron-beam-computed tomography (CT) in normocholesterolemic pigs after 12 wk of experimental RAS, RAS supplemented with simvastatin (RAS+simvastatin), and normal controls. Renal circulation was also studied in vivo using angiography and ex vivo using a unique 3D micro-CT imaging technique. Angiogenic and remodeling pathways were subsequently explored in renal tissue. Blood pressure and the degree of stenosis were similarly increased in RAS groups. Simvastatin in RAS enhanced both intrarenal angiogenesis and peri-stenosis arteriogenesis and increased the expression of angiogenic growth factors and hypoxia-inducible factor-1alpha. Furthermore, simvastatin decreased tissue-transglutaminase expression and IMV inward remodeling, restored IMV endothelial function, decreased fibrogenic activity, and improved renal function. Chronic simvastatin supplementation promoted angiogenesis in vivo, decreased ischemia-induced IMV remodeling, and improved IMV function in the stenotic kidney, independent of lipid lowering. These novel renoprotective effects suggest a role for simvastatin in preserving the ischemic kidney in chronic RAS.

Angiogenic Proteins↗

PubMed2006

Role of oxidative stress in remodeling of the myocardial microcirculation in hypertension.

OBJECTIVE: We tested the hypothesis that in early hypertension (HT), increased oxidative stress leads to myocardial microvascular remodeling. METHODS AND RESULTS: Pigs were studied after a 12-week observation: normal (n=8), untreated renovascular HT (n=8), or HT+chronic antioxidant supplementation (HT+A, n=6). Left ventricular muscle mass (LVMM) and myocardial blood flow (MBF) reserve were determined using electron beam computer tomography (CT), and the spatial density and tortuousity of myocardial microvessels (<500 microm) was then measured in myocardial samples with micro-CT. Myocardial microvascular morphology, oxidative stress, inflammation, and growth factor expression were determined in vitro. HT and HT+A had similarly increased arterial pressure and LVMM, but only HT showed impaired MBF response to adenosine. Compared with normal, HT had increased spatial density of myocardial microvessels, which was preserved in HT+A (111.8+/-7.8, 166.3+/-15.7, and 106.4+/-6.1 vessels per cm2, respectively). HT also showed microvascular wall thickening, increased systemic and tissue oxidative stress, inflammation, and expression of vascular endothelial growth factor and its receptor Flk-1, most of which were attenuated by antioxidants. CONCLUSIONS: Myocardial microvascular remodeling in early HT is accompanied by tissue oxidative stress, inflammation, and altered growth factor expression, and attenuated by antioxidant intervention. This study underscores a role of increased oxidative stress in modulating myocardial microvascular architecture in early HT.

Animals↗

PubMed2006

Atherosclerotic process, renovascular disease and outcomes from bench to bedside.

PURPOSE OF REVIEW: Atherosclerotic renal artery stenosis has become an important cause of secondary hypertension and renal dysfunction in the aging population. Its presence increases cardiovascular morbidity and mortality independent of other atherosclerotic risk factors. Therefore, novel renoprotective strategies are needed to decrease the impact of this disease. RECENT FINDINGS: Although medical therapy can be effective in patients with atherosclerotic renal artery stenosis and mild renal dysfunction, revascularization is desirable for patients with target-organ injury. Technical developments (such as drug-eluting or low-profile stents and distal protection devices) have increased the safety and effectiveness of renal revascularization, but in a significant proportion of patients renal function is not fully restored. Recent experimental evidence suggests that atherosclerotic renal artery stenosis is associated with the activation of intrarenal fibrogenic and inflammatory pathways, oxidative stress, and microvascular remodeling, and blocking these mechanisms can improve renal hemodynamics and function. SUMMARY: Despite significant advances in revascularization techniques, it remains unclear why the kidney affected by atherosclerotic renal artery stenosis often does not improve or even progressively deteriorates. In addition to the restoration of blood flow, targeted interventions to attenuate injurious intrarenal mechanisms should probably become part of a comprehensive management plan to preserve the ischemic kidney.

Atherectomy↗

PubMed2005

Acute inhibition of the endogenous xanthine oxidase improves renal hemodynamics in hypercholesterolemic pigs.

Hypercholesterolemia (HC), a major risk factor for onset and progression of renal disease, is associated with increased oxidative stress, potentially causing endothelial dysfunction. One of the sources of superoxide anion is xanthine oxidase (XO), but its contribution to renal endothelial function in HC remains unclear. We tested the hypothesis that XO modulates renal hemodynamics and endothelial function in HC pigs. Four groups (n = 23) of female domestic pigs were studied 12 wk after either normal (n = 11) or HC diet (n = 12). Oxidative stress was assessed by plasma isoprostanes and oxidized LDL, and the XO system by plasma uric acid, urinary xanthine, and renal XO expression (by immunoblotting and immunohistochemistry). Renal hemodynamics and function were studied with electron beam-computed tomography before and after endothelium-dependent (ACh) and -independent (sodium nitroprusside) challenge, during a concurrent intrarenal infusion of either oxypurinol or saline (n = 5-6 in each group). HC showed elevated oxidative stress, higher plasma uric acid (23.8 +/- 3.8 vs. 6.2 +/- 0.8 microM/mM creatinine, P = 0.001), lower urinary xanthine, and greater renal XO expression compared with normal. Inhibition of XO in HC significantly improved the blunted responses to ACh of cortical perfusion (13.5 +/- 12.1 and 37.2 +/- 10.6%, P = 0.01 and P = not significant vs. baseline, respectively), renal blood flow, and glomerular filtration rate; restored medullary perfusion; and improved the blunted cortical perfusion response to sodium nitroprusside. This study demonstrates that the endogenous XO system is activated in swine HC. Furthermore, it suggests an important role for XO in regulation of renal hemodynamics, function, and endothelial function in experimental HC.

Animals↗

PubMed2005

Functional and structural remodeling of the myocardial microvasculature in early experimental hypertension.

Advanced hypertension (HT), associated with left ventricular hypertrophy (LVH), impairs myocardial microvascular function and structure and leads to increased myocardial hypoxia and growth factor activation. However, the effect of HT on microvascular architecture and its relation to microvascular function, before the development of LVH (early HT), remains unclear. By way of method, pigs were studied after 12 wk of renovascular HT (n = 7) or control (n = 7) animals. Myocardial microvascular function (blood volume and blood flow at baseline and in response to adenosine) was assessed by using electron beam computed tomography (CT). Microvascular architecture was subsequently studied ex vivo using micro-CT, and microvessels (diameter, <500 microm) were counted in situ in three-dimensional images (40-microm on-a-side cubic voxels). Myocardial expression of vascular endothelial growth factor, basic fibroblast growth factor, and hypoxia-inducible factor-1alpha were also measured. By way of results, left ventricular muscle mass was similar between the groups. The blood volume response to intravenous adenosine was attenuated in HT animals compared with normal animals (+7.4 +/- 17.0 vs. +46.2 +/- 12.3% compared with baseline, P = 0.48 and P = 0.01, respectively). Microvascular spatial density in HT animals was significantly elevated compared with normal animals (246 +/- 26 vs. 125 +/- 20 vessels/cm2, P < 0.05) and correlated inversely with the blood volume response to adenosine. Growth factors expression was increased in HT animals compared with control animals. In conclusion, early HT elicits changes in myocardial microvascular architecture, which are associated with microvascular dysfunction and precede changes in muscle mass. These observations underscore the direct and early effects of HT on the myocardial vasculature.

Animals↗

PubMed2005

Pathways of renal fibrosis and modulation of matrix turnover in experimental hypercholesterolemia.

Dyslipidemia often accompanies and accelerates renal disease, partly by promoting fibrosis. However, the mechanisms mediating this effect are unclear. We hypothesized that hypercholesterolemia modulates several interlinked pathways that promote deposition and blunt degradation of extracellular matrix, and that these could be manipulated by reversal of hypercholesterolemia. Fourteen pigs were fed a 16-week 2% high-cholesterol diet (HC-HC; n=7) or normal diet (n=7), whereas in 7 others, a 10-week HC was followed by a 6-week normal diet (HC-N). Renal endothelial function was assessed in vivo with electron-beam computed tomography, and renal tissue was then studied ex vivo using Western blot, real-time quantitative polymerase chain reaction, gelatin zymography, and immunostaining. HC-HC kidneys showed endothelial dysfunction, accompanied by increased intrarenal oxidative stress, inflammation, activation of the endothelin and transforming-growth factor-beta systems, and decreased matrix metalloproteinase expression and activity. Accordingly, HC-HC kidneys showed increased collagen IV expression and fibrosis. A lipid-lowering dietary intervention reversed most of these changes. In conclusion, this study indicates that renal fibrosis in early atherosclerosis is a result of a simultaneous increase in extracellular matrix deposition and blunted matrix metalloproteinase-mediated degradation, overall promoting perivascular and tubulointerstitial fibrosis. Notably, many of these pathways may be reversible in hypercholesterolemia, and crucial targets could potentially be identified for early interventions to preserve the kidney.

Animals↗

PubMed2005

Kidney in early atherosclerosis.

Atherosclerosis represents one of the major causes of premature death in the United States today, and it is frequently associated with, exacerbates, and is aggravated by chronic kidney disease (CKD). Atherosclerosis integrates the response to a number of insults, and consequently, the accelerated atherosclerosis found in CKD patients is associated with activation of a variety of humoral and tissue mechanisms. Hypertension, diabetes, dyslipidemia, obesity, metabolic syndrome, and additional nontraditional risk factors can damage the kidney directly and by promoting intrarenal atherogenesis, even in the absence of obstructive lesions in the renal artery. Evidence indicates that increased oxidative stress and inflammation may mediate a large part of the effects of risk factors on the kidney. In turn, progressive deterioration of renal function in CKD may lead to dyslipidemia or accumulation of uremic toxins, which can induce production of free radicals and activate proinflammatory and fibrogenic factors, leading to vascular endothelial cell dysfunction and injury, and favoring development of atherosclerosis. Therefore, the kidney can be a villain or a victim during atherogenesis. The purpose of this review is to provide new insights into the mechanisms by which atherogenic factors may instigate early renal injury.

Atherosclerosis↗

PubMed2005

Effects of proteasome inhibition on the kidney in experimental hypercholesterolemia.

Hypercholesterolemia (HC) and atherosclerosis often accompany and aggravate renal disease. Proteasome inhibitors (PSI) can decrease proliferation and inflammation, likely by reducing activation of the proinflammatory NF-kappaB. However, chronic proteasome inhibition has never been demonstrated in the HC kidney. Four groups of pigs (n = 7 each) were studied after a 12-wk normal (N) or 2% HC diet alone or supplemented (N+PSI and HC+PSI) with MLN-273 (0.08 mg/kg subcutaneously twice weekly). Renal hemodynamics and function were quantified in vivo using electron-beam computed tomography at baseline and after vasodilator challenge using acetylcholine. Renal tissue was studied ex vivo using immunoblotting, PCR, and immunohistochemistry. Serum cholesterol was similarly elevated in HC and HC+PSI. Basal renal blood flow was similar among the groups, whereas GFR was decreased in both N+PSI and HC+PSI. The blunted renovascular and functional responses to acetylcholine in HC were normalized in HC+PSI (suggesting renal endothelial function improvement), which was accompanied by decreased renal endothelin, NF-kappaB, and augmented endothelial nitric oxide synthase expression. In parallel, HC+PSI animals also showed elevated NAD(P)H oxidase expression and circulating oxidized LDL, suggesting a potential for increased oxidative stress. This study shows that chronic PSI intervention in HC improves renal endothelial functional responses to challenge, possibly by modulating nitric oxide availability and endothelin. Furthermore, PSI may decrease intrarenal inflammation through modulation of the NF-kappaB pathway but may potentially increase oxidative stress, which warrants further investigation. This study may support a role for the ubiquitin/proteasome system in the kidney in HC and early atherosclerosis.

Acetylcholine↗

PubMed2005

Animal models of hypertension: an overview.

Hypertension is a multifactorial disease involving complex interactions between genetic and environmental factors. Development of experimental models of hypertension allowed dissection and isolation of various factors associated with regulation of blood pressure, inheritance of hypertensive traits, and cellular responses to injury. The phenotype-driven approach is taking advantage of selective breeding of animals (primarily rats) that exhibit a desired phenotype, like the useful SHR. Genotype-driven models include transgenic techniques, in which mice are the most successful for selective deletion or overexpression of target genes. Notably, a combination of comparative genomics strategies and phenotypic correlates enhances the utility of hypertension models and their clinical relevance. Indeed, experimental models enabled development of targeted interventions aimed at decreasing not only blood pressure but also target organ injury. Continued utilization of experimental models simulating human hypertension, particularly those that combine other clinically relevant comorbidities like obesity or hypercholesterolemia, may afford development of effective strategies to address this common disease. Nevertheless, a cautious approach is mandatory when experimental findings in these models are extrapolated to human hypertension.

Animals↗

PubMed2004

Cortical microvascular remodeling in the stenotic kidney: role of increased oxidative stress.

OBJECTIVE: Mechanisms of renal injury distal to renal artery stenosis (RAS) remain unclear. We tested the hypothesis that it involves microvascular remodeling consequent to increased oxidative stress. METHODS AND RESULTS: Three groups of pigs (n=6 each) were studied after 12 weeks of RAS, RAS+antioxidant supplementation (100 IU/kg vitamin E and 1 g vitamin C daily), or controls. The spatial density and tortuousity of renal microvessels (<500 microm) were tomographically determined by 3D microcomputed tomography. The in situ production of superoxide anion and the expression of vascular endothelial growth factor (VEGF), its receptor VEGFR-2, hypoxia-inducible-factor (HIF)-1alpha, von Hippel-Lindau (VHL) protein, and NAD(P)H oxidase (p47phox and p67phox subunits) were determined in cortical tissue. RAS and RAS+antioxidant groups had similar degrees of stenosis and hypertension. The RAS group showed a decrease in spatial density of cortical microvessels, which was normalized in the RAS+antioxidant group, as was arteriolar tortuousity. RAS kidneys also showed tissue fibrosis (by trichrome and Sirius red staining), increased superoxide anion abundance, NAD(P)H oxidase, VHL protein, and HIF-1alpha mRNA expression. In contrast, expression of HIF-1alpha, VEGF, and VEGFR-2 protein was downregulated. These were all significantly improved by antioxidant intervention. CONCLUSIONS: Increased oxidative stress in the stenotic kidney alters growth factor activity and plays an important role in renal microvascular remodeling, which can be prevented by chronic antioxidant intervention.

Animals↗

PubMed2004

Antioxidant intervention attenuates myocardial neovascularization in hypercholesterolemia.

BACKGROUND: Hypercholesterolemia (HC) and atherosclerosis can elicit oxidative stress, coronary endothelial dysfunction, and myocardial ischemia, which may induce growth-factor expression and lead to myocardial neovascularization. We tested the hypothesis that chronic antioxidant intervention in HC would attenuate neovascularization and preserve the expression of hypoxia-inducible factor (HIF)-1alpha and vascular endothelial growth factor (VEGF). METHODS AND RESULTS: Three groups of pigs (n=6 each) were studied after 12 weeks of normal or 2% HC diet or HC+antioxidant supplementation (100 IU/kg vitamin E and 1 g vitamin C daily). Myocardial samples were scanned ex vivo with a novel 3D micro-CT scanner, and the spatial density and tortuosity of myocardial microvessels were determined in situ. VEGF mRNA, protein levels of VEGF and VEGF receptor-1, HIF-1alpha, nitrotyrosine, and superoxide dismutase (SOD) were determined in myocardial tissue. The HC and HC+antioxidant groups had similar increases in serum cholesterol levels. HC animals showed an increase in subendocardial spatial density of microvessels compared with normal (160.5+/-11.8 versus 95.3+/-8.2 vessels/cm2, P<0.05), which was normalized in HC+antioxidant (92.5+/-20.5 vessels/cm2, P<0.05 versus HC), as was arteriolar tortuosity. In addition, HC induced upregulation of VEGF, HIF-1alpha, and nitrotyrosine expression and decreased SOD expression and activity, all of which were preserved by antioxidant intervention. CONCLUSIONS: Changes in myocardial microvascular architecture invoked by HC are accompanied by increases in HIF-1alpha and VEGF expression and attenuated by antioxidant intervention. This underscores a role of increased oxidative stress in modulating myocardial microvascular architecture in early atherogenesis.

Animals↗

PubMed2004

Comparison of acute and chronic antioxidant interventions in experimental renovascular disease.

Reactive oxygen species (ROS) can modulate renal hemodynamics and function both directly, by leading to vasoconstriction, and indirectly, by inducing renal inflammation and tissue growth. The involvement of oxidative stress in the pathogenesis of renovascular disease (RVD) is increasingly recognized, but the relative contribution of long-term tissue injury to renal dysfunction remains unclear. We hypothesized that functional and structural alterations elicited by oxidative stress in RVD would be more effectively modulated by chronic than by acute antioxidant intervention. Renal hemodynamics and function were quantified in vivo in pigs using electron-beam computed tomography at baseline and after vasoactive challenge (ACh and sodium nitroprusside); after 12 wk of RVD (simulated by concurrent hypercholesterolemia and renal artery stenosis, n = 7); RVD acutely infused with the SOD-mimetic tempol (RVD+tempol, n = 7); RVD chronically supplemented with antioxidant vitamins C (1 g) and E (100 IU/kg; RVD+vitamins, n = 7); or control (normal, n = 7). Renal tissue was studied ex vivo using immunoblotting and immunohistochemistry. Basal renal blood flow (RBF) and glomerular filtration rate were similarly decreased in all RVD groups. ACh-stimulated RBF remained unchanged in RVD, increased in RVD+tempol, but further increased (similarly to normal) in RVD+vitamins (P < 0.05 vs. RVD). Furthermore, RVD+vitamins also showed a decreased presence of superoxide anion, decreased NAD(P)H-oxidase and nitrotyrosine expression, increased endothelial nitric oxide synthase expression, and attenuated renal fibrosis. Chronic antioxidant intervention in early RVD improved renal hemodynamic responses more effectively than acute intervention, likely due to increased nitric oxide bioavailability and decreased structural injury. These suggest that chronic tissue changes play an important role in renal compromise mediated by oxidative stress in RVD.

Acetylcholine↗

PubMed2004

Long-term antioxidant intervention improves myocardial microvascular function in experimental hypertension.

Hypertension increases oxidative stress, which can impair myocardial microvascular function and integrity. However, it is yet unclear whether long-term antioxidant intervention in early hypertension would preserve myocardial perfusion and vascular permeability responses to challenge. Pigs were studied after 12 weeks of renovascular hypertension without (n=8) or with daily supplementation of antioxidants (100 IU/kg vitamin E and 1 g vitamin C, n=6), and compared with normal controls (n=7). Myocardial perfusion and microvascular permeability were measured in vivo by electron beam computed tomography before and after 2 cardiac challenges (intravenous adenosine and dobutamine). Basal left ventricular muscle mass was also obtained. Mean arterial pressure was significantly increased in both groups of hypertensive animals (without and with antioxidants, 123+/-9 and 126+/-4 mm Hg, respectively, versus normal, 101+/-4 mm Hg; both P<0.05), but muscle mass was not different among the groups. The impaired myocardial perfusion response to adenosine observed in hypertensives (normal, +51+/-14%; P<0.05 versus baseline; hypertension, +14+/-15%; P=0.3 versus baseline) was preserved in hypertensive pigs that received antioxidants (+44+/-15%; P=0.01 compared with baseline). Long-term antioxidant intervention also preserved subendocardial microvascular permeability responses in hypertension. On the other hand, antioxidant intervention had little effect on the hypertension-induced myocardial vascular dysfunction observed in response to dobutamine. This study demonstrates that the impaired myocardial perfusion and permeability responses to increased cardiac demand in early hypertension are significantly improved by long-term antioxidant intervention. These results support the involvement of oxidative stress in myocardial vascular dysfunction in hypertension and suggest a role for antioxidant strategies to preserve the myocardial microvasculature.

Animals↗

PubMed2004

Antioxidant intervention blunts renal injury in experimental renovascular disease.

Atherosclerotic renovascular disease (RVD) amplifies damage in a stenotic kidney by inducing pro-inflammatory mechanisms and disrupting tissue remodeling. Oxidative stress is increased in RVD, but its direct contribution to renal injury has not been fully established. The authors hypothesized that chronic antioxidant intervention in RVD would improve renal function and attenuate tissue injury. Single-kidney hemodynamics and function at baseline and during vasoactive challenge were quantified using electron-beam computed tomography in pigs after 12 wk of experimental RVD (simulated by concurrent hypercholesterolemia and renal artery stenosis, n = 7), RVD daily supplemented with antioxidant vitamins C (1 g), and E (100 IU/kg) (RVD+Vitamins, n = 7), or controls (normal, n = 7). Renal tissue was studied ex vivo using Western blot analysis and immunohistochemistry. Basal renal blood flow (RBF) and glomerular filtration rate (GFR) were similarly decreased in the stenotic kidney of both RVD groups. RBF and GFR response to acetylcholine was blunted in RVD, but significantly improved in RVD+Vitamins (P < 0.05 versus RVD). RVD+Vitamins also showed increased renal expression of endothelial nitric oxide synthase (eNOS) and decreased expression of NAD(P)H-oxidase, nitrotyrosine, inducible-NOS, and NF-kappaB, suggesting decreased superoxide abundance and inflammation. Furthermore, decreased expression of pro-fibrotic factors in RVD+Vitamins was accompanied by augmented expression of extracellular (matrix metalloproteinase-2) and intracellular (ubiquitin) protein degradation systems, resulting in significantly attenuated glomerulosclerosis and renal fibrosis. In conclusion, chronic antioxidant intervention in early experimental RVD improved renal functional responses, enhanced tissue remodeling, and decreased structural injury. This study supports critical pathogenic contribution of increased oxidative stress to renal injury and scarring in RVD and suggests a role for antioxidant strategies in preserving the atherosclerotic and ischemic kidney.

Acetylcholine↗