Acute respiratory distress syndrome or acute lung injury (ARDS)/(ALI) involve the severe lung inj... more Acute respiratory distress syndrome or acute lung injury (ARDS)/(ALI) involve the severe lung injury with pulmonary vascular hyper-permeability and hypoxemia induced by inflammatory reactions. Since ARDS/ALI carries high mortality, the development of new drugs against ARDS/ALI is required. We examined the effect of tranilast, an anti-allergic drug, on vascular hyper-permeability in the lungs and airways, and on hypoxemia, in oleic acid (OA)-induced acute lung injury, an animal model of ARDS/ALI. The increase in pulmonary and airway vascular permeability and the decrease in partial oxygen pressure of arterial blood induced by an intravenous injection of OA were drastically ameliorated by the oral administration of tranilast in a dose-dependent manner. This is the first report to prove that tranilast prevents pulmonary and airway vascular permeability and hypoxemia induced by OA. These results suggest that tranilast may be a candidate drug for the treatment of ARDS/ALI.
Several clinical studies demonstrate a beneficial role of angiotensin-converting enzyme (ACE) inh... more Several clinical studies demonstrate a beneficial role of angiotensin-converting enzyme (ACE) inhibitors in patients with myocardial infarction, hypertension and diabetes mellitus. This review focuses on the effects of ramipril, a weak inhibitor of ACE that is rapidly hydrolyzed to ramiprilat, an active metabolite. The Heart Outcome Prevention Evaluation (HOPE) study evaluated the effects of ramipril in patients with a high risk for cardiovascular events without pre-existing left ventricular dysfunction or heart failure. In this review, we summarized the effects of ramipril on myocardial infarction, death, diabetes mellitus, and stroke.
American Journal of Physiology - Heart and Circulatory Physiology, 2015
Psychological stresses are associated with cardiovascular diseases to the extent that cardiovascu... more Psychological stresses are associated with cardiovascular diseases to the extent that cardiovascular 26 diseases are amongst the most important group of psychosomatic diseases. The longstanding 27 association between stress and cardiovascular disease exists despite a large ambiguity about the 28 underlying mechanisms. An array of possibilities have been proposed including overactivity of the 29 autonomic nervous system and humoral changes, which then converge on endothelial dysfunction that 30
Obstructive sleep apnea (OSA) occurs in 2% of middle-aged women and 4% of middle-aged men and is ... more Obstructive sleep apnea (OSA) occurs in 2% of middle-aged women and 4% of middle-aged men and is considered an independent risk factor for cerebrovascular and cardiovascular diseases. Nitric oxide (NO) is an important endothelium derived vasodilating substance that plays a critical role in maintaining vascular homeostasis. Low levels of NO are associated with impaired endothelial function. Asymmetric dimethylarginine (ADMA), an analogue of L-arginine, is a naturally occurring product of metabolism found in the human circulation. Elevated levels of ADMA inhibit NO synthesis while oxidative stress decreases its bioavailability, so impairing endothelial function and promoting atherosclerosis. Several clinical trials report increased oxidative stress and ADMA levels in patients with OSA. This review discusses the role of oxidative stress and increased ADMA levels in cardiovascular disease resulting from OSA.
The effect of antioxidants on ageing type 2 diabetic (T2D) hearts during exercise is unclear. We ... more The effect of antioxidants on ageing type 2 diabetic (T2D) hearts during exercise is unclear. We hypothesized that GSH therapy during exercise reduces mitochondrial oxidative stress (mOXS) and cell death in ageing db/db mice hearts. The effect of GSH on cardiac mOXS and cell death was evaluated both in vivo and in vitro. During exercise, GSH treatment protected db/db hearts from exaggerated mOXS without reducing total cell death. Despite similar cell death, investigations on apoptosis-specific single-stranded DNA breaks and necrosis-specific damage provided the first in vivo evidence of a shift from necrosis to apoptosis, with reduced fibrosis following GSH administration in exercised db/db hearts. Further support for a GSH-regulated 'switch' in death phenotypes came from NIH-3T3 fibroblasts and H9c2 cardiomyocytes treated with H2 O2 , a reactive oxygen species (ROS). Similar to in vivo findings, augmenting GSH by overexpressing glutamyl cysteine ligase (GCLc) protected fibr...
Medical science monitor: international medical journal of experimental and clinical research
Reactive oxygen species (ROS) have deleterious or beneficial effects; this dual nature of ROS mea... more Reactive oxygen species (ROS) have deleterious or beneficial effects; this dual nature of ROS means that ROS act as intracellular signaling molecules and as defense mechanisms against micro-organisms. An overproduction of ROS results in oxidative stress, a deleterious process that damages cell structures, including lipids, proteins, and DNA. Oxidative stress plays a major role in various human disease states, including endocrine dysfunction. As a safeguard against oxidative stress, several endogenous nonenzymatic and enzymatic antioxidant systems exist. Antioxidants can delay or prevent oxidative stress and are widely used in the hope of maintaining health and preventing diseases. Although early studies suggested that antioxidant supplements promoted health, later clinical trials revealed that it may not be true in all cases. In this article, we provide a brief review of the pathophysiologic aspects of oxidative stress in a number of the most commonly human endocrionopathies (diabet...
Oleic acid-induced hypoxemia is an animal model of acute respiratory distress syndrome (ARDS). In... more Oleic acid-induced hypoxemia is an animal model of acute respiratory distress syndrome (ARDS). Increased capillary permeability is a cause of hypoxemia in lung injury. Endothelial cells form a major capillary barrier, and disruption of the barrier appears to involve a decreased level of ATP in the cells. Phosphoenolpyruvate (PEP) is an endogenous substance that is one of the ATP precursors and can cross some cell membranes via anion exchanger. We examined the effect of PEP on oleic acid-induced lung injury in guinea pigs. An intravenous injection of oleic acid (15 microl/kg) caused severe hypoxemia. Pretreatment with PEP at a dose of 2, 20, or 200 micromol/kg attenuated the oleic acid-induced decrease in the arterial partial pressure of oxygen in a dose-dependent manner. Furthermore, PEP attenuated the oleic acid-induced increase in vascular permeability in the proximal and distal bronchi, as indicated by the extravascular leakage of Evans Blue dye. The combination of PEP with ATP (...
Type 2 diabetes accounts for more than 90% of diabetes mellitus. Urinary bladder dysfunction is a... more Type 2 diabetes accounts for more than 90% of diabetes mellitus. Urinary bladder dysfunction is a frequent complication of diabetes and can lead to urinary incontinence (UI), infection and impaired bladder emptying leading to retention of urine and loss of sensation in the patients. Of these, UI is a most debilitating condition that leads to decreased quality of life especially in women. It is estimated to affect approximately 30-50% of the elderly. Exercise is the initial recommended management strategy in diabetes but its effect on diabetic urinary bladder dysfunction or urinary incontinence (UI) is unknown. We hypothesize that exercise improves bladder dysfunction and reduces the voiding frequency in the db/db mouse, a frequently used animal model of type 2 diabetes.
The metabolic syndrome is a clustering of obesity, diabetes, hyperlipidemia, and hypertension tha... more The metabolic syndrome is a clustering of obesity, diabetes, hyperlipidemia, and hypertension that is occurring in increasing frequency across the global population. Although there is some controversy about its diagnostic criteria, oxidative stress, which is defined as imbalance between the production and inactivation of reactive oxygen species, has a major pathophysiological role in all the components of this disease. Oxidative stress and consequent inflammation induce insulin resistance, which likely links the various components of this disease. We briefly review the role of oxidative stress as a major component of the metabolic syndrome and then discuss the impact of exercise on these pathophysiological pathways. Included in this paper is the effect of exercise in reducing fat-induced inflammation, blood pressure, and improving muscular metabolism.
Physical inactivity is increasingly recognized as modifiable behavioral risk factor for cardiovas... more Physical inactivity is increasingly recognized as modifiable behavioral risk factor for cardiovascular diseases. A partial list of proposed mechanisms for exercise-induced cardioprotection include induction of heat shock proteins, increase in cardiac antioxidant capacity, expression of endoplasmic reticulum stress proteins, anatomical and physiological changes in the coronary arteries, changes in nitric oxide production, adaptational changes in cardiac mitochondria, increased autophagy, and improved function of sarcolemmal and/or mitochondrial ATP-sensitive potassium channels. It is currently unclear which of these protective mechanisms are essential for exercise-induced cardioprotection. However, most investigations focus on sarcolemmal KATP channels, NO production, and mitochondrial changes although it is very likely that other mechanisms may also exist. This paper discusses current information about these aforementioned topics and does not consider potentially important adaptations within blood or the autonomic nervous system. A better understanding of the molecular basis of exercise-induced cardioprotection will help to develop better therapeutic strategies.
The lack of adequate physical activity and obesity created a worldwide pandemic. Obesity is chara... more The lack of adequate physical activity and obesity created a worldwide pandemic. Obesity is characterized by the deposition of adipose tissue in various parts of the body; it is now evident that adipose tissue also acts as an endocrine organ capable of secreting many cytokines that are though to be involved in the pathophysiology of obesity, insulin resistance, and metabolic syndrome. Adipokines, or adipose tissue-derived proteins, play a pivotal role in this scenario. Increased secretion of proinflammatory adipokines leads to a chronic inflammatory state that is accompanied by insulin resistance and glucose intolerance. Lifestyle change in terms of increased physical activity and exercise is the best nonpharmacological treatment for obesity since these can reduce insulin resistance, counteract the inflammatory state, and improve the lipid profile. There is growing evidence that exercise exerts its beneficial effects partly through alterations in the adipokine profile; that is, exercise increases secretion of anti-inflammatory adipokines and reduces proinflammatory cytokines. In this paper we briefly describe the pathophysiologic role of four important adipokines (adiponectin, leptin, TNF-, and IL-6) in the metabolic syndrome and review some of the clinical trials that monitored these adipokines as a clinical outcome before and after exercise.
Gestational diabetes mellitus (GDM) is defined as glucose intolerance first diagnosed during preg... more Gestational diabetes mellitus (GDM) is defined as glucose intolerance first diagnosed during pregnancy. This condition shares same array of underlying abnormalities as occurs in diabetes outside of pregnancy, for example, genetic and environmental causes. However, the role of a sedentary lifestyle and/or excess energy intake is more prominent in GDM. Physically active women are less likely to develop GDM and other pregnancy-related diseases. Weight gain in pregnancy causes increased release of adipokines from adipose tissue; many adipokines increase oxidative stress and insulin resistance. Increased intramyocellular lipids also increase cellular oxidative stress with subsequent generation of reactive oxygen species. A well-planned program of exercise is an important component of a healthy lifestyle and, in spite of old myths, is also recommended during pregnancy. This paper briefly reviews the role of adipokines in gestational diabetes and attempts to shed some light on the mechanisms by which exercise can be beneficial as an adjuvant therapy in GDM. In this regard, we discuss the mechanisms by which exercise increases insulin sensitivity, changes adipokine profile levels, and boosts antioxidant mechanisms.
The endothelium plays a critical role in the maintenance of cardiovascular health by producing ni... more The endothelium plays a critical role in the maintenance of cardiovascular health by producing nitric oxide and other vasoactive materials. Aging is associated with a gradual decline in this functional aspect of endothelial regulation of cardiovascular homeostasis. Indeed, age is an independent risk factor for cardiovascular diseases and is in part an important factor in the increased exponential mortality rates from vascular disease such as myocardial infarction and stroke that occurs in the ageing population. There are a number of mechanisms suggested to explain age-related endothelial dysfunction. However, recent scientific studies have advanced the notion of oxidative stress and inflammation as the two major risk factors underlying aging and age-related diseases. Regular physical activity, known to have a favorable effect on cardiovascular health, can also improve the function of the ageing endothelium by modulating oxidative stress and inflammatory processes, as we discuss in this paper.
Diabetes is a chronic metabolic disease which is characterized by absolute or relative deficienci... more Diabetes is a chronic metabolic disease which is characterized by absolute or relative deficiencies in insulin secretion and/or insulin action. The key roles of oxidative stress and inflammation in the progression of vascular complications of this disease are well recognized. Accumulating epidemiologic evidence confirms that physical inactivity is an independent risk factor for insulin resistance and type II diabetes. This paper briefly reviews the pathophysiological pathways associated with oxidative stress and inflammation in diabetes mellitus and then discusses the impact of exercise on these systems. In this regard, we discuss exercise induced activation of cellular antioxidant systems through "nuclear factor erythroid 2-related factor." We also discuss anti-inflammatory myokines, which are produced and released by contracting muscle fibers. Antiapoptotic, anti-inflammatory and chaperon effects of exercise-induced heat shock proteins are also reviewed.
Individuals with high spinal cord injury (SCI) are prone to significant fluctuation in blood pres... more Individuals with high spinal cord injury (SCI) are prone to significant fluctuation in blood pressure with episodes of very high and low blood pressure during autonomic dysreflexia (AD) and orthostatic hypotension, respectively. We do not know how such blood pressure lability affects the vasculature. We used a well-characterized animal model of AD to determine whether increasing the frequency of AD during recovery from SCI would exacerbate injury-induced dysfunction in resistance vessels. Experimental animal study. International Collaboration On Repair Discoveries (ICORD), University of British Columbia, Canada. Complete transection of the T3 spinal cord was performed in male Wistar rats. For 14 days after injury, AD was induced via colorectal distension (CRD; 30 minutes per day) in the experimental group (SCI-CRD). One month after SCI, baseline cardiovascular parameters and severity of CRD-induced AD were assessed in SCI-CRD animals and SCI-only controls. Mesenteric arteries were harvested for in vitro myography to characterize vasoactive responses to phenylephrine (PE) and acetylcholine (ACh). Mesenteric arteries from SCI-CRD animals exhibited larger maximal responses to PE than arteries from SCI-only controls. Hyperresponsiveness to PE was not a product of endothelial dysfunction because mesenteric arteries from both groups had similar vasodilator responses to ACh. Both SCI-only controls and SCI-CRD animals exhibited CRD-evoked AD 1 month after SCI; however, CRD-induced hypertension was less pronounced in animals that were previously exposed to CRD. Injury-induced changes within the vasculature may contribute to the development of AD after SCI. Here, we provide evidence that AD itself has significant and long-lasting effects on vascular function. This finding has implications for the medical management of AD and provides an impetus for maintaining stable blood pressure.
Background: Obstructive sleep apnea (OSA) is a common disorder characterized by chronic intermitt... more Background: Obstructive sleep apnea (OSA) is a common disorder characterized by chronic intermittent hypoxia (CIH). OSA is prevalent in obese subjects and is associated with endothelial dysfunction and cardiovascular disorders. We tested the hypothesis that the deleterious effects of IH could be further modulated by diet-induced obesity. Design: Thirty adult (8-10 weeks) male C57BL/6J mice were divided into four groups. Mice were subjected to CIH or intermittent air (IA) for 12 h a day and fed either a high fat (HF) or a low fat control diet (CD) for 6 weeks. We analyzed endothelial function using a wire myograph, and measured markers of oxidative stress (plasma malondialdehyde (MDA) and total antioxidant capacity (TAC)) using colorimetrical assays. We also measured C-reactive protein (CRP) using ELISA and endothelial nitric oxide (eNOS) gene expression using real time PCR. Results: Stimulated endothelial dependent dilation was significantly impaired only in the group fed high fat diet and subjected to CIH (E max : HFIH 78 ± 2%, p < 0.0001) when compared to the other groups (E max : HFIA 95 ± 0.7%, CDIH 94 ± 2%, CDIA 97 ± 1%). Also basal endothelial dependant dilation was attenuated in the HFIH group compared to the HFIA group (E max : HFIH: 179 ± 10% vs. HFIA: 149 ± 11% in the presence of L-NAME). Levels of MDA were elevated in the CDIH group when compared to CDIA (0.68 ± 0.04 vs.
Naunyn-Schmiedeberg's Archives of Pharmacology, 2011
The key roles that obesity, hyperglycemia, hyperlipidemia, inflammation, and oxidative stress pla... more The key roles that obesity, hyperglycemia, hyperlipidemia, inflammation, and oxidative stress play in the progression of diabetes vascular complications are well recognized; however, the relative contribution and importance of these individual factors remain uncertain. At 6, 10, or 14 weeks old, blood samples and thoracic aortae were collected from db/db mice and their non-diabetic controls. Plasma samples were analyzed for glucose, 8-isoprostane, CRP, triglycerides, LDL, and HDL as markers of glycemic status, oxidative stress, inflammation, and dyslipidemia, respectively. The responses of the aortic rings to high KCl, phenylephrine (PE), acetylcholine (ACh), and sodium nitroprusside were examined. Statistical methods were used to estimate the strength of the association between plasma variables and vascular functions. Systemic inflammation occurred in db/db mice at an earlier age than did hyperglycemia or oxidative stress. Aortae of db/db showed augmented contractions to PE which were positively correlated with weight, plasma glucose, 8-isoprostane, and CRP. Also, db/db mice showed impaired endotheliumdependent ACh vasorelaxation which was negatively correlated with weight, plasma glucose, and 8-isoprostane. Multivariate analysis and stepwise modeling show that CRP is the major determinant of the contractile responses, while weight and HDL are the major determinants of ACh-induced relaxation. Among the traditional risk factors of obesity, hyperglycemia, oxidative stress, inflammation, and dyslipidemia, our study reveals that weight and inflammation are the major determinants of vascular dysfunction in the aortae of db/db mice. Our findings partially resolve the complexity of diabetes vasculopathies and suggest targeting weight loss and inflammation for effective therapeutic approaches.
An intravenous injection of oleic acid into animals can produce a lung injury with hypoxaemia and... more An intravenous injection of oleic acid into animals can produce a lung injury with hypoxaemia and pulmonary vascular hyper-permeability. Although oleic acid lung injury is used as a model of acute respiratory distress syndrome (ARDS), the precise mechanisms of the lung injury are still unclear. We have investigated whether thromboxane A 2 (TXA 2 ) participated in the lung injury and have evaluated the efficacy of ozagrel, a TXA 2 synthase inhibitor, on the lung injury in guinea-pigs. Oleic acid injection increased the plasma level of TXB 2 , a stable metabolite of TXA 2 , and the time-course of plasma TXB 2 was similar to that of the decreased partial oxygen pressure of arterial blood (Pao 2 ) induced with oleic acid. Ozagrel administered intravenously 30 min before oleic acid injection prevented the decrease in Pao 2 and pulmonary vascular hyper-permeability. It also prevented increases in lactate dehydrogenase activity, a measure of lung cell injury, TXB 2 and its weight ratio to 6-keto prostaglandin F 1a in bronchoalveolar lavage fluid. Although ozagrel administered simultaneously with oleic acid ameliorated the decrease in Pao 2 , post treatment showed little effect. We suggest that TXA 2 participated in the oleic acid lung injury, as an ''early phase'' mediator, and rapidly-acting TXA 2 synthase inhibitors were effective in the prevention of acute lung injury.
Acute respiratory distress syndrome or acute lung injury (ARDS)/(ALI) involve the severe lung inj... more Acute respiratory distress syndrome or acute lung injury (ARDS)/(ALI) involve the severe lung injury with pulmonary vascular hyper-permeability and hypoxemia induced by inflammatory reactions. Since ARDS/ALI carries high mortality, the development of new drugs against ARDS/ALI is required. We examined the effect of tranilast, an anti-allergic drug, on vascular hyper-permeability in the lungs and airways, and on hypoxemia, in oleic acid (OA)-induced acute lung injury, an animal model of ARDS/ALI. The increase in pulmonary and airway vascular permeability and the decrease in partial oxygen pressure of arterial blood induced by an intravenous injection of OA were drastically ameliorated by the oral administration of tranilast in a dose-dependent manner. This is the first report to prove that tranilast prevents pulmonary and airway vascular permeability and hypoxemia induced by OA. These results suggest that tranilast may be a candidate drug for the treatment of ARDS/ALI.
Several clinical studies demonstrate a beneficial role of angiotensin-converting enzyme (ACE) inh... more Several clinical studies demonstrate a beneficial role of angiotensin-converting enzyme (ACE) inhibitors in patients with myocardial infarction, hypertension and diabetes mellitus. This review focuses on the effects of ramipril, a weak inhibitor of ACE that is rapidly hydrolyzed to ramiprilat, an active metabolite. The Heart Outcome Prevention Evaluation (HOPE) study evaluated the effects of ramipril in patients with a high risk for cardiovascular events without pre-existing left ventricular dysfunction or heart failure. In this review, we summarized the effects of ramipril on myocardial infarction, death, diabetes mellitus, and stroke.
American Journal of Physiology - Heart and Circulatory Physiology, 2015
Psychological stresses are associated with cardiovascular diseases to the extent that cardiovascu... more Psychological stresses are associated with cardiovascular diseases to the extent that cardiovascular 26 diseases are amongst the most important group of psychosomatic diseases. The longstanding 27 association between stress and cardiovascular disease exists despite a large ambiguity about the 28 underlying mechanisms. An array of possibilities have been proposed including overactivity of the 29 autonomic nervous system and humoral changes, which then converge on endothelial dysfunction that 30
Obstructive sleep apnea (OSA) occurs in 2% of middle-aged women and 4% of middle-aged men and is ... more Obstructive sleep apnea (OSA) occurs in 2% of middle-aged women and 4% of middle-aged men and is considered an independent risk factor for cerebrovascular and cardiovascular diseases. Nitric oxide (NO) is an important endothelium derived vasodilating substance that plays a critical role in maintaining vascular homeostasis. Low levels of NO are associated with impaired endothelial function. Asymmetric dimethylarginine (ADMA), an analogue of L-arginine, is a naturally occurring product of metabolism found in the human circulation. Elevated levels of ADMA inhibit NO synthesis while oxidative stress decreases its bioavailability, so impairing endothelial function and promoting atherosclerosis. Several clinical trials report increased oxidative stress and ADMA levels in patients with OSA. This review discusses the role of oxidative stress and increased ADMA levels in cardiovascular disease resulting from OSA.
The effect of antioxidants on ageing type 2 diabetic (T2D) hearts during exercise is unclear. We ... more The effect of antioxidants on ageing type 2 diabetic (T2D) hearts during exercise is unclear. We hypothesized that GSH therapy during exercise reduces mitochondrial oxidative stress (mOXS) and cell death in ageing db/db mice hearts. The effect of GSH on cardiac mOXS and cell death was evaluated both in vivo and in vitro. During exercise, GSH treatment protected db/db hearts from exaggerated mOXS without reducing total cell death. Despite similar cell death, investigations on apoptosis-specific single-stranded DNA breaks and necrosis-specific damage provided the first in vivo evidence of a shift from necrosis to apoptosis, with reduced fibrosis following GSH administration in exercised db/db hearts. Further support for a GSH-regulated 'switch' in death phenotypes came from NIH-3T3 fibroblasts and H9c2 cardiomyocytes treated with H2 O2 , a reactive oxygen species (ROS). Similar to in vivo findings, augmenting GSH by overexpressing glutamyl cysteine ligase (GCLc) protected fibr...
Medical science monitor: international medical journal of experimental and clinical research
Reactive oxygen species (ROS) have deleterious or beneficial effects; this dual nature of ROS mea... more Reactive oxygen species (ROS) have deleterious or beneficial effects; this dual nature of ROS means that ROS act as intracellular signaling molecules and as defense mechanisms against micro-organisms. An overproduction of ROS results in oxidative stress, a deleterious process that damages cell structures, including lipids, proteins, and DNA. Oxidative stress plays a major role in various human disease states, including endocrine dysfunction. As a safeguard against oxidative stress, several endogenous nonenzymatic and enzymatic antioxidant systems exist. Antioxidants can delay or prevent oxidative stress and are widely used in the hope of maintaining health and preventing diseases. Although early studies suggested that antioxidant supplements promoted health, later clinical trials revealed that it may not be true in all cases. In this article, we provide a brief review of the pathophysiologic aspects of oxidative stress in a number of the most commonly human endocrionopathies (diabet...
Oleic acid-induced hypoxemia is an animal model of acute respiratory distress syndrome (ARDS). In... more Oleic acid-induced hypoxemia is an animal model of acute respiratory distress syndrome (ARDS). Increased capillary permeability is a cause of hypoxemia in lung injury. Endothelial cells form a major capillary barrier, and disruption of the barrier appears to involve a decreased level of ATP in the cells. Phosphoenolpyruvate (PEP) is an endogenous substance that is one of the ATP precursors and can cross some cell membranes via anion exchanger. We examined the effect of PEP on oleic acid-induced lung injury in guinea pigs. An intravenous injection of oleic acid (15 microl/kg) caused severe hypoxemia. Pretreatment with PEP at a dose of 2, 20, or 200 micromol/kg attenuated the oleic acid-induced decrease in the arterial partial pressure of oxygen in a dose-dependent manner. Furthermore, PEP attenuated the oleic acid-induced increase in vascular permeability in the proximal and distal bronchi, as indicated by the extravascular leakage of Evans Blue dye. The combination of PEP with ATP (...
Type 2 diabetes accounts for more than 90% of diabetes mellitus. Urinary bladder dysfunction is a... more Type 2 diabetes accounts for more than 90% of diabetes mellitus. Urinary bladder dysfunction is a frequent complication of diabetes and can lead to urinary incontinence (UI), infection and impaired bladder emptying leading to retention of urine and loss of sensation in the patients. Of these, UI is a most debilitating condition that leads to decreased quality of life especially in women. It is estimated to affect approximately 30-50% of the elderly. Exercise is the initial recommended management strategy in diabetes but its effect on diabetic urinary bladder dysfunction or urinary incontinence (UI) is unknown. We hypothesize that exercise improves bladder dysfunction and reduces the voiding frequency in the db/db mouse, a frequently used animal model of type 2 diabetes.
The metabolic syndrome is a clustering of obesity, diabetes, hyperlipidemia, and hypertension tha... more The metabolic syndrome is a clustering of obesity, diabetes, hyperlipidemia, and hypertension that is occurring in increasing frequency across the global population. Although there is some controversy about its diagnostic criteria, oxidative stress, which is defined as imbalance between the production and inactivation of reactive oxygen species, has a major pathophysiological role in all the components of this disease. Oxidative stress and consequent inflammation induce insulin resistance, which likely links the various components of this disease. We briefly review the role of oxidative stress as a major component of the metabolic syndrome and then discuss the impact of exercise on these pathophysiological pathways. Included in this paper is the effect of exercise in reducing fat-induced inflammation, blood pressure, and improving muscular metabolism.
Physical inactivity is increasingly recognized as modifiable behavioral risk factor for cardiovas... more Physical inactivity is increasingly recognized as modifiable behavioral risk factor for cardiovascular diseases. A partial list of proposed mechanisms for exercise-induced cardioprotection include induction of heat shock proteins, increase in cardiac antioxidant capacity, expression of endoplasmic reticulum stress proteins, anatomical and physiological changes in the coronary arteries, changes in nitric oxide production, adaptational changes in cardiac mitochondria, increased autophagy, and improved function of sarcolemmal and/or mitochondrial ATP-sensitive potassium channels. It is currently unclear which of these protective mechanisms are essential for exercise-induced cardioprotection. However, most investigations focus on sarcolemmal KATP channels, NO production, and mitochondrial changes although it is very likely that other mechanisms may also exist. This paper discusses current information about these aforementioned topics and does not consider potentially important adaptations within blood or the autonomic nervous system. A better understanding of the molecular basis of exercise-induced cardioprotection will help to develop better therapeutic strategies.
The lack of adequate physical activity and obesity created a worldwide pandemic. Obesity is chara... more The lack of adequate physical activity and obesity created a worldwide pandemic. Obesity is characterized by the deposition of adipose tissue in various parts of the body; it is now evident that adipose tissue also acts as an endocrine organ capable of secreting many cytokines that are though to be involved in the pathophysiology of obesity, insulin resistance, and metabolic syndrome. Adipokines, or adipose tissue-derived proteins, play a pivotal role in this scenario. Increased secretion of proinflammatory adipokines leads to a chronic inflammatory state that is accompanied by insulin resistance and glucose intolerance. Lifestyle change in terms of increased physical activity and exercise is the best nonpharmacological treatment for obesity since these can reduce insulin resistance, counteract the inflammatory state, and improve the lipid profile. There is growing evidence that exercise exerts its beneficial effects partly through alterations in the adipokine profile; that is, exercise increases secretion of anti-inflammatory adipokines and reduces proinflammatory cytokines. In this paper we briefly describe the pathophysiologic role of four important adipokines (adiponectin, leptin, TNF-, and IL-6) in the metabolic syndrome and review some of the clinical trials that monitored these adipokines as a clinical outcome before and after exercise.
Gestational diabetes mellitus (GDM) is defined as glucose intolerance first diagnosed during preg... more Gestational diabetes mellitus (GDM) is defined as glucose intolerance first diagnosed during pregnancy. This condition shares same array of underlying abnormalities as occurs in diabetes outside of pregnancy, for example, genetic and environmental causes. However, the role of a sedentary lifestyle and/or excess energy intake is more prominent in GDM. Physically active women are less likely to develop GDM and other pregnancy-related diseases. Weight gain in pregnancy causes increased release of adipokines from adipose tissue; many adipokines increase oxidative stress and insulin resistance. Increased intramyocellular lipids also increase cellular oxidative stress with subsequent generation of reactive oxygen species. A well-planned program of exercise is an important component of a healthy lifestyle and, in spite of old myths, is also recommended during pregnancy. This paper briefly reviews the role of adipokines in gestational diabetes and attempts to shed some light on the mechanisms by which exercise can be beneficial as an adjuvant therapy in GDM. In this regard, we discuss the mechanisms by which exercise increases insulin sensitivity, changes adipokine profile levels, and boosts antioxidant mechanisms.
The endothelium plays a critical role in the maintenance of cardiovascular health by producing ni... more The endothelium plays a critical role in the maintenance of cardiovascular health by producing nitric oxide and other vasoactive materials. Aging is associated with a gradual decline in this functional aspect of endothelial regulation of cardiovascular homeostasis. Indeed, age is an independent risk factor for cardiovascular diseases and is in part an important factor in the increased exponential mortality rates from vascular disease such as myocardial infarction and stroke that occurs in the ageing population. There are a number of mechanisms suggested to explain age-related endothelial dysfunction. However, recent scientific studies have advanced the notion of oxidative stress and inflammation as the two major risk factors underlying aging and age-related diseases. Regular physical activity, known to have a favorable effect on cardiovascular health, can also improve the function of the ageing endothelium by modulating oxidative stress and inflammatory processes, as we discuss in this paper.
Diabetes is a chronic metabolic disease which is characterized by absolute or relative deficienci... more Diabetes is a chronic metabolic disease which is characterized by absolute or relative deficiencies in insulin secretion and/or insulin action. The key roles of oxidative stress and inflammation in the progression of vascular complications of this disease are well recognized. Accumulating epidemiologic evidence confirms that physical inactivity is an independent risk factor for insulin resistance and type II diabetes. This paper briefly reviews the pathophysiological pathways associated with oxidative stress and inflammation in diabetes mellitus and then discusses the impact of exercise on these systems. In this regard, we discuss exercise induced activation of cellular antioxidant systems through "nuclear factor erythroid 2-related factor." We also discuss anti-inflammatory myokines, which are produced and released by contracting muscle fibers. Antiapoptotic, anti-inflammatory and chaperon effects of exercise-induced heat shock proteins are also reviewed.
Individuals with high spinal cord injury (SCI) are prone to significant fluctuation in blood pres... more Individuals with high spinal cord injury (SCI) are prone to significant fluctuation in blood pressure with episodes of very high and low blood pressure during autonomic dysreflexia (AD) and orthostatic hypotension, respectively. We do not know how such blood pressure lability affects the vasculature. We used a well-characterized animal model of AD to determine whether increasing the frequency of AD during recovery from SCI would exacerbate injury-induced dysfunction in resistance vessels. Experimental animal study. International Collaboration On Repair Discoveries (ICORD), University of British Columbia, Canada. Complete transection of the T3 spinal cord was performed in male Wistar rats. For 14 days after injury, AD was induced via colorectal distension (CRD; 30 minutes per day) in the experimental group (SCI-CRD). One month after SCI, baseline cardiovascular parameters and severity of CRD-induced AD were assessed in SCI-CRD animals and SCI-only controls. Mesenteric arteries were harvested for in vitro myography to characterize vasoactive responses to phenylephrine (PE) and acetylcholine (ACh). Mesenteric arteries from SCI-CRD animals exhibited larger maximal responses to PE than arteries from SCI-only controls. Hyperresponsiveness to PE was not a product of endothelial dysfunction because mesenteric arteries from both groups had similar vasodilator responses to ACh. Both SCI-only controls and SCI-CRD animals exhibited CRD-evoked AD 1 month after SCI; however, CRD-induced hypertension was less pronounced in animals that were previously exposed to CRD. Injury-induced changes within the vasculature may contribute to the development of AD after SCI. Here, we provide evidence that AD itself has significant and long-lasting effects on vascular function. This finding has implications for the medical management of AD and provides an impetus for maintaining stable blood pressure.
Background: Obstructive sleep apnea (OSA) is a common disorder characterized by chronic intermitt... more Background: Obstructive sleep apnea (OSA) is a common disorder characterized by chronic intermittent hypoxia (CIH). OSA is prevalent in obese subjects and is associated with endothelial dysfunction and cardiovascular disorders. We tested the hypothesis that the deleterious effects of IH could be further modulated by diet-induced obesity. Design: Thirty adult (8-10 weeks) male C57BL/6J mice were divided into four groups. Mice were subjected to CIH or intermittent air (IA) for 12 h a day and fed either a high fat (HF) or a low fat control diet (CD) for 6 weeks. We analyzed endothelial function using a wire myograph, and measured markers of oxidative stress (plasma malondialdehyde (MDA) and total antioxidant capacity (TAC)) using colorimetrical assays. We also measured C-reactive protein (CRP) using ELISA and endothelial nitric oxide (eNOS) gene expression using real time PCR. Results: Stimulated endothelial dependent dilation was significantly impaired only in the group fed high fat diet and subjected to CIH (E max : HFIH 78 ± 2%, p < 0.0001) when compared to the other groups (E max : HFIA 95 ± 0.7%, CDIH 94 ± 2%, CDIA 97 ± 1%). Also basal endothelial dependant dilation was attenuated in the HFIH group compared to the HFIA group (E max : HFIH: 179 ± 10% vs. HFIA: 149 ± 11% in the presence of L-NAME). Levels of MDA were elevated in the CDIH group when compared to CDIA (0.68 ± 0.04 vs.
Naunyn-Schmiedeberg's Archives of Pharmacology, 2011
The key roles that obesity, hyperglycemia, hyperlipidemia, inflammation, and oxidative stress pla... more The key roles that obesity, hyperglycemia, hyperlipidemia, inflammation, and oxidative stress play in the progression of diabetes vascular complications are well recognized; however, the relative contribution and importance of these individual factors remain uncertain. At 6, 10, or 14 weeks old, blood samples and thoracic aortae were collected from db/db mice and their non-diabetic controls. Plasma samples were analyzed for glucose, 8-isoprostane, CRP, triglycerides, LDL, and HDL as markers of glycemic status, oxidative stress, inflammation, and dyslipidemia, respectively. The responses of the aortic rings to high KCl, phenylephrine (PE), acetylcholine (ACh), and sodium nitroprusside were examined. Statistical methods were used to estimate the strength of the association between plasma variables and vascular functions. Systemic inflammation occurred in db/db mice at an earlier age than did hyperglycemia or oxidative stress. Aortae of db/db showed augmented contractions to PE which were positively correlated with weight, plasma glucose, 8-isoprostane, and CRP. Also, db/db mice showed impaired endotheliumdependent ACh vasorelaxation which was negatively correlated with weight, plasma glucose, and 8-isoprostane. Multivariate analysis and stepwise modeling show that CRP is the major determinant of the contractile responses, while weight and HDL are the major determinants of ACh-induced relaxation. Among the traditional risk factors of obesity, hyperglycemia, oxidative stress, inflammation, and dyslipidemia, our study reveals that weight and inflammation are the major determinants of vascular dysfunction in the aortae of db/db mice. Our findings partially resolve the complexity of diabetes vasculopathies and suggest targeting weight loss and inflammation for effective therapeutic approaches.
An intravenous injection of oleic acid into animals can produce a lung injury with hypoxaemia and... more An intravenous injection of oleic acid into animals can produce a lung injury with hypoxaemia and pulmonary vascular hyper-permeability. Although oleic acid lung injury is used as a model of acute respiratory distress syndrome (ARDS), the precise mechanisms of the lung injury are still unclear. We have investigated whether thromboxane A 2 (TXA 2 ) participated in the lung injury and have evaluated the efficacy of ozagrel, a TXA 2 synthase inhibitor, on the lung injury in guinea-pigs. Oleic acid injection increased the plasma level of TXB 2 , a stable metabolite of TXA 2 , and the time-course of plasma TXB 2 was similar to that of the decreased partial oxygen pressure of arterial blood (Pao 2 ) induced with oleic acid. Ozagrel administered intravenously 30 min before oleic acid injection prevented the decrease in Pao 2 and pulmonary vascular hyper-permeability. It also prevented increases in lactate dehydrogenase activity, a measure of lung cell injury, TXB 2 and its weight ratio to 6-keto prostaglandin F 1a in bronchoalveolar lavage fluid. Although ozagrel administered simultaneously with oleic acid ameliorated the decrease in Pao 2 , post treatment showed little effect. We suggest that TXA 2 participated in the oleic acid lung injury, as an ''early phase'' mediator, and rapidly-acting TXA 2 synthase inhibitors were effective in the prevention of acute lung injury.
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