Transcapillary fluid responses to lower body negative pressure

The effect of lower body negative pressure (LBNP) on transcapillary fluid balance is unknown. Therefore, our objective was to assess leg interstitial fluid pressures (IFP), leg circumference, plasma volume (PV), and net whole body transcapillary fluid transport (TFT) during and after supine LBNP and to evaluate the addition of oral saline ingestion on transcapillary exchange. Six healthy men 23-41 yr old underwent 4 h of 30 mmHg LBNP, followed by 50 min of supine recovery on two separate occasions, once with and once without ingestion of 1 liter of isotonic saline. IFP was measured continuously in subcutis as well as superficial and deep regions of the tibialis anterior muscle by slit catheters. TFT was calculated by subtracting urine production and calculated insensible fluid loss from changes in PV. During exposure to LBNP, IFP decreased in parallel with chamber pressure, foot venous pressure did not change, leg circumference increased by 3 +/- 0.35% (SE) (P < 0.05), and PV decreased by 14 +/- 2.3%. IFP returned to near control levels after LBNP. At the end of minute 50 of recovery, PV remained decreased (by 7.5 +/- 5.2%) and leg circumference remained elevated (by 1 +/- 0.37%). LBNP alone produced significant movement of fluid into the lower body but no net TFT (-7 +/- 12 ml/h). During LBNP with saline ingestion, 72 +/- 4% of the ingested fluid volume filtered out of the vascular space (TFT = 145 +/- 10 ml/h), and PV decreased by 6 +/- 3%.(ABSTRACT TRUNCATED AT 250 WORDS)     

Hemodynamic and hormonal responses to lower body negative pressure in men with varying profiles of strength and aerobic power

Hemodynamic, cardiac, and hormonal responses to lower-body negative pressure (LBNP) were examined in 24 healthy men to test the hypothesis that responsiveness of reflex control of blood pressure during orthostatic challenge is associated with interactions between strength and aerobic power. Subjects underwent treadmill tests to determine peak oxygen uptake (VO2max) and isokinetic dynamometer tests to determine knee extensor strength. Based on predetermined criteria, subjects were classified into one of four fitness profiles of six subjects each, matched for age, height, and body mass: (a) low strength/average aerobic fitness, (b) low strength/high aerobic fitness, (c) high strength/average aerobic fitness, and (d) high strength/high aerobic fitness. Following 90 min of 0.11 rad (6 degrees) head-down tilt (HDT), each subject underwent graded LBNP to -6.7 kPa or presyncope, with maximal duration 15 min, while hemodynamic, cardiac, and hormonal responses were measured. All groups exhibited typical hemodynamic, hormonal, and fluid shift responses during LBNP, with no intergroup differences between high and low strength characteristics. Subjects with high aerobic power exhibited greater (P < 0.05) stroke volume and lower (P < 0.05) heart rate, vascular peripheral resistance, and mean arterial pressure during rest, HDT, and LBNP. Seven subjects, distributed among the four fitness profiles, became presyncopal. These subjects showed greatest reduction in mean arterial pressure during LBNP, had greater elevations in vasopressin, and lesser increases in heart rate and peripheral resistance. Neither VO2max nor leg strength were associated with fall in arterial pressure or with syncopal episodes. We conclude that interactions between aerobic and strength fitness characteristics do not influence responses to LBNP challenge.     

Changes in body core temperatures and heat balance after an abrupt release of lower body negative pressure in humans

Changes in body core temperature (T(cor)) and heat balance after an abrupt release of lower body negative pressure (LBNP) were investigated in 5 volunteers under the following conditions: (1) an ambient temperature (Ta) of 20 degrees C or (2) 35 degrees C, and (3) Ta of 25 degrees C with a leg skin temperature of 30 degrees C or (4) 35 degrees C. The leg skin temperature was controlled with water perfusion devices wound around the legs. Rectal (T(re)), tympanic (T(ty)) and esophageal (T(es)) temperatures, skin temperatures (7 sites) and oxygen consumption were measured. The intensity of LBNP was adjusted so that the amount of blood pooled in the legs was the same under all conditions. When a thermal balance was attained during LBNP, application of LBNP was suddenly halted. The skin temperatures increased significantly after the release of LBNP under all conditions, while oxygen consumption hardly changed. The release of LBNP caused significant falls in T(cor)s under conditions (1) and (3), but lowered T(cor)s very slightly under conditions (2) and (4). The changes in T(es) were always more rapid and greater than those of T(ty) and T(re). The falls in T(ty) and T(re) appeared to be explained by changes in heat balance, whereas the sharp drop of T(es) could not be explained especially during the first 8 min after the release of LBNP. The results suggest that a fall in T(cor) after a release of LBNP is attributed to an increase in heat loss due to reflexive skin vasodilation and is dependent on the temperature of venous blood returning from the lower body.(ABSTRACT TRUNCATED AT 250 WORDS)     

Improved psychological well-being, quality of life, and health practices in moderately overweight women participating in a 12-week structured weight loss program

The first objective of this study was to confirm that 4 days of head-down tilt (HDT) were sufficient to induce orthostatic intolerance, and to check if 4 days of physical confinement may also induce orthostatic intolerance. Evidence of orthostatic intolerance during tilt-up tests was obtained from blood pressure and clinical criteria. The second objective was to quantify the arterial and venous changes associated with orthostatic intolerance and to check whether abnormal responses to the tilt test and lower body negative pressure (LBNP) may occur in the absence of blood pressure or clinical signs of orthostatic intolerance. The cerebral and lower limb arterial blood flow and vascular resistance, the flow redistribution between these two areas, and the femoral vein distension were assessed during tilt-up and LBNP by ultrasound. Eight subjects were given 4 days of HDT and, 1 month later, 4 days of physical confinement. Tilt and LBNP test were performed pre- and post-HDT and confinement. Orthostatic intolerance was significantly more frequent after HDT (63%) than after confinement (25%, P < 0.001). Cerebral haemodynamic responses to tilt-up and LBNP tests were similar pre- and post-HDT or confinement. Conversely, during both tilt and LBNP tests the femoral vascular resistances increased less (P < 0.002), and the femoral blood flow reduced less (P < 0.001) after HDT than before HDT or after confinement. The cerebral to femoral blood flow ratio increased less after HDT than before (P < 0.002) but remained unchanged before and after confinement. This ratio was significantly more disturbed in the subjects who did not complete the tilt test. The femoral superficial vein was more distended during post-HDT LBNP than pre-HDT or after confinement (P < 0.01). In conclusion, 4 days of HDT were enough to alter the lower limb arterial vasoconstriction and venous distensibility during tilt-up and LBNP, which reduced the flow redistribution in favour of the brain in all HDT subjects. Confinement did not alter significantly the haemodynamic responses to orthostatic tests. The cerebral to femoral blood flow ratio measured during LBNP was the best predictor of orthostatic intolerance.     

Effects of alpha1-blockade on the forearm vascular resistance responses to lower body negative pressure in young borderline hypertensives

To determine whether alpha1-blockade affects the forearm vascular resistance responses to lower body negative pressure (LBNP) in borderline hypertensives, six hypertensives (HTN; mean arterial pressure [MAP] = 109.9 +/- 1.7 mm Hg, mean +/- SE) and seven normotensives (NTN; MAP = 81.5 +/- 1.4 mm Hg) underwent exposures of LBNP at pressures of -10, -20, and -40 mm Hg during systemic alpha1-receptor blockade (BLK) and during placebo (PLA). Resting forearm vascular resistance (FVR) was greater in HTN than in NTN during PLA (34.8 +/- 5.4 v 17.5 +/- 3.1 units; P < .05), but not during BLK (28.1 +/- 5.2 v 25.3 +/- 9.9 units). When expressed as a percentage of resting FVR, LBNP evoked an increased FVR (P < .001) that did not differ significantly between BLK and PLA in either group. FVR was higher (P < .001) in HTN than in NTN throughout both trials; at -40 mm Hg of LBNP during BLK, the increase in FVR was greater (P < .05) in HTN than in NTN (131 +/- 42 v 48 +/- 15%). MAP (relative to resting) was maintained throughout LBNP during PLA but, at -40 mm Hg, was lower (P < .01) during BLK for both groups. HR was elevated in BLK and was increased at -40 mm Hg (P < .01) for each group in each trial. This increase was greater during BLK (P < .05). These data suggest that borderline hypertensives have a greater vasoconstrictor response to LBNP than do normotensives and alpha1-blockade does not appear to attenuate this response.     

Relative contributions of cardiopulmonary and sinoaortic baroreflexes in causing sympathetic activation in the human skeletal muscle circulation during orthostatic stress

The aim of this study was to reexamine the hypothesis that cardiopulmonary baroreflexes are more important than sinoaortic baroreflexes in causing vasoconstriction in the skeletal muscle circulation during orthostatic stress. We recorded muscle sympathetic nerve activity (MSNA) with microelectrodes in the peroneal nerve (and forearm blood flow with venous occlusion plethysmography) in normal subjects (innervated ventricles) and in heart transplant recipients (denervated ventricles) during graded lower body negative pressure (LBNP) performed alone and in combination with intravenous infusion of phenylephrine, which was titrated to eliminate the orthostatically induced fall in blood pressure and thus the unloading of both carotid and aortic baroreceptors. The principal new findings are as follows: (1) The increases in both MSNA and forearm vascular resistance during multiple levels of LBNP were not attenuated by heart transplantation, which causes ventricular but not sinoaortic deafferentation. (2) In heart transplant recipients, a small increase in MSNA during mild LBNP was dependent on a decrease in arterial pressure, but in normal subjects, a similar increase in MSNA occurred in the absence of any detectable decrease in the aortic pressure stimulus to the sinoaortic baroreceptors. (3) In normal subjects, the large increase in MSNA during a high level of LBNP was dependent on a decrease in arterial pressure and could be dissociated from the decrease in central venous pressure. Taken together, the findings strongly suggest that sinoaortic baroreflexes are much more important and ventricular baroreflexes are much less important than previously thought in causing reflex sympathetic activation and vasoconstriction in the human skeletal muscle circulation during orthostatic stress.     

R-(-)-alpha-methyl-histamine has nitric oxide-mediated vasodilator activity in the mesenteric vascular bed of the cat

Responses to the histamine H3 receptor agonist R-(-)-alpha-methyl-histamine were investigated in the mesenteric vascular bed of the cat under constant-flow conditions. Injections of R-(-)-alpha-methyl-histamine and histamine caused dose-related decreases in mesenteric perfusion pressure with R-(-)-alpha-methyl-histamine being 1000-fold less potent than histamine when doses were compared on a nmol basis to take molecular weight into account. Responses to R-(-)-alpha-methyl-histamine were not altered by histamine H1 or H2 receptor antagonists at a time when responses to histamine were significantly reduced. The histamine H3 receptor antagonist thioperamide reduced responses to R-(-)-alpha-methyl-histamine but was without effect on responses to histamine [6-[2-(4-imidazolyl)ethylamino]-N-(4-trifluoro-methylphenyl)heptaneca rdoxamide dimaleate] (HTMT), or dimaprit. These data suggest the presence of histamine H1, H2 and H3 receptors mediating vasodilation in the mesenteric vascular bed. Responses to R-(-)-alpha-methyl-histamine and histamine were reduced by the nitric oxide synthase inhibitor N(omega)-nitro-L-arginine methyl ester (L-NAME) but were not altered by the cyclooxygenase inhibitor meclofenamate, the alpha-adrenoceptor blocker phentolamine, or adrenergic nerve terminal depleting agent reserpine. The present data suggest that histamine H3 receptors mediating vasodilation are present in the mesenteric vascular bed and that responses are mediated by the release of nitric oxide but not vasodilator prostaglandins or an effect on the adrenergic nervous system. These results indicate that vasodilator responses to histamine involve the activation of histamine H1 and H2 receptors and the release of nitric oxide in the mesenteric vascular bed of the cat.     

Leg mass and lower body negative pressure tolerance in men and women

To explore the hypothesis that lower body muscle mass correlates with orthostatic tolerance, 18 healthy volunteers (age 18-48 yr; 10 men, 8 women) underwent a graded lower body negative pressure (LBNP) protocol consisting of six, 5-min stages of suction up to 60 mmHg in 10-mmHg increments. Forearm blood flow, heart rate, and blood pressure were measured, and forearm vascular resistance was calculated. Leg muscle mass was assessed by dual-energy X-ray absorptiometry. All subjects received standard intravenous hydration for at least 8 h before the study. Six men and four women completed all stages of LBNP. Four men and four women developed presyncopal symptoms, including marked bradycardia and/or hypotension, at LBNP levels of 30 mmHg (n = 2;1 man, 1 woman), 40 mmHg (n = 2;1 man, 1 woman), and 50 mmHg (n = 4;2 men, 2 women). The presyncopal subjects had leg muscle masses ranging from 19.5 to 25.2 kg in men and from 11.7 to 16.6 kg in women. In subjects who completed all stages of LBNP, leg muscle mass ranged from 17.5 to 24.1 kg in men and from 10.4 to 18.0 kg in women. Leg muscle mass did not differ between presyncopal subjects and those who completed the protocol. Furthermore, there were no differences in the hemodynamic responses to LBNP between subjects with low vs. high leg mass. These data suggest that leg muscle mass is not a critical determinant of LBNP tolerance in otherwise healthy men and women.     

Cardiovascular reactivity to and recovery from psychological challenge as predictors of 3-year change in blood pressure.

The authors examined whether cardiovascular reactivity to and recovery from psychological challenge predict 3-year change in blood pressure (BP) among 216 initially normotensive, community-dwelling adults. Clinic BP assessments were conducted at baseline and follow-up. BP and heart rate (HR) readings were obtained before, during, and after 5 psychological tasks at baseline. Following adjustment for traditional predictors of BP and lifestyle factors, poorer systolic BP recovery across the tasks was associated with greater 3-year increases in clinic systolic and diastolic BP. Both diastolic BP recovery and HR recovery were also related to 3-year change in clinic BP, though cardiovascular reactivity measures were not. These findings suggest that the duration of stress-related cardiovascular responses may be important for predicting longitudinal changes in BP. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Studies towards the synthesis of the hypermodified nucleoside of rat liver phenylalanine transfer ribonucleic acid: improved synthesis of the base beta-hydroxywybutine

An improved synthesis of the key intermediates (3 and 8) for the synthesis of beta-hydroxywybutines [[R-(R*,S*)]- and [S-(R*,R*)]-4], the most probable structures for the minor base from rat liver tRNA(Phe), has been achieved by the Wittig reaction between 1-benzyl-7-formylwye (1) and the phosphorane derived from (R)-2-[(methoxycarbonyl)amino]-3-(triphenylphosphonio)propanoate (10), followed by methylation, OsO4 oxidation, and cyclocondensation with COCl2 in the presence of pyridine. The racemic forms of beta-hydroxywybutines [(R*,S*)- and (R*,R*)-4], which were required for the determination of the optical purity of [R-(R*,S*)]- and [S-(R*,R*)]-4 by means of chiral HPLC, were conveniently prepared through pyrolysis of the cyclic carbonate 3 followed by NaBH4 reduction and catalytic hydrogenolysis. The samples of [R-(R*,S*)]- and [S-(R*,R*)]-4 were thus shown to be optically pure.     

Baroreceptor reflex function in young normotensive men with a family history of hypertension

The purpose of this study is to evaluate the baroreflex function using lower body negative pressure (LBNP) and neck suction in young normotensive men with or without a family history of hypertension. Twenty-two young normotensive men with a family history of hypertension (FH+) and eight young normotensive men who had no family history of hypertension (FH-) were studied. FH(+) consisted of men who had a family history of hypertension within second degree relatives. We studied cardiopulmonary baroreflex function using LBNP and carotid sinus baroreflex function using neck suction and evaluated the reflex function under stimulated conditions using both LBNP and neck suction at the same time. Systolic arterial pressure (SAP)(F = 5.42, p < 0.0001) and pulse pressure (PP)(F = 15.57, p < 0.0001) decreased similarly in both groups in response to LBNP. SAP and PP responses to LBNP were not significantly affected by the family history of hypertension. Diastolic arterial pressure (DAP) increased (F = 2.89, p < 0.005) in both groups. There was a relationship between the LBNP level and family history of hypertension (F = 2.53, p < 0.013), and the increment in DAP during LBNP -30, -40 mmHg was larger in the FH(+) group. Through mean arterial pressure (MAP) was not effected by LBNP, there LBNP level was related to the family history of hypertension (F = 2.23, p < 0.02). Heart rate increased progressively (F = 25.7, p < 0.0001) with increasing levels of LBNP; however, these changes did not differ significantly in either group.(ABSTRACT TRUNCATED AT 250 WORDS)     

Developmental toxicity of steviol, a metabolite of stevioside, in the hamster

Family history of hypertension (positive and negative) and gender groups were compared on cardiovascular responses at rest, during stressors and during recovery. Two tasks were employed, mental arithmetic and an anger recall interview. Both levels and reactivity measures of blood pressure, heart rate, cardiac output and total peripheral resistance were included. In addition, participants filled out several questionnaires measuring state feelings during the task and recovery periods, trait anger/hostility and emotions. Both men and women with a positive family history of hypertension exhibited higher tonic levels of blood pressure and heart rate at rest, recovery and during both tasks. They also exhibited greater heart rate reactivity during the mental arithmetic task and greater blood pressure reactivity to both tasks when post-math recovery, but not initial rest, was used as a covariate. Positive family history individuals reported less trust and gregariousness, more depression and aggression, less awareness of somatic responses to the tasks and less effort to relax during the post-task rest periods. Finally, significant correlations were found between low anger expression how anger experience and high anger control and task SBP levels in positive family history individuals.     

Hormonal interaction with stimulus situational factors in the initiation of maternal behavior in nonpregnant rats.

Previous hormonal studies have identified the hormonal and stimulus factors mediating the initiation of maternal behavior but have failed to reduce hormone-induced latencies of nonpregnant females to less than 1–2 days of continuous pup exposure. For the purpose of testing whether this delay is due to an olfactory-vomeronasal-mediated aversive reaction to pups like that found in untreated virgins, in 3 experiments estrogen-injected hysterectomized-ovariectomized (HO-EB) nonpregnant Charles River CD females were subjected to olfactory-vomeronasal deafferentation. Findings indicate that after HO-EB treatment, tendencies to initially avoid pup contact remain strong. Next, the hypothesis was explored that experiences during late pregnancy and/or parturition interact with hormonal priming to modify pup avoidance. Nonpregnant HO-EB females that had been exposed to pregnant-parturient females for 2 wks were tested under conditions simulating parturition. A high percentage rapidly initiated maternal behavior, but conditions during testing proved more important than prior exposure to pregnancy/parturition. Hormonally treated but not sham-treated females initiated maternal behavior most rapidly when first exposed to 1 newborn in the nest during the light phase. Prepartum caesarean-delivered females, however, responded maternally to 4 3–8 day old pups outside the nest, which indicates that additional factors operate at parturition. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

A role for thyroid hormones in the regulation of diet-induced thermogenesis in birds

The possible involvement of thyroid hormones in avian diet-induced thermogenesis (DIT) was investigated in two lines of cockerels divergently selected for high (R-) or low (R+) food efficiency. For a given body weight, R+ cockerels exhibited a higher food intake than R- cockerels (+49 to +76%) and increased DIT (+25%). Plasma thyroxine (T4) level did not differ between lines whatever the feeding status of the birds. Plasma 3,5,3'-triiodothyronine (T3) level was lower in fasted R+ than in fasted R- cockerels while the opposite was observed after a meal. Iopanic acid injections reduced both plasma T3 concentrations and heat production to the same levels in both lines. Hepatic 5'-deiodinase activity measured with an exogenous sulfhydryl group (dithiothreitol) did not differ between lines, but when the sulfhydryl group was omitted, the activity was higher in R+ than in R- birds (90 v. 42 pmol T3/min per liver). T3-binding capacity of isolated hepatic nuclei was higher (+76%) in R+ than in R- birds. Long-term or acute pair-feeding of R+ cockerels to the level of R- controls did not alter these results. The present results suggest that T3, mainly originating from peripheral conversion of T4 to T3, is involved in DIT in the R+ line. Availability of endogenous sulfhydryl groups appears to play an important part in the modulation of hepatic deiodinase activity. The higher concentration of nuclear T3 receptors may further increase the effects of the hormone, suggesting a major role of thyroid hormones associated with catecholamines in the stimulation of avian DIT. The underlying thermogenic mechanisms remain to be elucidated.     

Effect of carbon tetrachloride-induced hepatic injury on stereoselective N-demethylation of chlorpheniramine by rat hepatic cytochrome P450 2C11 isozyme

We examined the effect of a carbon tetrachloride (CCl4)-induced hepatic injury on the stereoselective N-demethylation of RS-(+/-)-chlorpheniramine (Chp) by cytochrome P450 (CYP) 2C11 isozyme. In the non-treated rat liver microsomes, the stereoselective N-demethylation of racemic Chp was observed. However, in the CCl4-treated (0.5 ml/kg, i.p.) rat liver microsomes, the N-demethylation activities of S-(+)- and R-(-)-Chp decreased continuously up to the third day after the treatment with CCl4, and reached about 9 and 13% of control values, respectively, and the stereoselective N-demethylation of Chp was not observed. Moreover, in the liver microsomes at the 7th day after the treatment with CCl4, the N-demethylation activities of both enantiomers recovered to an original level, and the stereoselective N-demethylation of Chp was again observed. The addition of 30 microliters of the anti-rat CYP2C11 serum to the reaction mixture containing 1 mg of microsomal protein inhibited the formation of monodesmethylchlorpheniramine (DMChp) from both enantiomers to 74 and 57% of the control values for S-(+)- and R-(-)-Chp, respectively. In the liver microsomes of a male rat at the 1st day after the treatment of CCl4, the addition of the anti-rat CYP 2C11 serum (30 microliters) also caused 25% inhibition of the formation of DMChp from S-(+)-Chp, but anti-rat CYP2C11 had no inhibitory effect on the rates of microsomal N-demethylation of R-(-)-enantiomer. On the other hand, in the liver microsomes of a male rat at the 7th day after the treatment with CCl4, the anti-rat CYP2C11 serum had an inhibitory effect on the rates of microsomal N-demethylation of either S-(+)- or R-(-)-enantiomers again. Moreover, it was confirmed by Western blotting analysis that the density of the stained bands of CYP2C11 in the liver microsomes from male rats at the 1st, 2nd and 3rd days after the treatment with CCl4, was thinner than that from non-treatment male rats. These results indicated that the changes of N-demethylation activities of Chp in the CCl4-induced hepatic injury were due to the variation of microsomal CYP2C11.     

Diminished venous vascular capacitance in patients with univentricular hearts after the Fontan operation

Patients who have undergone Fontan's operation are known to have impaired cardiac output response to dynamic exercise. This may be due to either poor cardiac function or a limited ability to mobilize blood from capacitance vessels due to increased resting venous tone. We tested the latter hypothesis by determining venous vascular capacitance at rest and during orthostatic stress produced by lower body negative pressure (LBNP) in 6 subjects who had undergone the Fontan operation and 6 healthy age-, sex-, height-, and weight-matched controls. Resting blood volume was similar for Fontan and control subjects (79 +/- 6 vs 70 +/- 3 ml/kg body weight, respectively), while central venous pressure (CVP) was elevated in Fontan subjects (18.4 +/- 1.0 vs 3.5 +/- 0.9 mm Hg, p < 0.05). Forearm venous capacitance at a distending pressure of 40 mm Hg was less in Fontan subjects than in controls (2.6 +/- 0.1 vs 3.9 +/- 0.5 ml/100 ml), while resting plasma norepinephrine level was elevated in Fontan subjects (255 +/- 28 vs 144 +/- 9 pg/ml, p < 0.05). The increase in calf volume (1.6 +/- 0.2 vs 2.3 +/- 0.2 ml) and decrease in CVP (-5.0 +/- 0.5 vs -6.7 +/- 1.1 mm Hg) during -30 mm Hg LBNP were smaller for Fontan than control subjects (p < 0.05). Reduced forearm venous capacitance and diminished pooling of blood into capacitance vessels of the leg during orthostatic stress indicated higher venous tone in Fontan than control subjects.(ABSTRACT TRUNCATED AT 250 WORDS)     

Plasmin, substilisin-like endoproteases, tissue plasminogen activator, and urokinase plasminogen activator are involved in activation of latent TGF-beta 1 in human seminal plasma

OBJECTIVES: To compare the effects of simulated and mild actual hemorrhage on parameters used traditionally to assess hemorrhaging patients: heart rate (HR), blood pressure (BP), and Shock Index (SI = HR/systolic BP), with stroke distance (SD) measured ultrasonically as an index of cardiac stroke volume. MATERIALS and METHODS: Hemorrhage was simulated in 19 healthy volunteers by the application of graded lower-body negative pressure (LBNP) (0, -20, -40, and -60 mm Hg) to pool blood in the lower body and reduce venous return. Measurements were also made before and after a standard blood donation (450 mL) in nine healthy volunteers. MEASUREMENTS and MAIN RESULTS: SD decreased significantly and progressively from the baseline level of 23.8+/-5.7 cm (mean+/-SD) at each level of LBNP: by 3.4+/-1.9, 7.4+/-2.5, and 11.8+/-3.2 cm at LBNP of -20, -40, and -60 mm Hg, respectively. Neither HR nor SI changed significantly at the lowest level of LBNP (-20 mm Hg), but they showed progressive, significant increases thereafter. Mean BP did not change significantly at any level of LBNP. Similarly, after a controlled hemorrhage of 450 mL, SD decreased significantly by 3.3+/-1.6 cm from 22.2+/-2.8 cm, whereas HR and SI remained unchanged and mean BP increased slightly. CONCLUSION: Changes in SD may provide an earlier indication of progressive blood loss than either HR or BP alone or in combination.     

Characterization of stereoselectivity and genetic polymorphism of the debrisoquine hydroxylation in man via analysis of urinary debrisoquine and 4-hydroxydebrisoquine by capillary electrophoresis

Using capillary zone electrophoresis with a phosphate buffer at pH 2.5 containing 50 mM heptakis-(2,3,6-tri-O-methyl)-beta-CD as chiral selector, the separation of the enantiomers of the main metabolite of debrisoquine (DEB), 4-hydroxydebrisoquine (4-OHDEB), is reported. For extraction of underivatized urinary DEB, S-4-OHDEB and R-4-OHDEB, a procedure using disposable cartridges containing a polystyrene-based polymer was developed. A few nL of the extracts were analyzed in a 60 cm fused-silica capillary of 50 microns ID and solute detection was effected at 195 nm. For all three compounds, a mean (n = 5) recovery of about 73% and a detection limit of about 150 ng/mL were noted. Data obtained with urines that were received for routine phenotyping with DEB and mephenytoin confirmed the almost exclusive formation of S-4-OHDEB. Under the described conditions, no R-4-OHDEB could be detected. With these data and those obtained employing no chiral selector in the buffer, differentiation between extensive metabolizer phenotypes (EM) and poor metabolizer phenotypes (PM) for DEB was unambiguously possible by the presence of a significant peak and no (or minor) peak for 4-OHDEB, respectively. Data obtained for ten EM subjects and five PM subjects were found to agree with those generated by the routine assay based on gas chromatography. The capillary electrophoretic assays described are simple, reproducible (relative standard deviation of peak area ratios < 3%), require no sample derivatization, consume no halogenated organic solvents, and operate with inexpensive separation columns as well as small amounts of chemicals.