The impact of milk proteins and peptides on blood pressure and vascular function: a review of evidence from human intervention studies.

CVD are the leading cause of death worldwide. Hypertension, a major controllable risk factor of CVD, is intimately associated with vascular dysfunction, a defect which is also now recognised to be a major, modifiable risk factor for the development of CVD. The purpose of the present review was to critically evaluate the evidence for the effects of milk proteins and their associated peptides on blood pressure (BP) and vascular dysfunction. After a detailed literature search, the number of human trials evaluating the antihypertensive effects of casein-derived peptides (excluding isoleucine-proline-proline and valine-proline-proline) was found to be limited; the studies were preliminary with substantial methodological limitations. Likewise, the data from human trials that examined the effects of whey protein and peptides were also scarce and inconsistent. To date, only one study has conducted a comparative investigation on the relative effects of the two main intact milk proteins on BP and vascular function. While both milk proteins were shown to reduce BP, only whey protein improved measures of arterial stiffness. In contrast, a growing number of human trials have produced evidence to support beneficial effects of both milk proteins and peptides on vascular health. However, comparison of the relative outcomes from these trials is difficult owing to variation in the forms of assessment and measures of vascular function. In conclusion, there is an accumulating body of evidence to support positive effects of milk proteins in improving and/or maintaining cardiovascular health. However, the variable quality of the studies that produced this evidence, and the lack of robust, randomised controlled intervention trials, undermines the formulation of firm conclusions on the potential benefits of milk proteins and peptides on vascular health.

Correlations between ovarian follicular blood flow and superovulatory responses in ewes

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Resting state cerebral blood flow and objective motor activity reveal basal ganglia dysfunction in schizophrenia

Reduced motor activity has been reported in schizophrenia and was associated with subtype, psychopathology and medication. Still, little is known about the neurobiology of motor retardation. To identify neural correlates of motor activity, resting state cerebral blood flow (CBF) was correlated with objective motor activity of the same day. Participants comprised 11 schizophrenia patients and 14 controls who underwent magnetic resonance imaging with arterial spin labeling and wrist actigraphy. Patients had reduced activity levels and reduced perfusion of the left parahippocampal gyrus, left middle temporal gyrus, right thalamus, and right prefrontal cortex. In controls, but not in schizophrenia, CBF was correlated with activity in the right thalamic ventral anterior (VA) nucleus, a key module within basal ganglia-cortical motor circuits. In contrast, only in schizophrenia patients positive correlations of CBF and motor activity were found in bilateral prefrontal areas and in the right rostral cingulate motor area (rCMA). Grey matter volume correlated with motor activity only in the left posterior cingulate cortex of the patients. The findings suggest that basal ganglia motor control is impaired in schizophrenia. In addition, CBF of cortical areas critical for motor control was associated with volitional motor behavior, which may be a compensatory mechanism for basal ganglia dysfunction.

Outer skull landmark-based coordinates for measurement of cerebral blood flow and intracranial pressure in rabbits

Despite the increased use of intracranial neuromonitoring during experimental subarachnoid hemorrhage (SAH), coordinates for probe placement in rabbits are lacking. This study evaluates the safety and reliability of using outer skull landmarks to identify locations for placement of cerebral blood flow (CBF) and intraparenchymal intracranial pressure (ICP) probes. Experimental SAH was performed in 17 rabbits using an extracranial-intracranial shunt model. ICP probes were placed in the frontal lobe and compared to measurements recorded from the olfactory bulb. CBF probes were placed in various locations in the frontal cortex anterior to the coronary suture. Insertion depth, relation to the ventricular system, and ideal placement location were determined by post-mortem examination. ICP recordings at the time of SAH from the frontal lobe did not differ significantly from those obtained from the right olfactory bulb. Ideal coordinates for intraparenchymal CBF probes in the left and right frontal lobe were found to be located 4.6±0.9 and 4.5±1.2 anterior to the bregma, 4.7±0.7mm and 4.7±0.5mm parasagittal, and at depths of 4±0.5mm and 3.9±0.5mm, respectively. The results demonstrate that the presented coordinates based on skull landmarks allow reliable placement of intraparenchymal ICP and CBF probes in rabbit brains without the use of a stereotactic frame.

Effects of low abdominal blood flow and dobutamine on blood flow distribution and on the hepatic arterial buffer response in anaesthetized pigs

Low cardiac output impairs the hepatic arterial buffer response (HABR). Whether this is due to low abdominal blood flow per se is not known. Dobutamine is commonly used to increase cardiac output, and it may further modify hepatosplanchnic and renal vasoregulation. We assessed the effects of isolated abdominal aortic blood flow changes and dobutamine on hepatosplanchnic and renal blood flow. Twenty-five anesthetized pigs with an abdominal aorto-aortic shunt were randomized to 2 control groups [zero (n = 6) and minimal (n = 6) shunt flow], and 2 groups with 50% reduction of abdominal blood flow and either subsequent increased abdominal blood flow by shunt reduction (n = 6) or dobutamine infusion at 5 and 10 microg kg(-1) min(-1) with constant shunt flow (n = 7). Regional (ultrasound) and local (laser Doppler) intra-abdominal blood flows were measured. The HABR was assessed during acute portal vein occlusion. Sustained low abdominal blood flow, by means of shunt activation, decreased liver, gut, and kidney blood flow similarly and reduced local microcirculatory blood flow in the jejunum. Shunt flow reduction partially restored regional blood flows but not jejunal microcirculatory blood flow. Low-but not high-dose dobutamine increased gut and celiac trunk flow whereas hepatic artery and renal blood flows remained unchanged. Neither intervention altered local blood flows. The HABR was not abolished during sustained low abdominal blood flow despite substantially reduced hepatic arterial blood flow and was not modified by dobutamine. Low-but not high-dose dobutamine redistributes blood flow toward the gut and celiac trunk. The jejunal microcirculatory flow, once impaired, is difficult to restore.

Endothelin inhibition improves cerebral blood flow and is neuroprotective in pneumococcal meningitis

By using an infant rat model of pneumococcal meningitis, we determined whether endothelins contribute to neuronal damage in this disease. Cerebrospinal fluid analysis demonstrated a significant increase of endothelin-1 in infected animals compared with uninfected controls. Histopathological examination 24 hours after infection showed brain damage in animals treated with ceftriaxone alone (median, 9.2% of cortex; range, 0-49.1%). In infected animals treated intraperitoneally with the endothelin antagonist bosentan (30 mg/kg, every 12 hours) also, injury was reduced to 0.5% (range, 0-8.6%) of cortex. Cerebral blood flow was reduced in infected animals (6.5 +/- 4.0 ml/min/100 g of brain vs 14.9 +/- 9.1 ml/min/100 g in controls. Treatment with bosentan restored cerebral blood flow to levels similar to controls (12.8 +/- 5.3 ml/min/100 g). Improved blood flow was not mediated by nitric oxide production, because bosentan had no effect on cerebrospinal fluid or plasma nitrite/nitrate concentrations at 6, 12, or 18 hours. These data indicate that endothelins contribute to neuronal injury in this model of pneumococcal meningitis by causing cerebral ischemia.

Effect of hydration status on cerebral blood flow and cerebrospinal fluid lactic acidosis in rabbits with experimental meningitis

The effects of hydration status on cerebral blood flow (CBF) and development of cerebrospinal fluid (CSF) lactic acidosis were evaluated in rabbits with experimental pneumococcal meningitis. As loss of cerebrovascular autoregulation has been previously demonstrated in this model, we reasoned that compromise of intravascular volume might severely affect cerebral perfusion. Furthermore, as acute exacerbation of the inflammatory response in the subarachnoid space has been observed after antibiotic therapy, animals were studied not only while meningitis evolved, but also 4-6 h after treatment with antibiotics to determine whether there would also be an effect on CBF. To produce different levels of hydration, animals were given either 50 ml/kg per 24 h of normal saline ("low fluid") or 150 ml/kg 24 h ("high fluid"). After 16 h of infection, rabbits that were given the lower fluid regimen had lower mean arterial blood pressure (MABP), lower CBF, and higher CSF lactate compared with animals that received the higher fluid regimen. In the first 4-6 h after antibiotic administration, low fluid rabbits had a significant decrease in MABP and CBF compared with, and a significantly greater increase in CSF lactate concentration than, high fluid rabbits. This study suggests that intravascular volume status may be a critical variable in determining CBF and therefore the degree of cerebral ischemia in meningitis.

ASSESSMENT OF SKELETAL MUSCLE BLOOD FLOW AND GLUCOSE METABOLISM WITH POSITRON EMITTING RADIONUCLIDES

In order to evaluate factors regulating substrate metabolism in vivo positron emitting radionuclides were used for the assessment of skeletal muscle blood flow and glucose utilization. The potassium analog, Rb-82 was used to measure skeletal muscle blood flow and the glucose analog, 18-F-2-deoxy-2-fluoro-D-glucose (FDG) was used to examine the kinetics of skeletal muscle transport and phosphorylation.^ New Zealand white rabbits' blood flow ranged from 1.0-70 ml/min/100g with the lowest flows occurring under baseline conditions and the highest flows were measured immediately after exercise. Elevated plasma glucose had no effect on increasing blood flow, whereas high physiologic to pharmacologic levels of insulin doubled flow as measured by the radiolabeled microspheres, but a proportionate increase was not detected by Rb-82. The data suggest that skeletal muscle blood flow can be measured using the positron emitting K+ analog Rb-82 under low flow and high flow conditions but not when insulin levels in the plasma are elevated. This may be due to the fact that insulin induces an increase in the Na+/K+-ATPase activity of the cell indirectly through a direct increase in the Na+/H+pump activity. This suggests that the increased cation pump activity counteracts the normal decrease in extraction seen at higher flows resulting in an underestimation of flow as measured by rubidium-82.^ Glucose uptake as measured by FDG employed a three compartment mathematical model describing the rates of transport, countertransport and phosphorylation of hexose. The absolute values for the metabolic rate of FDG were found to be an order of magnitude higher than those reported by other investigators. Changes noted in the rate constant for transport (k1) were found to disagree with the a priori information on the effects of insulin on skeletal muscle hexose transport. Glucose metabolism was however, found to increase above control levels with administration of insulin and electrical stimulation. The data indicate that valid measurements of skeletal muscle glucose transport and phosphorylation using the positron emitting glucose analog FDG requires further model application and biochemical validation. (Abstract shortened with permission of author.) ^

Correlation of regional cerebral blood flow and change of plasma sodium concentration during genesis and satiation of thirst

Positron emission tomography studies were conducted during genesis of moderate thirst by rapid i.v. infusion of hypertonic saline (0.51 M) and after satiation of thirst by drinking water. The correlation of regional cerebral blood flow with the change in the plasma Na concentration showed a significant group of cerebral activations in the anterior cingulate region and also a site in the middle temporal gyrus and in the periaqueductal gray. Strongest deactivations occurred in the parahippocampal and frontal gyri. The data are consistent with an important role of the anterior cingulate in the genesis of thirst.

Blood flow and oxygen delivery to human brain during functional activity: Theoretical modeling and experimental data

Coupling of cerebral blood flow (CBF) and cerebral metabolic rate for oxygen (CMRO2) in physiologically activated brain states remains the subject of debates. Recently it was suggested that CBF is tightly coupled to oxidative metabolism in a nonlinear fashion. As part of this hypothesis, mathematical models of oxygen delivery to the brain have been described in which disproportionately large increases in CBF are necessary to sustain even small increases in CMRO2 during activation. We have explored the coupling of CBF and oxygen delivery by using two complementary methods. First, a more complex mathematical model was tested that differs from those recently described in that no assumptions were made regarding tissue oxygen level. Second, [15O] water CBF positron emission tomography (PET) studies in nine healthy subjects were conducted during states of visual activation and hypoxia to examine the relationship of CBF and oxygen delivery. In contrast to previous reports, our model showed adequate tissue levels of oxygen could be maintained without the need for increased CBF or oxygen delivery. Similarly, the PET studies demonstrated that the regional increase in CBF during visual activation was not affected by hypoxia. These findings strongly indicate that the increase in CBF associated with physiological activation is regulated by factors other than local requirements in oxygen.

Effects of anesthesia on functional activation of cerebral blood flow and metabolism

Functional brain mapping based on changes in local cerebral blood flow (lCBF) or glucose utilization (lCMRglc) induced by functional activation is generally carried out in animals under anesthesia, usually α-chloralose because of its lesser effects on cardiovascular, respiratory, and reflex functions. Results of studies on the role of nitric oxide (NO) in the mechanism of functional activation of lCBF have differed in unanesthetized and anesthetized animals. NO synthase inhibition markedly attenuates or eliminates the lCBF responses in anesthetized animals but not in unanesthetized animals. The present study examines in conscious rats and rats anesthetized with α-chloralose the effects of vibrissal stimulation on lCMRglc and lCBF in the whisker-to-barrel cortex pathway and on the effects of NO synthase inhibition with NG-nitro-l-arginine methyl ester (l-NAME) on the magnitude of the responses. Anesthesia markedly reduced the lCBF and lCMRglc responses in the ventral posteromedial thalamic nucleus and barrel cortex but not in the spinal and principal trigeminal nuclei. l-NAME did not alter the lCBF responses in any of the structures of the pathway in the unanesthetized rats and also not in the trigeminal nuclei of the anesthetized rats. In the thalamus and sensory cortex of the anesthetized rats, where the lCBF responses to stimulation had already been drastically diminished by the anesthesia, l-NAME treatment resulted in loss of statistically significant activation of lCBF by vibrissal stimulation. These results indicate that NO does not mediate functional activation of lCBF under physiological conditions.

A new method of determinating co-efficients of flow and of resistance in pipes and in open channels, and new formulae for head, diameter, mean hydraulic radius, velocity, etc., based on this new theory /

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