Showing papers in "Clinical and Experimental Pharmacology and Physiology in 2007"

Age-related changes in the structure and function of skeletal muscles

Abstract: 1. For animals of all ages, during activation of skeletal muscles and the subsequent contraction, the balance between the force developed by the muscle and the external load determines whether the muscle shortens, remains at fixed length (isometric) or is lengthened. With maximum activation, the force developed is least during shortening, intermediate when muscle length is fixed and greatest during lengthening contractions. During lengthening contractions, when force is high, muscles may be injured by the contractions. 2. 'Frailty' and 'failure to thrive' are most frequently observed in elderly, physically inactive people. A 'frail' person is defined as one of small stature, with muscles that are atrophied, weak and easily fatigued. The condition of 'failure to thrive' is typified by a lack of response to well-designed programmes of nutrition and physical activity. 3. With ageing, skeletal muscle atrophy in humans appears to be inevitable. A gradual loss of muscle fibres begins at approximately 50 years of age and continues such that by 80 years of age, approximately 50% of the fibres are lost from the limb muscles that have been studied. For both humans and rats, the observation that the timing and magnitude of the loss of motor units is similar to that for muscle fibres suggests that the mechanism responsible for the loss of fibres and the loss of whole motor units is the same. The degree of atrophy of the fibres that remain is largely dependent on the habitual level of physical activity of the individual. 4. 'Master athletes' maintain a high level of fitness throughout their lifespan. Even among master athletes, performance of marathon runners and weight lifters declines after approximately 40 years of age, with peak levels of performance decreased by approximately 50% by 80 years of age. The success of the master athletes and of previously sedentary elderly who undertake well-designed, carefully administered training programmes provide dramatic evidence that age-associated atrophy, weakness and fatigability can be slowed, but not halted.

Arginase: a critical regulator of nitric oxide synthesis and vascular function

Abstract: 1. Arginase is the focal enzyme of the urea cycle hydrolysing L-arginine to urea and L-ornithine. Emerging studies have identified arginase in the vasculature and have implicated this enzyme in the regulation of nitric oxide (NO) synthesis and the development of vascular disease. 2. Arginase inhibits the production of NO via several potential mechanisms, including competition with NO synthase (NOS) for the substrate L-arginine, uncoupling of NOS resulting in the generation of the NO scavenger, superoxide and peroxynitrite, repression of the translation and stability of inducible NOS protein, inhibition of inducible NOS activity via the generation of urea and by sensitization of NOS to its endogenous inhibitor asymmetric dimethyl-L-arginine. 3. Upregulation of arginase inhibits endothelial NOS-mediated NO synthesis and may contribute to endothelial dysfunction in hypertension, ageing, ischaemia-reperfusion and diabetes. 4. Arginase also redirects the metabolism of L-arginine to L-ornithine and the formation of polyamines and L-proline, which are essential for smooth muscle cell growth and collagen synthesis. Therefore, the induction of arginase may also promote aberrant vessel wall remodelling and neointima formation. 5. Arginase represents a promising novel therapeutic target that may reverse endothelial and smooth muscle cell dysfunction and prevent vascular disease.

Differences between pathological and physiological cardiac hypertrophy: novel therapeutic strategies to treat heart failure

Abstract: 1. In general, cardiac hypertrophy (an increase in heart mass) is a poor prognostic sign. Cardiac enlargement is a characteristic of most forms of heart failure. Cardiac hypertrophy that occurs in athletes (physiological hypertrophy) is a notable exception. 2. Physiological cardiac hypertrophy in response to exercise training differs in its structural and molecular profile to pathological hypertrophy associated with pressure or volume overload in disease. Physiological hypertrophy is characterized by normal organization of cardiac structure and normal or enhanced cardiac function, whereas pathological hypertrophy is commonly associated with upregulation of fetal genes, fibrosis, cardiac dysfunction and increased mortality. 3. It is now clear that several signalling molecules play unique roles in the regulation of pathological and physiological cardiac hypertrophy. 4. The present review discusses the possibility of targeting cardioprotective signalling pathways and genes activated in the athlete's heart to treat or prevent heart failure.

Maximal lactate steady state in running mice: effect of exercise training

Abstract: Univ Sao Paulo, Escola Educ Fis & Esporte, Dept Biodinam Movimento Corpo Humano, BR-05508900 Sao Paulo, Brazil

Age, hypertension and arterial function

Abstract: 1 Ageing exerts a marked effect on the cardiovascular system and, in particular, the large arteries Using a variety of techniques to assess arterial stiffness, many cross-sectional studies have demonstrated a significant relationship between age and aortic stiffness, although the age-related changes observed in peripheral arteries appear to be less marked 2 The relationship between arterial stiffness and hypertension is more complex The distending, or mean arterial, pressure is an important confounder of measurements of arterial stiffness and, therefore, must be taken into consideration when assessing arterial stiffness in hypertensive subjects or investigating the effect of antihypertensive agents Current methods for correcting for differences in distending pressure involve pharmacological manipulation, statistical correction or mathematical manipulation of stiffness indices 3 Many studies have provided evidence that both peripheral (muscular) and central (elastic) arteries are stiffer in subjects with mixed (systolic/diastolic) hypertension compared with normotensive subjects However, it is unclear to what extent differences in mean arterial pressure explain the observed differences in hypertensive subjects In contrast, isolated systolic hypertension is associated with increased aortic, but not peripheral artery, stiffness, although the underlying mechanisms are somewhat unclear 4 Traditional antihypertensive agents appear to reduce arterial stiffness, but mostly via an indirect effect of lowering mean pressure Therefore, therapies that target the large arteries to reduce stiffness directly are urgently required Agents such as nitric oxide donors and phosphodiesterase inhibitors may be useful in reducing stiffness via functional mechanisms In addition, inhibitors or breakers of advanced glycation end-product cross-links between proteins, such as collagen and elastin, hold substantial promise

Exercise training and sympathetic nervous system activity: evidence for physical activity dependent neural plasticity.

Abstract: 1. It has been generally accepted that regular physical activity is associated with beneficial effects on the cardiovascular system. In fact, the idea that exercise maintains cardiovascular health is evident by the direct links between a sedentary lifestyle and the risk of cardiovascular and other disease states. 2. Cardiovascular diseases, such as hypertension and heart failure, are often associated with sympathetic nervous system (SNS) overactivity. Conversely, exercise has been shown to reduce hypertension and decrease elevated SNS activity. In addition, there is evidence that exercise may reduce resting blood pressure and sympathetic outflow in normal individuals. 3. Although somewhat controversial in humans, evidence from animal studies also indicates that exercise training reduces baroreflex-mediated and other forms of sympathoexcitation in normal individuals. Collectively, these data are consistent with the hypothesis that physical activity may decrease, and physical inactivity may increase, the incidence of cardiovascular disease via alterations in SNS activity. Despite the important clinical implications of this possibility, the mechanisms by which exercise alters control of SNS activity remain to be fully elucidated. 4. Recent evidence suggests that central nervous system (CNS) plasticity occurs under a variety of conditions, including varying levels of physical activity. The purpose of the present brief review is to provide evidence that changes within the CNS contribute importantly to altered regulation of the SNS observed following exercise training. The primary hypothesis is that physical activity versus inactivity produces plasticity within neural networks that regulate SNS activity. This hypothesis is supported by published and preliminary data that suggest that exercise training may reduce sympathoexcitation by reducing activation of neurons within cardiovascular regions of the brain. These mechanisms are likely to be important in disease states of sympathetic overactivity and in normal healthy individuals whose risk of cardiovascular disease is reduced by leading an active versus sedentary lifestyle.

Identification of blood pressure control mechanisms by power spectral analysis

Abstract: SUMMARY 1 Blood pressure and organ perfusion are controlled by a variety of cardiovascular control systems, such as the baroreceptor reflex and the renin–angiotensin system (RAS), and by local vascular mechanisms, such as shear stress-induced release of nitric oxide (NO) from the endothelium and the myogenic vascular response. Deviations in arterial blood pressure from its set point activate these mechanisms in an attempt to restore blood pressure and/or secure organ perfusion. However, the response times at which different cardiovascular mechanisms operate differ considerably (e.g. blood pressure control by the RAS is slower than blood pressure control via the baroreceptor reflex). 2 Owing to these different response times, some cardiovascular control systems affect blood pressure more rapidly and others more slowly. Thus, identifying the frequency components of blood pressure variability (BPV) by power spectral analysis can potentially provide important information on individual blood pressure control mechanisms. 3 Evidence is presented that the RAS, catecholamines, endothelial-derived NO and myogenic vascular function affect BPV at very low frequencies (0.02–0.2 Hz) and that low-frequency (LF) BPV (0.2–0.6 Hz) is affected by sympathetic modulation of vascular tone and endothelial-derived NO in rats. In humans, LF BPV (0.075–0.15 Hz) is affected by sympathetic modulation of vascular tone and myogenic vascular function. The impact of the RAS and endothelial-derived NO on BPV in humans requires further investigation. 4 In conclusion, power spectral analysis is a powerful diagnostic tool that allows identification of pathophysiological mechanisms contributing to cardiovascular diseases, such as hypertension, heart failure and stroke, because it can separate slow from fast cardiovascular control mechanisms. The limitation that some cardiovascular control mechanisms affect the same frequency components of BPV requires the combination of blood pressure spectral analysis with other techniques.

Thymoquinone supplementation prevents the development of gentamicin-induced acute renal toxicity in rats.

Abstract: SUMMARY 1. The present study investigated the possible protective effects of thymoquinone (TQ), a compound derived from Nigella sativa with strong anti-oxidant properties, against gentamicin (GM)-induced nephrotoxicity. 2. A total of 40 adult male Wistar albino rats was divided into four groups. Rats in the first group were injected daily with normal saline (2.5 mL/kg, i.p.) for 8 consecutive days, whereas rats in the second group received TQ (50 mg/L in drinking water) for 8 consecutive days. Animals in the third group were injected daily with GM (80 mg/kg, i.p.) for 8 consecutive days, whereas animals in the fourth group received a combination of GM (80 mg/kg, i.p.) and TQ (50 mg/L in drinking water) for 8 consecutive days. 3. Gentamicin resulted in a significant increase in serum creatinine, blood urea nitrogen (BUN), thiobarbituric acidreactive substances (TBARS) and total nitrate/nitrite (NOx) and a significant decrease in reduced glutathione (GSH), glutathione peroxidase (GPx), catalase (CAT) and ATP levels in kidney tissues. 4. Interestingly, TQ supplementation resulted in a complete reversal of the GM-induced increase in BUN, creatinine, TBARS and NOx and decrease in GSH, GPx, CAT and ATP to control values. Moreover, histopathological examination of kidney tissues confirmed the biochemical data, wherein TQ supplementation prevents GM-induced degenerative changes in kidney tissues. 5. Data from the present study suggest that TQ supplementation prevents the development of GM-induced acute renal failure by a mechanism related, at least in part, to its ability to decrease oxidative stress and to preserve the activity of the anti-oxidant enzymes, as well as it ability to prevent the energy decline in kidney tissues.

Sickle cell disease: role of reactive oxygen and nitrogen metabolites.

Abstract: 1. Sickle cell disease (SCD) is an inherited disorder of haemoglobin synthesis that is associated with significant morbidity and mortality due to sequelae of episodic vaso-occlusive events: pain crises and multiorgan damage. The microvascular responses to the initiation, progression and resolution of vaso-occlusive events are consistent with an inflammatory phenotype as suggested by activation of multiple cell types, an oxidatively stressed environment and endothelial cell dysfunction. 2. Decreased anti-oxidant defences in SCD patients and mice are accompanied by activation of enzymatic (NADPH oxidase, xanthine oxidase) and non-enzymatic (sickle haemoglobin auto-oxidation) sources of reactive oxygen species. The resultant oxidative stress leads to dysfunction/activation of arteriolar and venular endothelial cells, resulting in impaired vasomotor function and blood cell-endothelial cell adhesion. 3. Changes in substrate and cofactor availability for endothelial cell nitric oxide synthase may underlie reactive oxygen- and nitrogen-induced events that contribute to SCD-induced vasculopathy. 4. The emerging role of reactive oxygen and nitrogen species in the pathogenesis of SCD provides a platform for the development of novel agents to treat this painful and lethal disease.

Combustion-derived nanoparticles: mechanisms of pulmonary toxicity.

Abstract: 1. The general term ‘nanoparticle’ (NP) is used to define any particle less than 100 nm in at least one dimension and NPs are generally classified as natural, anthropogenic or engineered in origin. Anthropogenic, also referred to as ‘ultrafine’ particles (UFPs), are predominately combustion derived and are characterized by having an equivalent spherical diameter less than 100 nm. 2. These particles, considered to be ‘combustion-derived nanoparticles’ (CDNPs), are of toxicological interest given their nanosized dimensions, with properties not displayed by their macroscopic counterparts. 3. The pulmonary deposition efficiency of inhaled UFPs, along with their large surface areas and bound transition metals, is considered important in driving the emerging health effects linked to respiratory toxicity. 4. The toxicology of CDNPs is currently used to predict the health outcomes in humans following exposure to manufactured NPs. Their similar physicochemistry would suggest similar adverse health effects (i.e. pulmonary (and perhaps cardiac) toxicity). As such, it is essential to fully understand CDNP nanotoxicology in order to minimize occupational and environmental exposure. Key words: carbon black, combustion-derived particles, diesel exhaust, fly ash, nanoparticles, pulmonary toxicity.

Nitric oxide, erectile dysfunction and beta-blocker treatment (MR NOED study): benefit of nebivolol versus metoprolol in hypertensive men.

Abstract: 1. Hypertensive men treated with beta-blockers frequently complain of erectile dysfunction. The present study investigated the effects of two beta(1)-adrenoceptor-selective antagonists, namely nebivolol and metoprolol, on erectile function in hypertensive men. 2. Male out-patients (age range 40-55 years) with newly diagnosed or existing stage 1 essential hypertension (mean seated systolic blood pressure 140-159 mmHg; diastolic blood pressure 90-99 mmHg) were enrolled in the study. All patients lived in a stable, heterosexual partnership and had no history of sexual dysfunction. After a 2-week placebo run-in period, patients were randomized double-blind to either Treatment group A (comprising nebivolol 5 mg once daily for 12 weeks, followed by placebo for 2 weeks and then metoprolol succinate 95 mg once daily for 12 weeks) or Treatment group B (comprising metoprolol succinate 95 mg for 12 weeks, placebo for 2 weeks and then nebivolol 5 mg for 12 weeks). An international index of erectile function (IIEF) questionnaire and a diary documented patients' sexual function and activity. 3. Nebivolol and metoprolol lowered blood pressure to a similar extent. Metoprolol, but not nebivolol, significantly decreased the IIEF erectile function subscore by 0.92 in the first 8 weeks after onset of beta-blocker treatment. In contrast with metoprolol, nebivolol improved secondary sexual activity scores and other IIEF subscores. 4. Despite similar antihypertensive efficacy of the cardioselective beta(1)-adrenoceptor antagonists nebivolol and metoprolol, nebivolol may offer additional benefits by avoiding erectile dysfunction in male hypertensive patients on long-term beta-adrenoceptor antagonist therapy.

Effect of gender and sex hormones on vascular oxidative stress.

Abstract: 1. It is well documented that the incidence and severity of several vascular diseases, such as hypertension, atherosclerosis and stroke, are lower in premenopausal women than men of similar age and post-menopausal women. The mechanisms responsible for gender differences in the incidence and severity of vascular disease are not well understood. However, emerging evidence suggests that sex hormone-dependent differences in vascular oxidative stress may play an important role. The aim of the present brief review is to provide an insight into the effect of gender and sex hormones on vascular oxidative stress. 2. When production of reactive oxygen species (ROS) is enhanced and/or their metabolism by anti-oxidant enzymes is impaired, a condition known as 'oxidative stress' can develop. Oxidative stress is believed to play an important role in both the initiation and progression of a variety of vascular diseases, including hypertension and atherosclerosis. NADPH oxidases are believed to be the major source of vascular ROS. Moreover, excessive production of ROS by NADPH oxidases has been linked to the development of vascular oxidative stress. 3. Increasing evidence suggests that levels of vascular ROS may be lower in women than men during health and disease. Indeed, the activity and expression of vascular NADPH oxidase is lower in female versus male animals under healthy, hypertensive and atherosclerotic conditions. 4. Gonadal sex hormones may play an important role in the regulation of vascular oxidative stress. For example, oestrogens, which are present in highest levels in premenopausal women, have been reported to lower vascular oxidative stress by modulating the expression and function of NADPH oxidases, as well as anti-oxidant enzymes. 5. Further studies are needed to clarify whether lower vascular oxidative stress in women in fact protects against the initiation and development of vascular disease and to further define the roles of gonadal sex hormones in such an effect. Knowledge gained from these studies may potentially lead to advances in the clinical diagnosis and treatment of vascular disease in both genders.

Role of macrophages in complications of type 2 diabetes.

Abstract: 1. Macrophage accumulation is a feature of Type 2 diabetes and is associated with the development of diabetic complications (nephropathy, atherosclerosis, neuropathy and retinopathy). The present article reviews the current evidence that macrophages contribute to the complications of Type 2 diabetes. 2. Macrophage-depletion studies in rodent models have demonstrated a causal role for macrophages in the development of diabetic complications. 3. Components of the diabetic milieu (high glucose, advanced glycation end-products and oxidized low-density lipoprotein) promote macrophage accumulation (via induction of chemokines and adhesion molecules) and macrophage activation within diabetic tissues. 4. Macrophages mediate diabetic injury through a variety of mechanisms, including production of reactive oxygen species, cytokines and proteases, which result in tissue damage leading to sclerosis. 5. A number of existing and experimental therapies can indirectly reduce macrophage-mediated injury in diabetic complications. The present article discusses the use of these therapies, given alone and in combination, in suppressing macrophage accumulation and activity. 6. In conclusion, current evidence supports a critical role for macrophages in the evolution of diabetic complications. Present therapies are limited in slowing the progression of macrophage-mediated injury. Novel strategies that are more specific at targeting macrophages may provide better protection against the development of Type 2 diabetic complications.

Functions of SK channels in central neurons.

Abstract: 1. SK channels are small-conductance calcium-activated potassium channels that are widely expressed in neurons. The traditional view of the functional role of SK channels is in mediating one component of the after-hyperpolarization that follows action potentials. Calcium influx via voltage-gated calcium channels active during action potentials opens SK channels and the resultant hyperpolarization lowers the firing frequency of action potentials in many neurons. 2. Recent advances have shown that, in addition to controlling action potential firing frequency, SK channels are also important in regulating dendritic excitability, synaptic transmission and synaptic plasticity. 3. In accordance with their role in modulating synaptic plasticity, SK channels are also important in regulating several learning and memory tasks and may also play a role in a number of neurological disorders. 4. The present review discusses recent findings on the role of SK channels in central neurons.

Arterial stiffness and cardiovascular outcome.

Abstract: 1. Studies have reported an association between arterial function indices and cardiovascular risk factors, as well as the risk of incident cardiovascular events, including coronary heart disease and stroke. 2. The data are overwhelmingly in favour of an independent role for aortic pulse wave velocity in predicting fatal and non-fatal cardiovascular events in healthy and diseased populations and in the evaluation of cardiovascular risk. 3. Augmentation index may independently predict all-cause mortality and cardiovascular events in coronary and end-stage renal disease patients, but some outcome studies have questioned its usefulness in hypertensive subjects and dialysis patients. 4. Systemic arterial compliance, to this time, has not been shown to independently predict cardiovascular outcome. 5. Future cardiovascular risk is greatly modified by prior disease and risk factors; the greatest additional value in measuring arterial stiffness and compliance may be in those with little or no end-organ disease.

Cerebrovascular effects of oestrogen: multiplicity of action.

Abstract: 1. Cerebral vessels express oestrogen receptors (ER) in both the smooth muscle and endothelial cell layers of cerebral blood vessels. Levels of ERalpha are higher in female rats chronically exposed to oestrogen, either endogenous or exogenous. 2. Chronic exposure to oestrogen, either endogenous (normally cycling females) or exogenous (ovariectomized with oestrogen replacement), results in cerebral arteries that are more dilated than arteries from ovariectomized counterparts when studied in vitro. This effect is primarily mediated by an increase in the production of vasodilator factors, including nitric oxide (NO) and prostacylin. In contrast, oestrogen appears to suppress the production of endothelial-derived hyperpolarizing factor. Oestrogen treatment increases cerebrovascular levels of endothelial nitric oxide synthase (eNOS), cyclo-oxygenase (COX)-1 and prostacyclin synthase. In addition, via activation of the phosphatidylinositol 3-kinase/Akt pathway, both acute and chronic oestrogen exposure increases eNOS phosphorylation, increasing NO production. 3. Oestrogen receptors have also been localized to cerebrovascular mitochondria and exposure to oestrogen increases the efficiency of energy production while simultaneously reducing mitochondrial production of reactive oxygen species. Oestrogen increases the production of mitochondrial proteins encoded by both mitochondrial and nuclear DNA, including cytochrome c, subunits I and IV of complex IV and Mn-superoxide dismutase. Oestrogen treatment increases the activity of citrate synthase and complex IV and decreases mitochondrial production of H(2)O(2). 4. Oestrogen also has potent anti-inflammatory effects in the cerebral circulation that may have important implications for the incidence and severity of cerebrovascular disease. Administration of lipopolysaccharide or interleukin-1beta to ovariectomized female rats induces cerebrovascular COX-2 and inducible nitric oxide synthase (iNOS) protein expression and increases prostaglandin E(2) expression. Levels of COX-2 and iNOS expression vary with the stage of the oestrous cycle, and the cerebrovascular inflammatory response is suppressed in ovariectomized animals treated with oestrogen. Interleukin-1beta induction of COX-2 protein is prevented by treatment with a nuclear factor (NF)-kappaB inhibitor, and oestrogen treatment reduces cerebrovascular NF-kappaB activity. 5. Cerebrovascular dysfunction and pathology contribute to the pathogenesis of stroke, brain trauma, oedema and dementias, such as Alzheimer's disease. A better understanding of the action of oestrogen on cerebrovascular function holds promise for the development of new therapeutic entities that could be useful in preventing or treating a wide variety of cerebrovascular diseases.

Cholesterol, statins and cancer.

Abstract: 1. The link between cholesterol and cardiovascular disease is well-established. Emerging evidence is now forging a tantalizing link between cholesterol and cancer. 2. Results from a number of case-control studies have indicated that the commonly prescribed cholesterol-lowering drugs, the statins, may reduce the risk of certain cancers, although this area certainly remains controversial. 3. Herein, the recent literature examining statins and cancer is reviewed briefly and the relationship between a key cholesterol homeostatic pathway and signalling pathways that are involved in carcinogenesis is discussed. In particular, how the sterol-regulatory element binding protein, Akt and Hedgehog pathways may converge in cancer is reviewed.

Optimizing dosage of ketamine and xylazine in murine echocardiography.

Abstract: 1. Ketamine and xylazine (KX) mixture is the most commonly used anaesthetic drug during echocardiography in mice to induce sedation and immobility. Nevertheless, the doses of KX reported in the literature vary substantially with associated significant difference in cardiac function. To explore the optimal KX dosage and observation time for murine echocardiography, we compared the effects of various KX combinations on echocardiographic measurement. 2. Mice were anaesthetized with ketamine (50 or 100 mg/kg) and xylazine (0-10 mg/kg). Echocardiography was performed 5, 10, 20 and 40 min after induction of anaesthesia. Also, cardiac function was assessed in mice with and without pressure-overload induced left ventricle (LV) hypertrophy and dysfunction, either under anaesthesia with KX or whilst conscious. 3. Ketamine at 100 mg/kg alone or together with xylazine at 0.1 mg/kg was associated with a high and stable heart rate (HR), a high fractional shortening (FS) and produced the least effect on LV inner dimension at end of diastole (LVIDd). Ketamine and xylazine at 100 and 10 mg/kg, respectively, produced a lower and stable FS, but with a low and unstable HR. All other combinations resulted in depressed and unstable cardiac function during this period. 4. The dose-dependent suppression of FS by xylazine was counteracted partly by ketamine. 5. Although in the chronic pressure-overload model LV hypertrophy can be detected accurately in both the anaesthetized or conscious state, systolic dysfunction was masked partially by higher doses of xylazine (2.5 or 10 mg/kg) combined with ketamine at 100 mg/kg. 6. With KX anaesthesia, both the dose of xylazine and the anaesthetic duration are critical in achieving an ideal condition for murine echocardiography. Ketamine at 100 mg/kg alone produces acceptable anaesthesia, stable cardiac function with a minimal depressant effect and is therefore recommended if single-dose anaesthetic is to be used.

Sleep and metabolic control: waking to a problem?

Abstract: 1. The aim of the present review is to outline: (i) the association between sleep and metabolism; (ii) how sleep duration influences the development of disease; and (iii) how sex differences, ageing and obesity may potentially influence the relationship between sleep, metabolic control and subsequent disease. 2. Sleep is associated with a number of endocrine changes, including a change in insulin action in healthy young individuals. Sleep duration shows a prospective U-shaped relationship with all-cause mortality, cardiovascular disease and Type 2 diabetes. 3. Chronic sleep restriction is becoming more common. Experimental sleep restriction impedes daytime glucose control and increases appetite. 4. The sex hormones oestrogen and testosterone influence sleep duration and quality and may account for sex differences in the prevalence of sleep-related disorders. 5. Ageing is associated with a decreased sleep duration, decreased muscle mass and impaired insulin action. 6. Obesity impairs insulin action and is associated with the incidence and severity of obstructive sleep apnoea. 7. Sleep plays an integral role in metabolic control. Consequently, insufficient sleep may represent a modifiable risk factor for the development of Type 2 diabetes. The challenge ahead is to identify how sex differences, ageing and obesity could potentially influence the relationship between sleep and metabolism.

Nitric oxide and superoxide interactions in the kidney and their implication in the development of salt-sensitive hypertension.

Abstract: 1. Enhanced superoxide (O - 2 ) activity as a result of the inhibition of the superoxide dismutase (SOD) enzyme results in vasoconstrictor and antinatriuretic responses in the canine kidney; these responses were shown to be greatly enhanced during inhibition of nitric oxide synthase (NOS). Glomerular filtration rate remained mostly unchanged during SOD inhibition in the intact nitric oxide (NO) condition, but was markedly reduced during NOS inhibition. These findings indicate that endogenous NO has a major renoprotective effect against O - 2 by acting as an anti-oxidant. Nitric oxide synthase inhibition was also shown to enhance endogenous O - 2 activity. 2. Experiments in our laboratory using dogs, rats and gene knockout mice have shown that renal vasoconstrictor and antinatriuretic responses to acute or chronic angiotensin (Ang) II administration are mediated, in part, by O - 2 generation. In the absence of NO, enhanced O - 2 activity largely contributes to AngII-induced renal tubular sodium reabsorption. Acute or chronic treatment with the O - 2 scavenger tempol in experimental models of hypertension (induced by chronic low-dose treatment with AngII and NO inhibitors) causes an improvement in renal haemodynamics and in excretory function, abolishes salt sensitivity and reduces blood pressure. 3. The present mini review also discusses related studies from many other laboratories implicating a role for O - 2 and its interaction with NO in the development of salt-sensitive hypertension. 4. Overall, the collective data support the hypothesis that an imbalance between the production of NO and O - 2 in the kidney primarily determines the condition of oxidative stress that alters renal haemodynamics and excretory function leading to sodium retention and, thus, contributes to the development of salt-sensitive hypertension.

Regulators of adult neurogenesis in the healthy and diseased brain.

Abstract: 1. In recent decades evidence has accumulated demonstrating the birth and functional integration of new neurons in specific regions of the adult mammalian brain, including the dentate gyrus of the hippocampus and the subventricular zone. 2. Studies in a variety of models have revealed genetic, environmental and pharmacological factors that regulate adult neurogenesis. The present review examines some of the molecular and cellular mechanisms that could be mediating these regulatory effects in both the normal and dysfunctional brain. 3. The dysregulation of adult neurogenesis may contribute to the pathogenesis of neurodegenerative disorders, such as Huntington's, Alzheimer's and Parkinson's disease, as well as psychiatric disorders such as depression. Recent evidence supports this idea and, furthermore, also indicates that factors promoting neurogenesis can modify the onset and progression of specific brain disorders, including Huntington's disease and depression.

Expression of cyp3a isoforms and p-glycoprotein in human stomach, jejunum and ileum

Abstract: 1. CYP3A isoforms metabolise a diverse array of clinically important drugs and P-glycoprotein (P-gp), a transmembrane efflux pump, can extrude a wide variety of drugs from the cell. It has been suggested that the function of CYP3A4 is complementary to that of P-gp along the gastrointestinal (GI) tract, together forming a coordinated intestinal barrier against xenobiotics. Therefore, the expression of CYP3A4, CYP3A5, CYP3A7 and ABCB1 (P-gp) genes were quantified in five normal samples from the human stomach, seven from the jejunum and eight from the ileum by real-time reverse transcription-polymerase chain reaction and western blot analysis. 2. In the tissues examined, measurable mRNA expression of CYP3A was found in almost all samples from the stomach, jejunum and ileum. The rank order for CYP3A mRNA expression was CYP3A4 > CYP3A5 > CYP3A7 in the GI tract studied, whereas median mRNA CYP3A4 expression was highest in the small intestine and lowest in the stomach. Expression of ABCB1 mRNA was found in almost all samples and the median mRNA expression level was comparable in the jejunum and ileum, but lower in the stomach. Our data also show a significant correlation between all mRNA transcripts studied and a wide interindividual variation. 3. At the protein level, CYP3A4 was detected in all stomach and small intestine samples, the levels being substantially higher in the small intestine than in the stomach. P-Glycoprotein was detected in all GI samples, but no statistically significant difference was found along the GI tract considered. 4. Collectively, these results demonstrate that CYP3A4 is the main CYP3A expressed in the GI tract investigated, an extensive interindividual variability in the expression of the different CYP3A isoforms in all tissues examined and P-gp apoprotein levels similar in the stomach, jejunum and ileum.

Stress-dependent induction of protein oxidation, lipid peroxidation and anti-oxidants in peripheral tissues of rats: comparison of three stress models (immobilization, cold and immobilization-cold).

Abstract: SUMMARY 1 It is known that stress causes disruption of homeostasis and an imbalanced anti-oxidant status in several organs. The aim of the present study was to determine the effects of three stress models on protein oxidation, lipid peroxidation and anti-oxidant enzyme activities in the liver, kidney and heart, and to investigate the relationship between corticosterone and some oxidative stress parameters. In addition, we investigated the most effective stress model for each parameter in each tissue. 2 Thirty-six male Wistar rats (aged 3 months old, weighing 220 ± 20 g) were divided randomly into four groups of nine rats each: control (C), immobilization stress (IS), cold stress (CS), and immobilization–cold stress (ICS). 3 Results showed that corticosterone levels were increased in all stress groups. Levels of protein carbonyl (PC), conjugated dienes (CD) and thiobarbituric acid-reactive substances (TBARS) were increased, whereas reduced glutathione (GSH) levels were decreased in all tissues of all stress groups. Copper, zinc-superoxide dismutase (Cu,Zn-SOD) activities were increased in the liver and kidney of all stress groups, but were decreased in heart of the IS and CS groups. Catalase (CAT) activities were increased in liver of the CS group and in kidney and heart of all stress groups, but were decreased in liver of the IS and ICS groups. Selenium-dependent glutathione peroxidase (Se-GSH-Px) activities were increased in liver of the CS and ICS groups and in heart of all stress groups, but were decreased in kidney of the IS group. Also, Se-GSH-Px activity levels remained unchanged in liver of the IS group and in kidney of the CS and ICS groups. The increased CAT activity and unchanged Se-GSH-Px activity observed in kidney suggest that H2O2 may be primarily scavenged by CAT. 4 The strong correlations between corticosterone and oxidative damage markers (e.g. protein oxidation, lipid peroxidation and GSH levels) suggest a relationship between these parameters. Liver was affected most by the CS model, whereas kidney and heart were affected most by ICS model. Stress-induced changes in the activities of anti-oxidant enzymes and GSH levels were found to be tissue- and enzyme-specific. In conclusion, results of the present study suggest that each stress model affects the different organ tissues in different ways.

Effect of hydrogen sulphide on beta-amyloid-induced damage in PC12 cells.

Abstract: 1. Hydrogen sulphide (H(2)S) is a well-known cytotoxic gas. Recently, H(2)S has been shown to protect neurons against oxidative stress caused by glutamate, peroxynitrite and HOCl. Considerably lower H(2)S levels have been reported in the brain of Alzheimer's disease (AD) patients with accumulation of beta-amyloid (A beta). 2. The aim of present study was to explore the cytoprotection by H(2)S against A beta(25-35)-induced apoptosis and the molecular mechanisms underlying this effect in PC12 cells. 3. Our findings indicated that A beta(25-35) significantly reduced cell viability and induced apoptosis of PC12 cells, along with dissipation of the mitochondrial membrane potential (MMP) and overproduction of reactive oxygen species (ROS). 4. Sodium hydrosulphide (NaHS), an H(2)S donor, protected PC12 cells against A beta(25-35)-induced cytotoxicity and apoptosis not only by reducing the loss of MMP, but also by attenuating the increase in intracellular ROS. 5. The results of the present study suggest that the cytoprotection by H(2)S is related to the preservation of MMP and attenuation of A beta(25-35)-induced intracellular ROS generation. These findings could significantly advance therapeutic approaches to the neurodegenerative diseases that are associated with oxidative stress, such as AD.

Sex differences in oxidative stress and the impact on blood pressure control and cardiovascular disease

Abstract: 1. In the present review, we addressed studies in humans and rats to determine the role that oxidative stress may play in mediating cardiovascular outcomes. 2. Biochemical evaluation of oxidative stress in both humans and spontaneously hypertensive rats gives equivocal results as to the relative levels in males versus females. Clinical trials with anti-oxidants in humans have not shown consistent results in protecting against detrimental cardiovascular outcomes. In spontaneously hypertensive rats (SHR), blockade studies using tempol or apocynin reduce renal oxidative stress and blood pressure in male SHR, but not in female rats. In addition, increasing oxidative stress with molsidomine increases blood pressure in male, but not female, SHR. Treatment with vitamins E and C reduces blood pressure in young male, but not aged, animals. Furthermore tempol is unable to reduce blood pressure in young male SHR in the absence of a functional nitric oxide system. 3. Neither human nor animal studies are consistent in terms of whether oxidative stress levels are higher in males or females. Furthermore, anti-oxidant therapy in humans often does not ameliorate, or even attenuate, the negative cardiovascular consequences of increased oxidative stress. Our studies in SHR shed light on why these outcomes occur.

Interplay of reactive oxygen species and nitric oxide in the pathogenesis of experimental lead-induced hypertension.

Abstract: 1. Lead is a common environmental and industrial toxin that can cause a variety of acute and chronic illnesses. For example, chronic exposure to low levels of lead has been shown to raise arterial pressure and promote renal and cardiovascular complications. 2. Several mechanisms have been identified by which chronic lead exposure can cause hypertension and cardiovascular disease. In recent years, increasing evidence has emerged pointing to the role of oxidative stress as a major mediator of lead-induced hypertension. 3. The present article provides an overview of the published studies on this subject.

Progenitor cells and adult neurogenesis in neurodegenerative diseases and injuries of the basal ganglia.

Abstract: 1. The subventricular zone (SVZ) of the forebrain that overlies the caudate nucleus is one of the principal brain regions in which neurogenesis occurs in the human brain, throughout life. 2. In response to the degeneration that occurs in the caudate nucleus in Huntington's disease, or in the caudate nucleus or cortex in stroke models, the SVZ increases the production of progenitor cells that migrate towards the site of the damage where they can differentiate into mature neurons and glial cells. The SVZ contains three main cell types and these are progenitor cells, glial cells and migratory neuroblasts; glial cells are the most common cell type and, in response to Huntington's disease, most of the SVZ cell proliferation is glial, but the number of precursor and neuroblasts is also increased. 3. The SVZ is enriched in neuroactive compounds, such as neuropeptide Y and gamma-aminobutyric acid receptor subunits gamma2, which stimulate ongoing neurogenesis. Interestingly, these stimulating cues are upregulated in the SVZ in response to Huntington's disease. Thus, the SVZ comprises heterogeneous cell types that are maintained in an environment that is permissive to neurogenesis and gliogenesis, and responds to neurodegenerative changes in adjacent brain regions by increasing progenitor cell proliferation and neurogenesis in an attempt to replace the cells that die as a result of neurodegeneration.

Oestrogen and nigrostriatal dopaminergic neurodegeneration: animal models and clinical reports of parkinson's disease

Abstract: 1. The exact nature of oestrogen (positive, negative or no effect) in the dopaminergic neurodegenerative disorder Parkinson's disease is controversial. 2. In the present review, we summarize the data on oestrogen and nigrostriatal dopaminergic neurodegeneration in animal models and clinical reports of Parkinson's disease. 3. Most animal studies support the ability of oestrogen to function as a neuroprotectant against neurotoxins that target the nigrostriatal dopaminergic system. 4. Retrospective and prospective clinical studies generally support the findings from animal studies that oestrogen exerts a positive, or, at worst, no effect, in Parkinson's disease. 5. Oestrogen was chosen as one of the 12 neuroprotective compounds to be attractive candidates for further clinical trials (Phase II or III) in 2003.

Ca2+ stores regulate ryanodine receptor Ca2+ release channels via luminal and cytosolic Ca2+ sites.

Abstract: 1. In muscle, intracellular calcium concentration, hence skeletal muscle force and cardiac output, is regulated by uptake and release of calcium from the sarcoplasmic reticulum. The ryanodine receptor (RyR) forms the calcium release channel in the sarcoplasmic reticulum. 2. The free [Ca2+] in the sarcoplasmic reticulum regulates the excitability of this store by stimulating the Ca2+ release channels in its membrane. This process involves Ca2+-sensing mechanisms on both the luminal and cytoplasmic sides of the RyR. In the cardiac RyR, these have been shown to be a luminal Ca2+ activation site (L-site; 60 micromol/L affinity), a cytoplasmic activation site (A-site; 0.9 micromol/L affinity) and a cytoplasmic Ca2+ inactivation site (I2-site; 1.2 micromol/L affinity). 3. Cardiac RyR activation by luminal Ca2+ occurs by a multistep process dubbed 'luminal-triggered Ca2+ feed-through'. Binding of Ca2+ to the L-site initiates brief (1 msec) openings at a rate of up to 10/s. Once the pore is open, luminal Ca2+ has access to the A-site (producing up to 30-fold prolongation of openings) and to the I2-site (causing inactivation at high levels of Ca2+ feed-through). 4. The present paper reviews the evidence for the principal aspects of the 'luminal-triggered Ca2+ feed-through' model, the properties of the various Ca2+-dependent gating mechanisms and their likely role in controlling sarcoplasmic reticulum (SR) Ca2+ release in cardiac muscle. 5. The model makes the following important predictions: (i) there will be a close link between luminal and cytoplasmic regulation of RyRs and any cofactor that prolongs channel openings triggered by cytoplasmic Ca2+ will also promote RyR activation by luminal Ca2+; (ii) luminal Mg2+ (1 mmol/L) is essential for the control of SR excitability in cardiac muscle by luminal Ca2+; and (iii) the different RyR isoforms in skeletal and cardiac muscle will be controlled quite differently by the luminal milieu. For example, Mg2+ in the SR lumen (approximately 1 mmol/L) can strongly inhibit RyR2 by competing with Ca2+ for the L-site, whereas RyR1 is not affected by luminal Mg2+.

Glucose, insulin, diabetes and mechanisms of arterial dysfunction

Abstract: 1. This commentary reviews and discusses the association between increased arterial stiffness and indices of glucose and insulin metabolism and diabetes mellitus (DM). 2. Diabetes mellitus is associated with increased cardiovascular events, is an established major independent risk factor for cardiovascular disease and is included in current risk assessment algorithms. Based on Framingham risk assessment, the incremental risk due to DM, at a given level of baseline risk in non-diabetics, is approximately equivalent to 10 years and, at any given level of other major risk factors, DM increases risk three- to fourfold. 3. Increased aortic stiffness has been shown to be an independent risk factor for both cardiovascular and overall mortality in high-risk groups and recently in the general population. Both DM1 and DM2 are associated with accelerated stiffening of the elastic arteries, over and above that associated with normal ageing, and DM can be considered as imparting added biological age and, thus, added cardiovascular risk. 4. Aortic stiffness provides a plausible mechanism relating diabetes to increase cardiovascular disease. 5. A proportion of the increased risk of cardiovascular events in DM is a sequel of stiff arteries. Direct measures of arterial stiffness, such as aortic pulse wave velocity, are likely to be better candidates than pulse wave analysis for refining interventions to improve outcomes in diabetes.