The angiotensin IV/AT4 receptor

The angiotensin AT4 receptor was originally defined as the specific, high-affinity binding site for the hexapeptide angiotensin IV (Ang IV). Subsequently, the peptide LVV-hemorphin 7 was also demonstrated to be a bioactive ligand of the AT4 receptor. Central administration of Ang IV, its analogues or LVV-hemorphin 7 markedly enhance learning and memory in normal rodents and reverse memory deficits observed in animal models of amnesia. The AT4 receptor has a broad distribution and is found in a range of tissues, including the adrenal gland, kidney, lung and heart. In the kidney Ang IV increases renal cortical blood flow and decreases Na+ transport in isolated renal proximal tubules. The AT4 receptor has recently been identified as the transmembrane enzyme, insulin-regulated membrane aminopeptidase (IRAP). IRAP is a type II integral membrane spanning protein belonging to the M1 family of aminopeptidases and is predominantly found in GLUT4 vesicles in insulin-responsive cells. Three hypotheses for the memory-potentiating effects of the AT4 receptor/IRAP ligands, Ang IV and LVV-hemorphin 7, are proposed: (i) acting as potent inhibitors of IRAP, they may prolong the action of endogenous promnestic peptides; (ii) they may modulate glucose uptake by modulating trafficking of GLUT4; (iii) IRAP may act as a receptor, transducing the signal initiated by ligand binding to its C-terminal domain to the intracellular domain that interacts with several cytoplasmic proteins.

Myocardial ischemia-reperfusion injury, antioxidant enzyme systems, and selenium : A review

Coronary heart disease (CHD) remains the greatest killer in the Western world, and although the death rate from CHD has been falling, the current increased prevalence of major risk factors including obesity and diabetes, suggests it is likely that CHD incidence will increase over the next 20 years. In conjunction with preventive strategies, major advances in the treatment of acute coronary syndromes and myocardial infarction have occurred over the past 20 years. In particular the ability to rapidly restore blood flow to the myocardium during heart attack, using interventional cardiologic or thrombolytic approaches has been a major step forward. Nevertheless, while 'reperfusion' is a major therapeutic aim, the process of ischemia followed by reperfusion is often followed by the activation of an injurious cascade. While the pathogenesis of ischemia-reperfusion is not completely understood, there is considerable evidence implicating reactive oxygen species (ROS) as an initial cause of the injury.

ROS formed during oxidative stress can initiate lipid peroxidation, oxidize proteins to inactive states and cause DNA strand breaks, all potentially damaging to normal cellular function. ROS have been shown to be generated following routine clinical procedures such as coronary bypass surgery and thrombolysis, due to the unavoidable episode of ischemia-reperfusion. Furthermore, they have been associated with poor cardiac recovery post-ischemia, with recent studies supporting a role for them in infarction, necrosis, apoptosis, arrhythmogenesis and endothelial dysfunction following ischemia-reperfusion. In normal physiological condition, ROS production is usually homeostatically controlled by endogenous free radical scavengers such as superoxide dismutase, catalase, and the glutathione peroxidase and thioredoxin reductase systems. Accordingly, targeting the generation of ROS with various antioxidants has been shown to reduce injury following oxidative stress, and improve recovery from ischemia-reperfusion injury.

This review summarises the role of myocardial antioxidant enzymes in ischemia-reperfusion injury, particularly the glutathione peroxidase (GPX) and the thioredoxin reductase (TxnRed) systems. GPX and TxnRed are selenocysteine dependent enzymes, and their activity is known to be dependent upon an adequate supply of dietary selenium. Moreover, various studies suggest that the supply of selenium as a cofactor also regulates gene expression of these selenoproteins. As such, dietary selenium supplementation may provide a safe and convenient method for increasing antioxidant protection in aged individuals, particularly those at risk of ischemic heart disease, or in those undergoing clinical procedures involving transient periods of myocardial hypoxia.

X-ray velocimetry within the ex vivo carotid artery

X-ray velocimetry offers a non-invasive method by which blood flow, blood velocity and wall shear stress can be measured in arteries prone to atherosclerosis. Analytical tools for measuring haemodynamics in artificial arteries have previously been developed and here the first quantification of haemodynamics using X-ray velocimetry in a living mammalian artery under physiologically relevant conditions is demonstrated. Whole blood seeded with a clinically used ultrasound contrast agent was pumped with a steady flow through live carotid arterial tissue from a rat, which was kept alive in a physiological salt solution. Pharmacological agents were then used to produce vascular relaxation. Velocity measurements were acquired with a spatial resolution of 14 µm × 14 µm and at a rate of 5000 acquisitions per second. Subtle velocity changes that occur are readily measurable, demonstrating the ability of X-ray velocimetry to sensitively and accurately measure haemodynamics ex vivo. Future applications and possible limitations of the technique are discussed, which allows for detailed living tissue investigations to be carried out for various disease models, including atherosclerosis and diabetic vasculopathy.

cGMP phosphodiesterase inhibition improves the vascular and metabolic actions of insulin in skeletal muscle

There is considerable support for the concept that insulin-mediated increases in microvascular blood flow to muscle impact significantly on muscle glucose uptake. Since the microvascular blood flow increases with insulin have been shown to be nitric oxide-dependent inhibition of cGMP-degrading phosphodiesterases (cGMP PDEs) is predicted to enhance insulin-mediated increases in microvascular perfusion and muscle glucose uptake. Therefore, we studied the effects of the pan-cGMP PDE inhibitor zaprinast on the metabolic and vascular actions of insulin in muscle. Hyperinsulinemic euglycemic clamps (3 mU·min−1·kg−1) were performed in anesthetized rats and changes in microvascular blood flow assessed from rates of 1-methylxanthine metabolism across the muscle bed by capillary xanthine oxidase in response to insulin and zaprinast. We also characterized cGMP PDE isoform expression in muscle by real-time PCR and immunostaining of frozen muscle sections. Zaprinast enhanced insulin-mediated microvascular perfusion by 29% and muscle glucose uptake by 89%, while whole body glucose infusion rate during insulin infusion was increased by 33% at 2 h. PDE2, -9, and -10 were the major isoforms expressed at the mRNA level in muscle, while PDE1B, -9A, -10A, and -11A proteins were expressed in blood vessels. Acute administration of the cGMP PDE inhibitor zaprinast enhances muscle microvascular blood flow and glucose uptake response to insulin. The expression of a number of cGMP PDE isoforms in skeletal muscle suggests that targeting specific cGMP PDE isoforms may provide a promising avenue for development of a novel class of therapeutics for enhancing muscle insulin sensitivity.

Loss of insulin-mediated microvascular perfusion in skeletal muscle is associated with the development of insulin resistance

Aim: The aetiology of the development of type 2 diabetes remains unresolved. In the present study, we assessed whether an impairment of insulin-mediated microvascular perfusion occurs early in the onset of insulin resistance. Materials and methods: Hooded Wistar rats were fed either a normal diet (ND) or a high-fat diet (HFD) for 4 weeks. Anaesthetized animals were subjected to an isoglycaemic hyperinsulinaemic clamp (3 or 10 mU/min/kg × 2 h), and measurements were made of glucose infusion rate (GIR), hindleg glucose uptake, muscle glucose uptake by 2-deoxy-d-glucose (R′g), glucose appearance (Ra), glucose disappearance (Rd), femoral blood flow (FBF) and hindleg 1-methylxanthine disappearance (1-MXD, an index of microvascular perfusion). Results: Compared with ND-fed animal, HFD feeding led to a mild increase in fasting plasma glucose and plasma insulin, without an increase in total body weight. During the clamps, HFD rats showed an impairment of insulin-mediated action on GIR, hindleg glucose uptake, R′g, Ra, Rd and FBF, with a greater loss of insulin responsiveness at 3 mU/min/kg than at 10 mU/min/kg. The HFD also impaired insulin-mediated microvascular perfusion as assessed by 1-MXD. Interestingly, 1-MXD was the only measurement that remained unresponsive to the higher dose of 10 mU/min/kg insulin. Conclusions: We conclude that the early stage of insulin resistance is characterized by an impairment of the insulin-mediated microvascular responses in skeletal muscle. This is likely to cause greater whole body insulin resistance by limiting the delivery of hormones and nutrients to muscle.

Optimization of bypass graft using FSI numerical method

It is well documented in literature that the coronary artery bypass graft is normally fail after a short period of time, due to the development of plaque known as intimal hyperplasia within the graft. Various in vivo and in vitro studies have linked the development of intimal hyperplasia to the abnormal hemodynamics and compliance mismatch. Therefore, it is essential to fully understand the relationship between the hemodynamics inside the coronary artery bypass and its mechanical and geometrical characteristics under the correct physiological conditions. In this work, hemodynamic of the bypass graft is studied numerically. The effect of the host and graft diameters ratio, the angle of anastomosis and the graft configuration on the local flow patterns and the distribution of wall shear stress are examined. The pulsatile waveforms boundary conditions are adopted from in vivo measurement data to study the hemodynamics of composite grafts namely Consequence and Y grafting in terms temporal and spatial distributions of the blood flows. Moreover, various non-Newtonian and Newtonian models of blood have been carried out to examine the numerical simulation of blood flow in stenosis artery. The results are presented and discussed for various operating conditions.

Skeletal muscle nitric oxide signalling and exercise: a focus on glucose metabolism

Nitric oxide (NO) is an important vasodilator and regulator in the cardiovascular system, and this link was the subject of a Nobel prize in 1998. However, NO also plays many other regulatory roles, including thrombosis, immune function, neural activity, and gastrointestinal function. Low concentrations of NO are thought to have important signaling effects. In contrast, high concentrations of NO can interact with reactive oxygen species, causing damage to cells and cellular components.

A less-recognized site of NO production is within skeletal muscle, where small increases are thought to have beneficial effects such as regulating glucose uptake and possibly blood flow, but higher levels of production are thought to lead to deleterious effects such as an association with insulin resistance.

This review will discuss the role of NO in skeletal muscle during and following exercise, including in mitochondrial biogenesis, muscle efficiency, and blood flow with a particular focus on its potential role in regulating skeletal muscle glucose uptake during exercise.

Vascular occlusion training as an alternate method of gaining muscle

Training whilst under the effects of vascular occlusion has become increasingly popular due to the resultant muscle gain associated with this training technique. However, when exercising with the use of a tourniquet type device, it is possible for the pressure being applied to be inconsistent, due the constantly changing cross sectional area of the limb being occluded. This Paper describes the design of a device capable of causing vascular occlusion, but also being able to maintain a stable pressure required to create the blood flow restriction, this being able to be utilized in a sports science environment

Altered responsiveness of the kidney to activation of the renal nerves in fat-fed rabbits

We tested whether mild adiposity alters responsiveness of the kidney to activation of the renal sympathetic nerves. After rabbits were fed a high-fat or control diet for 9 wk, responses to reflex activation of renal sympathetic nerve activity (RSNA) with hypoxia and electrical stimulation of the renal nerves (RNS) were examined under pentobarbital anesthesia. Fat pad mass and body weight were, respectively, 74% and 6% greater in fat-fed rabbits than controls. RNS produced frequency-dependent reductions in renal blood flow, cortical and medullary perfusion, glomerular filtration rate, urine flow, and sodium excretion and increased renal plasma renin activity (PRA) overflow. Responses of sodium excretion and medullary perfusion were significantly enhanced by fat feeding. For example, 1 Hz RNS reduced sodium excretion by 79 ± 4% in fat-fed rabbits and 46 ± 13% in controls. RNS (2 Hz) reduced medullary perfusion by 38 ± 11% in fat-fed rabbits and 9 ± 4% in controls. Hypoxia doubled RSNA, increased renal PRA overflow and medullary perfusion, and reduced urine flow and sodium excretion, without significantly altering mean arterial pressure (MAP) or cortical perfusion. These effects were indistinguishable in fat-fed and control rabbits. Neither MAP nor PRA were significantly greater in conscious fat-fed than control rabbits. These observations suggest that mild excess adiposity can augment the antinatriuretic response to renal nerve activation by RNS, possibly through altered neural control of medullary perfusion. Thus, sodium retention in obesity might be driven not only by increased RSNA, but also by increased responsiveness of the kidney to RSNA.

Chronic intraocular pressure elevation impairs autoregulatory capacity in streptozotocin-induced diabetic rat retina

Purpose: To assess ocular blood flow responses to acute IOP stress following 4 weeks of chronic IOP elevation in streptozotocin (STZ)-induced diabetic and control rats. We hypothesise that chronic IOP elevation for 4 weeks will further impair blood flow regulation in STZ-induced diabetic rats eyes. Methods: Two weeks following citrate buffer or STZ-injections chronic IOP elevation was induced in Long Evans rats via fortnightly intracameral injections of microspheres (15 μm) suspended in 5% polyethylene glycol. IOP was monitored daily. Electroretinography (ERG, -6.79-2.07 log cd s m-2) was undertaken at Week 4 to compare photoreceptor (RmPIII), ON-bipolar cell (Vmax) and ganglion cell dominant ERG [scotopic threshold response (STR)] components. 4 weeks post-chronic IOP induction, ocular blood flow (laser Doppler flowmetry) was measured in response to acute IOP challenge (10-100 mmHg, in 5 mmHg steps, each 3 min). Results: Four weeks of chronic IOP (mean ± S.E.M., citrate: 24.0 ± 0.3 to 30.7 ± 1.3 and STZ-diabetes: 24.2 ± 0.2 to 31.1 ± 1.2 mmHg) was associated with reduced photoreceptor amplitude in both groups (-25.3 ± 2.2% and -17.2 ± 3.0%, respectively). STZ-diabetic eyes showed reduced photoreceptor sensitivity (citrate: 0.5 ± 1.8%, STZ-diabetic: -8.1 ± 2.4%). Paradoxically ON-bipolar cell sensitivity was increased, particularly in citrate control eyes (citrate: 166.8 ± 25.9%, STZ-diabetic: 64.8 ± 18.7%). The ganglion cell dominant STR was not significantly reduced in STZ-diabetic rats. Using acute IOP elevation to probe autoregulation, we show that STZ-diabetes impaired autoregulation compared with citrate control animals. The combination of STZ-diabetes and chronic IOP elevation further impaired autoregulation. Conclusions: STZ-diabetes and chronic IOP elevation appear to be additive risk factors for impairment of ocular blood flow autoregulation.

Switching to a 10-day Mediterranean-style diet improves mood and cardiovascular function in a controlled crossover study

OBJECTIVES: Even short-term adherence to a Mediterranean-style diet may benefit aspects of psychological functioning. The aim of the present study was to assess the effects of switching to a 10-d Mediterranean-style diet on mood, cognition, and cardiovascular measures. METHODS: Using a crossover design, 24 women were randomly assigned to either the diet change (where they switched to a Mediterranean-style diet) or no diet change (normal diet) condition for 10 days before switching to the other condition for the same duration. Mood, cognition, and cardiovascular measures of blood pressure, blood flow velocity, and arterial stiffness were assessed at baseline and at the completion of the two diets (days 11 and 22). RESULTS: Independent of whether the Mediterranean-style diet was undertaken before or after the crossover, it was associated with significantly elevated contentment and alertness, and significantly reduced confusion. Additionally, aspects of cognition, such as memory recall, improved significantly as a result of switching to the Mediterranean-style diet. Regarding cardiovascular measures, there was a significant reduction in augmentation pressure associated with the Mediterranean-style diet intervention, but blood flow velocity through the common carotid artery did not change. CONCLUSIONS: This Mediterranean-style diet has the potential to enhance aspects of mood, cognition, and cardiovascular function in a young, healthy adult sample.

Modulating exercise-induced hormesis: does less equal more?

Hormesis encompasses the notion that low levels of stress stimulate or upregulate existing cellular and molecular pathways that improve the capacity of cells and organisms to withstand greater stress. This notion underlies much of what we know about how exercise conditions the body and induces long-term adaptations. During exercise, the body is exposed to various forms of stress, including thermal, metabolic, hypoxic, oxidative, and mechanical stress. These stressors activate biochemical messengers, which in turn activate various signaling pathways that regulate gene expression and adaptive responses. Historically, antioxidant supplements, nonsteroidal anti-inflammatory drugs, and cryotherapy have been favored to attenuate or counteract exercise-induced oxidative stress and inflammation. However, reactive oxygen species and inflammatory mediators are key signaling molecules in muscle, and such strategies may mitigate adaptations to exercise. Conversely, withholding dietary carbohydrate and restricting muscle blood flow during exercise may augment adaptations to exercise. In this review article, we combine, integrate, and apply knowledge about the fundamental mechanisms of exercise adaptation. We also critically evaluate the rationale for using interventions that target these mechanisms under the overarching concept of hormesis. There is currently insufficient evidence to establish whether these treatments exert dose-dependent effects on muscle adaptation. However, there appears to be some dissociation between the biochemical/molecular effects and functional/performance outcomes of some of these treatments. Although several of these treatments influence common kinases, transcription factors, and proteins, it remains to be determined if these interventions complement or negate each other, and whether such effects are strong enough to influence adaptations to exercise.

Effect of retinal image defocus on the thickness of the human choroid

PURPOSE: To describe the time-course and amplitude of changes to sub-foveal choroidal thickness (SFCT) induced by imposed hyperopic and myopic retinal defocus and to compare the responses in emmetropic and myopic subjects. METHODS: Twelve East Asian subjects (age: 18-34 years; six were emmetropic and six had myopia between -2.00 and -5.00 dioptres (D)) viewed a distant target (video movie at 6 m) for 60 min on two separate occasions while optical coherence tomography (OCT) images of the choroid were taken in both eyes every 5 min to monitor SFCT. On each occasion, one eye was optimally corrected for distance with a contact lens while the other eye wore a contact lens imposing either 2.00 D hyperopic or 2.00 D myopic retinal defocus. RESULTS: Baseline SFCT in myopic eyes (mean ± S.D.): 256 ± 42 μm was significantly less than in emmetropic eyes (423 ± 62 μm; p < 0.01) and was correlated with magnitude of myopia (-39 μm per dioptre of myopia, R(2) = 0.67: p < 0.01). Repeated measures anova (General Linear Model) analysis revealed that in both subject groups, 2.00 D of myopic defocus caused a rapid increase in SFCT in the defocussed eye (significant by 10 min, increasing to approximately 20 μm within 60 min: p < 0.01), with little change in the control eye. In contrast, 2.00 D of hyperopic defocus caused a decrease in SFCT in the experimental eye (significant by 20-35 min. SFCT decreased by approximately 20 μm within 60 min: p < 0.01) with little change in the control eye. CONCLUSIONS: Small but significant changes in SFCT (5-8%) were caused by retinal defocus. SFCT increased within 10 min of exposure to 2.00 D of monocular myopic defocus, but decreased more slowly in response to 2.00 D of monocular hyperopic defocus. In our relatively small sample we could detect no difference in the magnitude of changes to SFCT caused by defocus in myopic eyes compared to emmetropic eyes.

Resistive exercise versus resistive vibration exercise to counteract vascular adaptations to bed rest

Bed rest results in marked vascular adaptations, and resistive vibration exercise (RVE) has been shown to be an effective countermeasure. As vibration exercise has practical and logistical limitations, the use of resistive exercise (RES) alone has the preference under specific circumstances. However, it is unknown if RES is sufficient to prevent vascular adaptations to bed rest. Therefore, the purpose of the present study was to examine the impact of RES and RVE on the vascular function and structure of the superficial femoral artery in young men exposed to 60 days of bed rest. Eighteen healthy men (age: 31 +/- 8 yr) were assigned to bed rest and randomly allocated to control, RES, or RVE groups. Exercise was applied 3 times/wk for 5-7 min/session. Resting diameter, blood flow, flow-mediated dilation (FMD), and dilator capacity of the superficial femoral artery were measured using echo-Doppler ultrasound. Bed rest decreased superficial femoral artery diameter and dilator capacity (P < 0.001), which were significantly attenuated in the RVE group (P < 0.01 and P < 0.05, respectively) but not in the RES group (P = 0.202 and P = 0.696, respectively). Bed rest significantly increased FMD (P < 0.001), an effect that was abolished by RVE (P < 0.005) but not RES (P = 0.078). Resting and hyperemic blood flow did not change in any of the groups. Thus, RVE abolished the marked increase in FMD and decrease in baseline diameter and dilator capacity normally associated with prolonged bed rest. However, the stimulus provided by RES alone was insufficient to counteract the vascular adaptations to bed rest.

Impact of bed rest on conduit artery remodeling: effect of exercise countermeasures

Physical inactivity is a potent stimulus for vascular remodeling, leading to a marked decrease in conduit artery diameter. However, little is known about the impact of physical inactivity on artery wall thickness or wall:lumen ratio or the potential of exercise countermeasures to modify artery wall thickness. The purpose of the study was to examine the impact of 60 days of bed rest, with or without exercise countermeasures, on carotid and superficial femoral artery wall thickness. Eighteen men were assigned to bed rest (second Berlin Bed Rest Study) and randomly allocated to control, resistive exercise, or resistive vibration exercise. Both exercise countermeasures were applied 3 times per week while the subjects were in the supine position on the bed. Sonography was used to examine baseline diameter and wall thickness of the carotid and femoral arteries. Bed rest decreased diameter of the superficial femoral artery (P=0.001) but not the carotid artery (P=0.29). Bed rest induced a significant increase in carotid and superficial femoral artery wall thickness (P=0.007 and 0.03) and wall:lumen ratio (P=0.009 and 0.001). Exercise prevented the increase in wall thickness of the carotid artery. In addition, exercise partly prevented the increased wall:lumen ratio in the superficial femoral artery. In conclusion, 8 weeks of bed rest resulted in approximately 20% increase in conduit artery wall thickness. Exercise countermeasures completely (carotid artery) or partly (superficial femoral artery) abolished the increase in wall thickness. These findings suggest that conduit artery wall thickness, a vascular characteristic associated previously with atherosclerosis, can rapidly adapt to physical inactivity and exercise in humans.