Multiple coherence of cerebral blood flow velocity in humans

The coherence function has been used in transfer function analysis of dynamic cerebral autoregulation to assess the statistical significance of spectral estimates of gain and phase frequency response. Interpretation of the coherence function and choice of confidence limits has not taken into account the intrinsic nonlinearity represented by changes in cerebrovascular resistance due to vasomotor activity. For small spontaneous changes in arterial blood pressure (ABP), the relationship between ABP and cerebral blood flow velocity (CBFV) can be linearized, showing that corresponding changes in cerebrovascular resistance should be included as a second input variable. In this case, the standard univariate coherence function needs to be replaced by the multiple coherence, which takes into account the contribution of both inputs to explain CBFV variability. With the use of two different indicators of cerebrovascular resistance index [CVRI = ABP/CBFV and the resistance-area product (RAP)], multiple coherences were calculated for 42 healthy control subjects, aged 20 to 40 yr (28 +/- 4.6 yr, mean +/- SD), at rest in the supine position. CBFV was measured in both middle cerebral arteries, and ABP was recorded noninvasively by finger photoplethysmography. Results for the ABP + RAP inputs show that the multiple coherence of CBFV for frequencies <0.05 Hz is significantly higher than the corresponding values obtained for univariate coherence (P < 10(-5)). Corresponding results for the ABP + CVRI inputs confirm the principle of multiple coherence but are less useful due to the interdependence between CVRI, ABP, and CBFV. The main conclusion is that values of univariate coherence between ABP and CBFV should not be used to reject spectral estimates of gain and phase, derived from small fluctuations in ABP, because the true explained power of CBFV in healthy subjects is much higher than what has been usually predicted by the univariate coherence functions.     

Differential sensitivities of cerebral and brachial blood flow to hypercapnia in humans.

Although it is known that the vasculatures of the brain and the forearm are sensitive to changes in arterial Pco(2), previous investigations have not made direct comparisons of the sensitivities of cerebral blood flow (CBF) (middle cerebral artery blood velocity associated with maximum frequency of Doppler shift; Vp) and brachial blood flow (BBF) to hypercapnia. We compared the sensitivities of Vp and BBF to hypercapnia in humans. On the basis of the critical importance of the brain for the survival of the organism, we hypothesized that Vp would be more sensitive than BBF to hypercapnia. Nine healthy males (30.1 +/- 5.2 yr, mean +/- SD) participated. Euoxic hypercapnia (end-tidal Po(2) = 88 Torr, end-tidal Pco(2) = 9 Torr above resting) was achieved by using the technique of dynamic end-tidal forcing. Vp was measured by transcranial Doppler ultrasound as an index of CBF, whereas BBF was measured in the brachial artery by echo Doppler. Vp and BBF were measured during two 60-min trials of hypercapnia, each trial separated by 60 min. Since no differences in the responses were found between trials, data from both trials were averaged to make comparisons between Vp and BBF. During hypercapnia, Vp and BBF increased by 34 +/- 8 and 14 +/- 8%, respectively. Vp remained elevated throughout the hypercapnic period, but BBF returned to baseline levels by 60 min. The Vp CO(2) sensitivity was greater than BBF (4 +/- 1 vs. 2 +/- 1%/Torr; P < 0.05). Our findings confirm that Vp has a greater sensitivity than BBF in response to hypercapnia and show an adaptive response of BBF that is not evident in Vp.     

Electrical stimulation of the cervical spinal cord increases cerebral blood flow in humans

Ten patients were studied to determine the effect of spinal cord stimulation on CBF. In 5 patients using a cervical spinal cord stimulator, the stimulation produced a significant increase in CBF in the hemisphere ipsilateral to the induced paresthesia. Thoracic cord stimulation, used by the other 5 patients, had no effect on CBF. Atropine had no effect on the alteration in CBF produced by cervical cord stimulation. Indomethacin, however, partially blocked the effect. These heuristic observations may have implications for the future treatment of cerebrovascular insufficiency in humans.     

Caffeine does not modulate nutritive blood flow to rat gastric submucosa--a microdialysis study

Background and Aims: Coffee irritates the gastric mucosa disrupting its barrier and increasing the risk of peptic ulcers. However, caffeine's contribution to these effects has not yet been elucidated. In this study we looked at the local effect of caffeine on the microcirculation and nitric oxide production in rats together with systemic marker of oxidative stress malondialdehyde as possible mechanisms whereby caffeine might participate in mucosal barrier impairment. Materials and Methods: Four groups of rats were anesthetized and administered as a bolus four different intraperitoneal doses of caffeine (0, 1, 10 and 50 mg kg(-1) b.wt.). The gastric submucosal microcirculation and nitric oxide production were then recorded for 2.5 hours by in situ microdialysis using the flow marker ethanol. At the completion of the experiments, plasma caffeine and malondialdehyde levels as well as morphological mucosal injury were determined. Results: There were no major differences in the macro- or microscopic pictures of the mucosa among the groups. Local microcirculatory (ethanol out/in ratio) and nitric oxide monitoring failed to demonstrate statistically significant changes as did measurement of plasma malondialdehyde in response to caffeine injections. Conclusions: Caffeine per se seems unlikely to contribute to the gastric mucosal barrier injury associated with coffee consumption by alterations in nutritive blood flow, nitric oxide production or aggravation of systemic oxidative stress. This information is relevant for better understanding of the mechanisms involved in caffeine-mediated influences on gastric physiology in relation to the irritant effects of coffee.     

Muscle pump does not enhance blood flow in exercising skeletal muscle.

The muscle pump theory holds that contraction aids muscle perfusion by emptying the venous circulation, which lowers venous pressure during relaxation and increases the pressure gradient across the muscle. We reasoned that the influence of a reduction in venous pressure could be determined after maximal pharmacological vasodilation, in which the changes in vascular tone would be minimized. Mongrel dogs (n = 7), instrumented for measurement of hindlimb blood flow, ran on a treadmill during continuous intra-arterial infusion of saline or adenosine (15-35 mg/min). Adenosine infusion was initiated at rest to achieve the highest blood flow possible. Peak hindlimb blood flow during exercise increased from baseline by 438 +/- 34 ml/min under saline conditions but decreased by 27 +/- 18 ml/min during adenosine infusion. The absence of an increase in blood flow in the vasodilated limb indicates that any change in venous pressure elicited by the muscle pump was not adequate to elevate hindlimb blood flow. The implication of this finding is that the hyperemic response to exercise is primarily attributable to vasodilation in the skeletal muscle vasculature.     

Hypohydration and prior heat stress exacerbates decreases in cerebral blood flow velocity during standing.

Hypohydration is associated with orthostatic intolerance; however, little is known about cerebrovascular mechanisms responsible. This study examined whether hypohydration reduces cerebral blood flow velocity (CBFV) in response to an orthostatic challenge. Eight subjects completed four orthostatic challenges (temperate conditions) twice before (Pre-EU and Pre-Hyp) and following recovery from passive heat stress ( approximately 3 h at 45 degrees C, 50% relative humidity, 1 m/s air speed) with (Post-EU) or without (Post-Hyp) fluid replacement of sweat losses (-3% body mass loss). Measurements included CBFV, mean arterial pressure (MAP), heart rate (HR), end-tidal CO(2), and core and skin temperatures. Test sessions included being seated (20 min) followed by standing (60 s) then resitting (60 s) with metronomic breathing (15 breaths/min). CBFV and MAP responses to standing were similar during Pre-EU and Pre-Hyp. Standing Post-Hyp exacerbated the magnitude (-28.0 +/- 1.4% of baseline) and duration (9.0 +/- 1.6 s) of CBFV reductions and increased cerebrovascular resistance (CVR) compared with Post-EU (-20.0 +/- 2.1% and 6.6 +/- 0.9 s). Standing Post-EU also resulted in a reduction in CBFV, and a smaller decrease in CVR compared with Pre-EU. MAP decreases were similar for Post-EU (-18 +/- 4 mmHg) and Post-Hyp (-21 +/- 5 mmHg) from seated to standing. These data demonstrate that despite similar MAP decreases, hypohydration, and prior heat stress (despite apparent recovery) produce greater CBFV reduction when standing. These observations suggest that hypohydration and prior heat stress are associated with greater reductions in CBFV with greater CVR, which likely contribute to orthostatic intolerance.     

Changes in regional cerebral blood flow distribution during postexercise hypotension in humans.

This investigation compared patterns of regional cerebral blood flow (rCBF) during exercise recovery both with and without postexercise hypotension (PEH). Eight subjects were studied on 3 days with randomly assigned conditions: 1) after 30 min of rest; 2) after 30 min of moderate exercise (M-Ex) at 60-70% heart rate (HR) reserve during PEH; and 3) after 30 min of light exercise (L-Ex) at 20% HR reserve with no PEH. Data were collected for HR, mean blood pressure (MBP), and ratings of perceived exertion and relaxation, and rCBF was assessed by use of single-photon-emission computed tomography. With the use of ANOVA across conditions, there were differences (P < 0.05; mean +/- SD) from rest during exercise recovery from M-Ex (HR = +12 +/- 3 beats/min; MBP = -9 +/- 2 mmHg), but not from L-Ex (HR = +2 +/- 2 beats/min; MBP = -2 +/- 2 mmHg). After M-Ex, there were decreases (P < 0.05) for the anterior cingulate (-6.7 +/- 2%), right and left inferior thalamus (-10 +/- 3%), right inferior insula (-13 +/- 3%), and left inferior anterior insula (-8 +/- 3%), not observed after L-Ex. There were rCBF decreases for leg sensorimotor regions after both M-Ex (-15 +/- 4%) and L-Ex (-12 +/- 3%) and for the left superior anterior insula (-7 +/- 3% and -6 +/- 3%), respectively. Data show that there are rCBF reductions within specific regions of the insular cortex and anterior cingulate cortex coupled with a postexercise hypotensive response after M-Ex. Findings suggest that these cerebral cortical regions, previously implicated in cardiovascular regulation during exercise, may also be involved in PEH.     

PPARalpha activation elevates blood pressure and does not correct glucocorticoid-induced insulin resistance in humans

Fibrates, activators of the nuclear receptor PPARalpha, improve dyslipidemia, but their effects on insulin resistance and vascular disease are unresolved. To test the hypothesis that PPARalpha activation improves insulin resistance and vascular function, we determined the effects of fenofibrate in healthy adults with insulin resistance induced by short-term glucocorticoid administration. Eighteen normal-weight subjects were studied in four stages: at baseline, after 21 days of fenofibrate (160 mg/day) alone, after 3 days of dexamethasone (8 mg/day) added to fenofibrate, and after 3 days of dexamethasone added to placebo (dexamethasone alone). Dexamethasone alone caused hyperinsulinemia, increased glucose, decreased glucose disposal, and reduced insulin-induced suppression of hepatic glucose production as determined by hyperinsulinemic euglycemic clamp and increased systolic blood pressure as determined by ambulatory monitoring, features associated with an insulin-resistant state. Fenofibrate improved fasting LDL and total cholesterol in the setting of dexamethasone treatment but had no significant effect on levels of insulin or glucose, insulin-stimulated glucose disposal, or insulin suppression of glucose production during clamps, or ambulatory monitored blood pressure. In the absence of dexamethasone, fenofibrate lowered fasting triglycerides and cholesterol but unexpectedly increased systolic blood pressure by ambulatory monitoring. These data suggest that PPARalpha activation in humans does not correct insulin resistance induced by glucocorticoids and may adversely affect blood pressure.     

Analysis of standing up and sitting down in humans: definitions and normative data presentation

A formal definition of human standing up and sitting down movements based on sagittal plane goniometric and force plate data from 20 normal subjects is presented. This definition is comparable to the established gait cycle diagram, and consists of defined characteristic events and relative time intervals between them. The characteristic events are selected primarily on changes in ground reaction forces. The terminology proposed may be valuable for introducing more formalized and standardized reporting of both qualitative and quantitative studies in both normals and in patients. This presentation is directed toward the process of defining generally acceptable standards for human standing up and sitting down movements.     

Endogenous enkephalin does not contribute to the cerebral anti-hyperalgesic action of gabapentin

The aim of this study was to investigate the role of endogenous enkephalin in the cerebral antihyperalgesic action of gabapentin. Neuropathic pain models and antihyperalgesic effect of gabapentin were confirmed by the presentation and changes of mechanical allodynia and thermal hyperalgesia of operated mouse hind paws. The results suggested that endogenous enkephalin may not be involved in the antihyperalgesic effect of gabapentin.     

The 400 microsphere per piece "rule" does not apply to all blood flow studies

Microsphere experiments are useful in measuring regional organ perfusion as well as heterogeneity of blood flow within organs and correlation of perfusion between organ pieces at different time points. A 400 microspheres/piece "rule" is often used in planning experiments or to determine whether experiments are valid. This rule is based on the statement that 400 microspheres must lodge in a region for 95% confidence that the observed flow in the region is within 10% of the true flow. The 400 microspheres precision rule, however, only applies to measurements of perfusion to a single region or organ piece. Examples, simulations, and an animal experiment were carried out to show that good precision for measurements of heterogeneity and correlation can be obtained from many experiments with <400 microspheres/piece. Furthermore, methods were developed and tested for correcting the observed heterogeneity and correlation to remove the Poisson "noise" due to discrete microsphere measurements. The animal experiment shows adjusted values of heterogeneity and correlation that are in close agreement for measurements made with many or few microspheres/piece. Simulations demonstrate that the adjusted values are accurate for a variety of experiments with far fewer than 400 microspheres/piece. Thus the 400 microspheres rule does not apply to many experiments. A "rule of thumb" is that experiments with a total of at least 15,000 microspheres, for all pieces combined, are very likely to yield accurate estimates of heterogeneity. Experiments with a total of at least 25,000 microspheres are very likely to yield accurate estimates of correlation coefficients.