Cognitive deficits and increases in creatine precursors in a brain-specific knockout of the creatine transporter gene Slc6a8.

Creatine transporter (CrT; SLC6A8) deficiency (CTD) is an X-linked disorder characterized by severe cognitive deficits, impairments in language and an absence of brain creatine (Cr). In a previous study, we generated floxed Slc6a8 (Slc6a8 flox ) mice to create ubiquitous Slc6a8 knockout (Slc6a8-/y ) mice. Slc6a8-/y mice lacked whole body Cr and exhibited cognitive deficits. While Slc6a8-/y mice have a similar biochemical phenotype to CTD patients, they also showed a reduction in size and reductions in swim speed that may have contributed to the observed deficits. To address this, we created brain-specific Slc6a8 knockout (bKO) mice by crossing Slc6a8flox mice with Nestin-cre mice. bKO mice had reduced cerebral Cr levels while maintaining normal Cr levels in peripheral tissue. Interestingly, brain concentrations of the Cr synthesis precursor guanidinoacetic acid were increased in bKO mice. bKO mice had longer latencies and path lengths in the Morris water maze, without reductions in swim speed. In accordance with data from Slc6a8 -/y mice, bKO mice showed deficits in novel object recognition as well as contextual and cued fear conditioning. bKO mice were also hyperactive, in contrast with data from the Slc6a8 -/y mice. The results show that the loss of cerebral Cr is responsible for the learning and memory deficits seen in ubiquitous Slc6a8-/y mice.

Vasopressin reduces cardiac function and augments cardiopulmonary baroreflex resistance increases in man.

We examined the effects of physiologic infusions of arginine vasopressin (AVP) on cardiovascular hemodynamics and on reflex responses initiated by decreasing cardiopulmonary baroreceptor stimulation (with lower body negative pressure) in 10 healthy, captopril-pretreated young men (19-27 yr). Their responses were compared with those of four volunteers given isosmotic infusion. Heart rate, stroke volume, blood pressure, and forearm blood flow were measured by electrocardiography, impedance cardiography, radial artery cannulation, and strain gauge plethysmography. Two 55-min infusions of AVP at rates of 0.15 and 0.40 ng/kg per min increased average plasma concentrations from control levels of 5 pg/ml to 18 and 36 pg/ml, respectively. These infusions resulted in progressive reductions of heart rate and cardiac output and increases of forearm and total peripheral resistance. Blood pressure increases were significant only during the larger AVP infusion rate. Lower body negative pressure provoked reflex increases of total peripheral resistance. These increases were enhanced 60% during AVP infusion compared with increases during control (pre-AVP). Baseline measurements and reflex responses were unchanged by isosmotic infusions. These results demonstrate that AVP has profound effects on cardiovascular function and augments cardiopulmonary baroreflex-mediated increases of peripheral resistance in man.

Inconsistent reporting of minimally invasive surgery errors.

INTRODUCTION: Minimally invasive surgery (MIS) is a complex task requiring dexterity and high level cognitive function. Unlike surgical 'never events', potentially important (and frequent) manual or cognitive slips ('technical errors') are underresearched. Little is known about the occurrence of routine errors in MIS, their relationship to patient outcome, and whether they are reported accurately and/or consistently. METHODS: An electronic survey was sent to all members of the Association of Surgeons of Great Britain and Ireland, gathering demographic information, experience and reporting of MIS errors, and a rating of factors affecting error prevalence. RESULTS: Of 249 responses, 203 completed more than 80% of the questions regarding the surgery they had performed in the preceding 12 months. Of these, 47% reported a significant error in their own performance and 75% were aware of a colleague experiencing error. Technical skill, knowledge, situational awareness and decision making were all identified as particularly important for avoiding errors in MIS. Reporting of errors was variable: 15% did not necessarily report an intraoperative error to a patient while 50% did not consistently report at an institutional level. Critically, 12% of surgeons were unaware of the procedure for reporting a technical error and 59% felt guidance is needed. Overall, 40% believed a confidential reporting system would increase their likelihood of reporting an error. CONCLUSION: These data indicate inconsistent reporting of operative errors, and highlight the need to better understand how and why technical errors occur in MIS. A confidential 'no blame' reporting system might help improve patient outcomes and avoid a closed culture that can undermine public confidence.

Control of adrenocorticotropin secretion and adrenocortical sensitivity in neurohypophysectomized conscious dogs: effects of acute and chronic vasopressin replacement.

We examined the effect of neurohypophysectomy with and without vasopressin replacement on the ACTH response to hypotension and ovine CRF infusion and on the adrenocortical response to ACTH and angiotensin II infusion in conscious dogs. Nitroprusside hypotension (decrease in mean arterial pressure of 25 mm Hg) in the intact state resulted in large increases in plasma arginine vasopressin (pAVP; from 2.6 +/- 0.3 to 296 +/- 63 pg/ml) and ACTH (from 35 +/- 6 to 395 +/- 92 pg/ml). Neurohypophysectomy resulted in greatly attenuated pAVP (8.4 +/- 1.6 pg/ml) and ACTH (80 +/- 10 pg/ml) responses to hypotension which were not normalized by physiological low dose vasopressin replacement (6-18 pg/kg.min continuously, iv, for 2 weeks). However, acute administration of vasopressin (4-6 ng/kg.min) simultaneously with hypotension in the neurohypophysectomized (neurohypox) dog, which produced pAVP levels equivalent to the hypotensive response to intact dogs, almost completely normalized the ACTH response to hypotension (to 248 +/- 74 pg/ml). The ACTH response to 20 ng/kg.min ovine CRF, iv (from 43 +/- 8 to 268 +/- 77 pg/ml), was not attenuated by neurohypophysectomy. The cortisol responses to infusion of 0.5 and 2 ng/kg.min ACTH-(1-24), iv, were essentially normal in neurohypox dogs. However, the ACTH and aldosterone responses to 5 ng/kg.min angiotensin II infusion iv were attenuated in neurohypox dogs off AVP replacement. Histological examination revealed normal adrenal glands and anterior pituitaries in neurohypox dogs. Immunocytochemical staining for vasopressin and neurophysin revealed normal cell bodies in the paraventricular and supraoptic nuclei of the hypothalami from neurohypox dogs. However, median eminence staining for AVP and neurophysin was greatly diminished in neurohypox dogs. In summary, neurohypophysectomy 1) attenuated the ACTH response to hypotension and angiotensin II, but not to CRF, and 2) attenuated the aldosterone response to high dose angiotensin II. Furthermore, the deficit in ACTH secretion was almost completely normalized by increasing plasma AVP levels to those observed in the intact dogs. We conclude that an action of circulating pAVP increases ACTH secretion by a direct effect at the pituitary and by activating afferent input to the hypothalamus.

Dynamic cardiovascular responses to infusions of atrial natriuretic factor in humans.

We sought to demonstrate a hypotensive effect from infusions of atrial natriuretic factor (ANF) into humans and to describe the mechanism(s) of this effect. Cardiovascular and hormonal responses to human ANF-(99-126) (125 ng/kg bolus followed by a 30-minute infusion at 25 ng/kg/min) were determined in eight conscious volunteers and compared with responses of eight time-control subjects who received isotonic saline. Baseline levels of ANF (52.8 +/- 5.5 pg/ml) increased 8.8-fold after 30 minutes of ANF infusion but were unchanged in the time controls. Plasma levels of renin, aldosterone, vasopressin, sodium, potassium, and osmolality did not change during infusions. A transient 5% reduction in mean arterial pressure related to a 12% reduction in peripheral resistance was observed 10 minutes after the priming bolus of ANF. This response was not sustained during the remainder of the ANF infusion period, nor did it occur in two additional subjects who received ANF infusions without the priming bolus. Steady state responses consisted of significant reductions in central venous pressure (15%), stroke volume (13%), and cardiac output (10%), but no reduction in blood pressure. Plasma norepinephrine levels and peripheral resistance increased (34% and 9%, respectively) during ANF administration. These data indicate that steady state responses to ANF in humans consist of decreases in cardiac filling pressures, which reduce cardiac output, unload cardiopulmonary baroreceptors, and activate the sympathetic nervous system. Blood pressure is well maintained despite striking increases in plasma ANF.

Water loading and restriction in essential hypertension.

Blood pressure, plasma arginine vasopressin (AVP), and renal excretory responses to short-term water loading (oral load of 20 ml/kg body weight over 30-45 minutes) were compared in 10 normotensive and 13 mild to moderately essential hypertensive subjects. In addition, we examined the renal concentrating ability of an additional group of 10 normotensive subjects and 12 hypertensive subjects in response to a 24-hour water restriction and intranasal administration of 10 micrograms of [1-deamino,8-D-arginine]vasopression. The hypertensive subjects exhibited both an exaggerated diuresis and natriuresis to the water load. At 20- and 60-minutes after water loading, hypertensive subjects had excreted 34 and 55% of the load, respectively, compared with 15 and 35% in normotensive subjects. Mean blood pressure rose significantly in both groups and hypertensive subjects exhibited a greater rise of systolic blood pressure (16 mm Hg) than normotensive subjects (8 mm Hg) 20 minutes after water loading. The maximum diuresis and natriuresis corresponded to the period in which the rise of blood pressure was greatest. The hypertensive subjects diluted and concentrated their urine as well as normotensive subjects did, indicating normal renal responsiveness to AVP. Plasma Na, osmolality, and AVP decreased similarly in both groups after water loading and rose similarly in the two groups after water restriction. This finding suggests that osmotic responsiveness of AVP is not altered in hypertensive subjects. In conclusion, the data suggest that the exaggerated renal response to water loading could be explained by the greater rise of blood pressure in hypertensive subjects rather than by altered AVP responses.

Are hypertensive effects of aldosterone, angiotensin, vasopressin, and norepinephrine chronically additive?

The effects of chronic combined administration of angiotensin II, norepinephrine, aldosterone, and arginine vasopressin were compared with the response to each of these hormones administered alone. The studies were performed in dogs to determine the extent to which moderately inappropriate elevations of these hormones could enhance each other's ability to produce chronic hypertension and influence Na and water homeostasis. Blood pressure sensitivity to Na intake was also evaluated by infusing the hormones for 11 days at normal levels of Na intake followed by 11 days at high Na intake with ad libitum drinking. Combined hormone administration did not enhance each hormone's singular hypertensive actions. With aldosterone infusion alone and normal Na intake, mean arterial pressure rose nearly 15 mm Hg and an additional 3 mm Hg during high Na intake. Combined hormone infusion also resulted in a nearly 15 mm Hg rise during normal Na intake and an additional 3 mm Hg rise in mean arterial pressure during high Na intake. Marked Na retention and hypernatremia were observed with aldosterone infusion, while hyponatremia characterized arginine vasopressin infusion. The combined hormone infusion resulted in a tendency toward hypernatremia, although daily Na balance was not significantly changed. Daily water turnover was substantially increased and urine osmolality fell to hypoosmotic levels, despite elevated arginine vasopressin levels. Even with high Na intake, dogs receiving either angiotensin II, arginine vasopressin, or norepinephrine at the same concentrations showed 4 to 10 mm Hg increases in mean arterial pressure. Thus, humoral summation or synergism of these hormones probably does not play a major role in the development of chronic hypertension.

Sex differences in the endocrine predictors of essential hypertension. Vasopressin versus renin.

The relationships between arterial pressure (BP) and plasma vasopressin levels, plasma renin activity, and other variables were determined in 96 untreated essential hypertensive men (146/100 mm Hg) and women (153/102 mm Hg) whose average age was 44 years, 80 normal men and women (121/79 mm Hg; mean age, 47 +/- 2 years), and 40 subjects defined as borderline hypertensive. An analysis of variance indicated significant sex differences in the population. Levels of plasma vasopressin were significantly elevated in hypertensive men, with 26% (high plasma vasopressin hypertensive) exhibiting levels greater than 2 SD of the normal mean, and multivariate regression analysis indicated a significant positive correlation between plasma vasopressin levels and systolic and diastolic blood pressure. Hypertensive men had a larger daily urine volume than normal men. Diastolic pressure and heart rate were significantly elevated in a subgroup of 12 weight-matched and age-matched hypertensive men in the high plasma vasopressin group compared with levels in normal plasma vasopressin hypertensive men. Hypertensive women had lower plasma renin activity than normal women, and multivariate analysis indicated a significant negative correlation between plasma renin activity and systolic and diastolic blood pressure. Other significant abnormalities in both sexes were noted: hypertensive men and women weighed more and excreted more sodium per day, and both had higher heart rates. With a discriminant analysis of 18 variables in male subjects, plasma vasopressin levels, urinary sodium excretion, and heart rate correctly classified 71% of normal and hypertensive subjects. In women, plasma renin activity, urinary sodium excretion, and heart rate correctly classified 77% of normal and hypertensive subjects. Despite the inability to ascertain causal relationships, the ability of the three variables in combination to correctly classify normal and hypertensive subjects indicates that these combined variables are reproducibly altered in persons with essential hypertension.

Hormonal responses and blood pressure maintenance in normal and hypertensive subjects during acute blood loss.

Blood pressure (BP) and plasma indices of three major pressure control systems--plasma norepinephrine and epinephrine, plasma renin activity (PRA), and plasma arginine vasopressin--were measured simultaneously in 12 normal and 15 mildly essential hypertensive subjects before and after removal of 480 ml of blood by phlebotomy, to determine if there were differences in the compensatory response to acute blood loss. Responses to postural stress (change from supine to sitting position) following phlebotomy were also compared in a second group of subjects. Before phlebotomy, supine plasma hormone levels did not differ in the two groups. After phlebotomy, both groups exhibited only slight decreases (5 mm Hg) in systolic BP and a transient rise in heart rate. Only plasma norepinephrine increased significantly in both groups (35% above control in normal and 43% in hypertensive subjects). Similar results were obtained in a second group of normal and hypertensive subjects, who were also subjected to a 10-minute postural challenge after phlebotomy. After 10 minutes in a sitting position, BP in these subjects remained unchanged but heart rate and plasma norepinephrine increased further to levels almost twice that produced by phlebotomy alone. Plasma epinephrine levels and PRA also increased with this additional stress, but plasma vasopressin remained unchanged. Changes in BP, heart rate, plasma norepinephrine and epinephrine, and PRA did not differ significantly between the two groups. These data indicate that hypertensive subjects are as capable as normal subjects of maintaining BP when subjected to standard phlebotomy, the sympathetic nervous system appears to be the predominant pressor mechanism activated following an acute, nonhypotensive blood loss in both groups of subjects,(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of plasma sodium on aldosterone secretion during angiotensin II stimulation in normal humans.

Studies were carried out in normal male subjects (n = 6, age 20-35 years) to determine the interaction of angiotensin II and plasma sodium on aldosterone secretion. These relations were quantified by elevation of plasma sodium with an infusion of 5% sodium chloride (4 ml/kg/30 min i.v.) with measurements of plasma aldosterone, atrial natriuretic factor (ANF), and arginine vasopressin (AVP) over 3 hours. Two hours before sodium chloride infusion, an intravenous infusion of angiotensin II was begun at 0.5 or 5.0 ng/kg/min and continued throughout the study. Plasma potassium was maintained constant by the addition of potassium to the infusate. NaCl/KCl infusion raised plasma sodium 4 meq/l with no decreases of plasma potassium. Plasma aldosterone averaged 7 +/- 1.8 ng/dl before NaCl infusion in subjects infused with 0.5 ng angiotensin II and was not significantly reduced with sodium chloride infusion. Angiotensin II infused at 5 ng/kg/min resulted in average plasma aldosterone levels of 31 +/- 3.6 ng/dl, which sodium chloride infusion decreased to 16.6 +/- 1.3 ng/dl (p less than 0.05) in 60 minutes. Plasma aldosterone remained depressed for the remaining period of study. Plasma ANF increased from 40 to 60 pg/ml with sodium chloride infusion. We conclude that small physiological elevations of plasma sodium concentrations can signal substantial decreases of plasma aldosterone in normal human subjects in situations where plasma angiotensin II is moderately elevated. The precise mechanisms of these responses remain to be determined.

Vasopressin elevation in essential hypertension and increased responsiveness to sodium intake.

The relationship of arterial pressure (AP) to plasma arginine vasopressin (AVP) and sodium (Na) intake was determined in untreated essential hypertensive (H) and normotensive (N) subjects. The AP of H subjects averaged 147/101 mm Hg and that of N subjects, 124/79 mm Hg. Plasma AVP was elevated significantly in H subjects, averaging 8.5 pg/ml compared to 4.7 pg/ml in N subjects. Multivariant regression analysis yielded a significant correlation (r2 = 0.34) between diastolic pressure, urine Na concentration, and changes in plasma AVP. Plasma Na of H subjects averaged 2.0 mEq/liter less and urine Na concentration 22 mEq/liter less than in N subjects. Sodium intake appeared to have no influence on the plasma AVP of N subjects, but H subjects excreting Na in excess of 250 mEq/day averaged a plasma AVP twice as high as that in H subjects excreting less than 150 mEq/day. In H subjects, the influence of Na intake appeared to be related to age. In subjects less than 50 years of age, Na intake did not appear to influence chronic levels of plasma AVP, while in subjects older than 50 years who were excreting Na in excess of 250 mEq/day, plasma AVP levels were twice (13.5 pg/ml) those observed in hypertensives of the same age excreting less than 150 mEq/ day (6.5 pg/ml). The data indicate that plasma AVP tends to be elevated in moderate essential hypertension. Reduced concentrating ability of the kidneys of these subjects is suggested by decreased urine Na concentrations despite elevated plasma AVP. The observed increases of plasma AVP could be exerting a direct influence on extra- and intravascular volumes by renal and systemic vasoconstriction.

Physiopathogenesis of acute aortic coarctation hypertension in conscious rats.

We investigated the role of vasopressin, angiotensin II, and catecholamines in the onset of acute (45-minute) aortic coarctation hypertension in conscious rats. Partial aortic constriction was performed by means of a pneumatic cuff placed around the abdominal aorta above the renal arteries for 15 or 45 minutes. A sham-operated group was used as control. Mean carotid pressure before aortic constriction did not differ between rat groups. Aortic constriction produced a similar increase of mean carotid pressure during 15 minutes (36 +/- 3 to 37 +/- 3 mm Hg above basal levels) and 45 minutes (37 +/- 2 to 39 +/- 3 mm Hg). Plasma vasopressin concentration after 15 minutes of coarctation (4.4 +/- 0.5 pg/mL) did not differ from that observed in control rats (3.0 +/- 0.8 pg/mL), whereas after 45 minutes, it was significantly higher (14.3 +/- 3.3 pg/mL). Plasma renin activity increased significantly after coarctation (21.7 +/- 4.1 and 29.9 +/- 2.9 ng angiotensin I/mL per hour, at 15 and 45 minutes, respectively) when compared with control rats (3.9 +/- 0.5 ng angiotensin I/mL per hour). After coarctation, plasma norepinephrine concentration was consistently reduced, whereas plasma epinephrine concentration did not differ from control rats. In conclusion, these data provide evidence for an effective vasopressor role for vasopressin in the genesis of acute (45-minute) aortic coarctation hypertension in conscious rats. In addition, although the results confirm that the renin-angiotensin system participates earlier in the onset of coarctation hypertension, they rule out a significant vasopressor role for catecholamines in the early development of hypertension.

Tubulointerstitial injury and loss of nitric oxide synthases parallel the development of hypertension in the Dahl-SS rat.

OBJECTIVE: Alterations in renal nitric oxide (NO) are involved in the hypertension of the Dahl salt-sensitive (Dahl-SS) rat We sought to identify the kinetics and sites of expression of the major NO synthase (NOS) isoforms. DESIGN: The renal expression of the major NOS were examined in Dahl-SS and salt-resistant rats (Dahl-SR) while on a low salt (0.1% NaCl) diet at 3 and 9 weeks of age. METHODS: Renal biopsies from Dahl-SS and Dahl-SR rats were compared for evidence of renal injury and for alterations in expression of the NOS enzymes by quantitative immunohistochemistry. RESULTS: At 3 weeks of age Dahl-SS and Dahl-SR rats have normal renal histology and similar immunohistochemical expression of NOS1, -2, and -3. At 9 weeks Dahl-SS rats had significantly higher blood pressure than Dahl-SR rats (P< 0.005 ), and lower macula densa NOS1 (P< 0.05) and cortical and medullary NOS3 (P< 0.05). NOS2 was reduced in cortical tubules in biopsies showing severe tubulointerstitial damage, but was not significantly different between Dahl-SS and Dahl-SR groups as a whole. Dahl-SS rats also manifested glomerular and tubulointerstitial injury. Tubular expression of osteopontin (OPN), which is an inhibitor of NOS2, correlated with the systolic BP in individual Dahl-SS rats (r2 = 0.80, P < 0.0001 ). CONCLUSION: Tubulointerstitial injury and the loss of NOS occur after birth and parallel the development of hypertension. We suggest that the structural and functional changes that occur with renal injury in the Dahl-SS rat may contribute to the development of hypertension.

Non-peptide RGD surrogates which mimic a Gly-Asp beta-turn: potent antagonists of platelet glycoprotein IIb-IIIa.

Cyclic heptapeptide 1, which contains an Arg-Gly-Asp sequence, has good affinity for the platelet receptor GPIIb-IIIa and was chosen for study by 1H NMR techniques. The key RGD sequence of this molecule was found to reside in a conformationally defined type II' Gly-Asp beta-turn, and this information was used in the design of simple non-peptide RGD mimics. Disubstituted isoquinolones, bearing an acidic side chain at position 2 and a basic side chain at position 6, were prepared and were found to have modest affinity for GPIIb-IIIa. Systematic modification of the basic residue contained in these molecules yielded compounds with high affinity for GPIIb-IIIa.

Feedback control of vasopressin and corticotrophin secretion in conscious dogs: effect of hypertonic saline.

Glucocorticoids are known to inhibit the ACTH response to a variety of stimuli. It has been suggested that vasopressin secretion is also inhibited by glucocorticoid negative feedback. The purpose of this study was to (1) determine the ACTH response to hypertonic saline and its sensitivity to glucocorticoid negative feedback and (2) to determine whether physiological elevations of plasma cortisol inhibit subsequent vasopressin responses to hypertonic saline. Five mongrel dogs (15-18 kg) were prepared with chronic arterial and venous catheters and studied while conscious. Ten experiments were performed on each dog in a randomized design separated by at least 5 days. Each experiment consisted of a pretreatment period (from -60 to -30 min except for dexamethasone administration) during which a glucocorticoid feedback signal was applied and a stimulus period (from 0 to 30 min) during which hypertonic saline was infused. The pretreatment and stimulus periods were separated by 30 min. Pretreatments were as follows: isotonic saline (control), half-maximal and maximal cortisol infusion (5.5 or 11 nmol/kg per min), ACTH(1-24) infusion (6.8 pmol/kg per min) which produces increases in endogenous cortisol, and dexamethasone (1.5 mg i.m.) given at 17.00 h the day before experimentation. Stimuli were as follows: hypertonic saline was infused at 0.2 or 0.4 mmol/kg per min which increased plasma sodium by about 6 or 12 mmol/l respectively. NaCl infusion at 0.2 mmol/kg per min had no effect on plasma ACTH or cortisol except when subsequent to ACTH(1-24) pretreatment when plasma ACTH actually increased to 41.4 +/- 2.9 pmol/l in response to hypertonic saline.(ABSTRACT TRUNCATED AT 250 WORDS)

Chronic pressure-natriuresis relationship in dogs with inherited essential hypertension.

A genetic model of essential hypertension in the dog was studied to describe the phenotypic expression of the arterial pressure, as well as to determine the relationship between mean arterial blood pressure (MAP), hormone, and renal excretory responses to four different levels of sodium intake (5, 40, 120, 240 mEq/day) delivered intravenously and isotonically. This model was developed at the University of Pennsylvania (U/Penn) and termed Pennsylvania hypertensive dogs (PHD). The MAP was recorded beat-by-beat, 24 h/day, in 16 dogs. Water and sodium balances were determined daily for 4 days at each level of intake and blood samples were collected on the last day of each salt step for analysis of plasma renin activity (PRA), atrial natriuretic peptide (ANP), aldosterone (ALDO), and vasopressin (AVP). After the study, the dogs were designated as hypertensive (PHD-HT) when the 24-h average MAP was greater than 110 mm Hg and systolic pressure was greater than 160 mm Hg. Dogs that failed to meet both criteria were designated as normotensive genetic controls (PHD-NT). Although sodium was retained during the first day of each increase of salt intake in both groups, a return to balance was observed within the 4 days. There was no apparent change in the slope of the chronic renal function curve in either group of PHD studied, although the PHD-HT exhibit a curve shifted to a higher level of MAP. Plasma hormone levels in both groups of PHD studied responded in a manner similar to normal mongrel dogs with reductions of PRA, ALDO, elevations of ANP, and no change in AVP.(ABSTRACT TRUNCATED AT 250 WORDS)

Elevated plasma vasopressin (AVP) levels during resection of pheochromocytomas.

During the evaluation of epidural blockade with light general anesthesia for pheochromocytoma resection, increases in plasma arginine vasopressin (AVP) concentrations were noted. We measured AVP levels in conjunction with plasma catecholamines during perioperative maneuvers in eight consecutive patients undergoing resection of pheochromocytomas. Hormonal responses (mean +/- SE) for preoperative baseline and peak values during tumor manipulation were as follows: AVP, 5 microgram/ml or picogram/ml (+/- 1.7) to a peak of 129 pg/ml (+/- 44) pg/ml; norepinephrine, 5,834 pg/ml (+/- 2,564) to 72,422 (+/- 31,433) pg/ml; epinephrine, 1,033 pg/ml (+/- 405) to 56,444 (+/- 23,542) pg/ml; and dopamine, 165 pg/ml (+/- 35) to 4,231 (+/- 1,318) pg/ml. Maximal AVP values occurred with tumor manipulation and remained elevated for 24 hours postoperatively. Neither epidural placement, induction of anesthesia, nor epidural narcotics used for postoperative pain control had any effect on AVP or catecholamine levels. These extraordinarily high concentrations of plasma AVP found during tumor manipulation may contribute to hemodynamic lability and fluid problems in patients undergoing surgery for the treatment of pheochromocytoma.

Lactate distribution in the blood during progressive exercise.

The purpose of this study was to examine the effect of increment durations of 1-min and 4-min during progressive incremental exercise tests on: 1) the distribution of lactate between plasma and red blood cells (RBCs), and 2) lactate threshold (LT) detection via three conventional methods using whole blood lactate concentration ([La]) or plasma [La]. Eight males (age, 22.5 +/- 0.6 yr: height, 170.6 +/- 2.3 cm, weight, 76.0 +/- 3.1 kg, and VO2peak, 42.8 +/- 2.0 mL.kg-1.min-1) performed two progressive load tests to volitional fatigue on a cycle ergometer. Work rate was increased 30 W at 1-min or 4-min intervals. All data were normalized to individual LT work rates. For both protocols, whole blood [La], plasma [La], RBC [La], and [La] gradient increased significantly (P < 0.05) after exercise intensity exceeded LT. However, the RBC:plasma [La] ratio remained at the resting value throughout the progressive exercise tests. The increase in [La] gradient after LT, with no change in the RBC:plasma lactate ratio, suggests that given an incremental work rate increase of 30 W, 1 min is adequate for equilibration of lactate between the plasma and RBCs. Also, under the conditions of this investigation, neither blood fraction analyzed nor exercise protocol had any effect on estimations of LT (in terms of VO2) by the Visual and Log-Log methods. However, LT determined by a fixed [La] of 2 mM may underestimate LT when plasma samples are used.

Lactate distribution in the blood during steady-state exercise.

PURPOSE: The purpose of this investigation was to examine the plasma to red blood cell (RBC) lactate concentration ([La]) gradient and RBC:plasma [La] ratio during 30 min of steady-state cycle ergometer exercise at work rates below lactate threshold ( LT. Blood samples were taken from a heated forearm vein, immediately cooled to 4 degrees C in a dry-ice ethanol slurry, and centrifuged at 4 degrees C to separate plasma and RBCs. RESULTS: During >LT, plasma [La] rose to 8.8+/-1.1 mM after 10 min and remained above 6 mM. RBC [La] (4.9+/-0.7 mM) was significantly lower than plasma [La] at 10 min and remained lower throughout exercise. As a result, there was a sizable [La] gradient (approximately 3.5 mM) from plasma to RBC during most of >LT. In LT, the ratio of RBC [La]:plasma [La] was the same for both (0.58+/-0.02) and not significantly different from rest. CONCLUSIONS: These results refuted our hypothesis that the RBC:plasma [La] ratio would decrease at the onset of >LT exercise because of muscle lactate release exceeding the ability of RBCs to take up the lactate. Instead, there appears to be an equilibrium between plasma [La] and RBC [La] in arterialized venous blood from a resting muscle group as evidenced by the constant RBC [La]:plasma [La] ratio.

Lactate influx into red blood cells from trained and untrained human subjects.

PURPOSE: The purpose of this study was to compare the fractional contributions of the three pathways of lactate transport (band 3 system, nonionic diffusion, and monocarboxylate pathway) into red blood cells (RBC) from trained and untrained humans. METHODS: Blood samples were obtained from 19 male subjects: 5 untrained, 5 aerobically-trained, 5 competitive collegiate cross-country runners, and 4 competitive collegiate sprinters. The influx of lactate into the RBC was measured by a radioactive tracer technique using [14C]lactate. Discrimination of each pathway of lactate transport was achieved by using PCMBS (1 mM) to block the monocarboxylate pathway and DIDS (0.2 mM) to block the band 3 system. Nonionic diffusion was calculated as the difference between total lactate influx and the sum of band 3 and monocarboxylate lactate influx. RESULTS: Total lactate influx into the RBC from the more aerobic individuals (trained subjects and cross-country runners) was significantly faster at 1.6 mM lactate concentration ([La]) as compared with the influx into RBC of the untrained subjects. Total influx of lactate was significantly higher (P < 0.05) in the RBC from the sprinters as compared with that in the RBC from the untrained subjects at 41 mM [La]. There were no significant differences among the four groups with regard to the total influx of lactate at 4.1, 8.1, and 20 mM [La]. In general, the percentage of total lactate influx accounted for by each of the three parallel pathways at 1.6, 8.1, and 41.0 mM [La] was not different among the four groups of subjects. CONCLUSIONS: Overall, the groups were more similar than different with regard to RBC lactate influx.