Pharmacokinetics and tolerability of oral sildenafil in adults with cystic fibrosis lung disease.

RATIONALE: Airway inflammation is central to cystic fibrosis (CF) pathophysiology. Pre-clinical models have shown that phosphodiesterase inhibitors (PDEi) like sildenafil have anti-inflammatory activity. PDEi have not been studied in CF subjects. OBJECTIVES: We evaluated the pharmacokinetics, tolerability, and safety of sildenafil in subjects with CF. Sputum biomarkers were used to explore efficacy. METHODS: An open-label pilot study of oral sildenafil administration was conducted in adults with mild to moderate CF lung disease. Subjects received oral sildenafil 20 or 40 mg p.o. t.i.d. for 6 weeks. MEASUREMENTS AND MAIN RESULTS: Twenty subjects completed the study. Estimated elimination rate constants were statistically different in subjects with CF compared to previously published non-CF subjects. Side effects were generally mild. There were no drug-related serious adverse events. Sputum neutrophil elastase activity decreased. CONCLUSIONS: Subjects with CF may eliminate sildenafil at a faster rate than non-CF subjects. Sildenafil administration was safe in subjects with CF and decreased sputum elastase activity. Sildenafil warrants further study as an anti-inflammatory in CF.

Exercise peripheral oxygen saturation (SpO2) accurately reflects arterial oxygen saturation (SaO2) and predicts mortality in systemic sclerosis.

BACKGROUND: Measures of oxygenation have not been assessed for prognostic significance in systemic sclerosis-related interstitial lung disease (SSc-ILD). METHODS: 83 subjects with SSc-ILD performed a maximal cardiopulmonary exercise test with an arterial line. The agreement between peripheral oxygen saturation (SpO2) and arterial oxygen saturation (SaO2) was examined and survival differences between subgroups of subjects stratified on SpO2 were analysed. Cox proportional hazards analyses were used to examine the prognostic capabilities of SpO2. RESULTS: At maximal exercise the mean (SD) difference between SpO2 and SaO2 was 2.98 (2.98) and only 15 subjects had a difference of >4 points. The survival of subjects with SSc-ILD whose maximum exercise SpO2 (Spo(2)max) fell below 89% or whose SpO2max fell >4 points from baseline was worse than subjects in comparator groups (log rank p = 0.01 and 0.01, respectively). The hazard of death during the median 7.1 years of follow-up was 2.4 times greater for subjects whose SpO2max fell below 89% (hazard ratio 2.4, 95% CI 1.1 to 4.9, p = 0.02) or whose SpO2max fell >4 points from baseline (hazard ratio 2.4, 95% CI 1.1 to 5.0, p = 0.02). CONCLUSION: In patients with SSc-ILD, SpO2 is an adequate reflection of SaO2 and radial arterial lines need not be inserted during cardiopulmonary exercise tests in these patients. Given the ease of measurement and its prognostic value, SpO2 should be considered as a meaningful clinical and research outcome in patients with SSc-ILD.

Determinants of adiponectin levels in young people with Type 1 diabetes.

AIMS: To determine whether adiponectin levels are higher in youth with Type 1 diabetes than in non-diabetic controls, and explore potential determinants for this difference. METHODS: Data are from the SEARCH for Diabetes in Youth Case-Control Study. A total of 440 youth with Type 1 diabetes and 191 non-diabetic healthy controls age 10-22 years of non-Hispanic White (NHW), African-American (AA) and Hispanic (H) origin were included in this analysis. Mean adiponectin levels were compared between persons with diabetes and controls within each racial/ethnic group, sequentially adjusting for the following variables: demographic (age, sex, Tanner stage), kidney function (albumin: creatinin ratio: ACR), obesity (body mass index: BMI; waist circumference), behavioral (percent calories from fat, physical activity), and glucose control (hemoglobin A1c: HbA(1c)). RESULTS: Mean adiponectin levels, adjusted for age, sex and Tanner stage, were higher in persons with Type 1 diabetes than in control subjects, among NHW (17.6 vs 13.0 microg/ml, P < 0.001) and H (17.2 vs 13.0, P = 0.01), and slightly higher but not significantly so among AA (14.5 vs 12.6, P = 0.1). The differences persisted after additionally adjusting for differences in ACR, BMI and waist circumference. We found a positive relationship between adiponectin and HbA(1c) in youth with Type 1 diabetes, even after adjustment for age, sex and race/ethnicity. CONCLUSIONS: Adiponectin is higher in an ethnically diverse group of youth with Type 1 diabetes than in control subjects. The relationship between glycemic control and adiponectin in Type 1 diabetes requires further exploration.

Organizing pneumonia and lymphoplasmacytic inflammation predict treatment response in idiopathic pulmonary fibrosis.

AIMS: To identify individual histopathological features within usual interstitial pneumonia pattern that predict responsiveness to immunosuppressive therapy. METHODS AND RESULTS: Fifty-six retrospectively confirmed usual interstitial pneumonia pattern surgical lung biopsy specimens from subjects with idiopathic pulmonary fibrosis treated with corticosteroid and cytotoxic therapy were included. Eleven prospectively defined histopathological features were evaluated by two expert pulmonary pathologists. Regression analysis identified predictors of response to therapy, as defined by the change in percent predicted forced vital capacity over 6 months. Additional end-points were change in dyspnoea score over 6 months, and survival time. Improvement in percent predicted forced vital capacity was associated with lymphoplasmacytic inflammation, while worsening of percent predicted forced vital capacity was associated with the presence of organizing pneumonia and fibroblast foci. Worsening dyspnoea was associated with fibroblast foci. Survival time was associated with age and baseline percent predicted forced vital capacity, but not with any individual histopathological feature. CONCLUSIONS: In pathological usual interstitial pneumonia pattern, the presence of lymphoplasmacytic inflammation predicts responsiveness to immunomodulatory therapy, while airspace organization predicts lack of response.

Lymphoblastic leukemia/lymphoma in mice overexpressing the Mer (MerTK) receptor tyrosine kinase.

Mer (MerTK) is a receptor tyrosine kinase important in platelet aggregation, as well as macrophage cytokine secretion and clearance of apoptotic cells. Mer is not normally expressed in thymocytes or lymphocytes; however, ectopic Mer RNA transcript and protein expression is found in a subset of acute lymphoblastic leukemia cell lines and patient samples, suggesting a role in leukemogenesis. To investigate the oncogenic potential of Mer in vivo, we created a transgenic mouse line (Mer(Tg)) that expresses Mer in the hematopoietic lineage under control of the Vav promoter. Ectopic expression and activation of the transgenic Mer protein was demonstrated in lymphocytes and thymocytes of the Mer(Tg) mice. At 12-24 months of age, greater than 55% of the Mer(Tg) mice, compared to 12% of the wild type, developed adenopathy, hepatosplenomegaly, and circulating lymphoblasts. Histopathological analysis and flow cytometry were consistent with T-cell lymphoblastic leukemia/lymphoma. Mer may contribute to leukemogenesis by activation of Akt and ERK1/2 anti-apoptotic signals, which were upregulated in Mer(Tg) mice. Additionally, a significant survival advantage was noted in Mer(Tg) lymphocytes compared to wild-type lymphocytes after dexamethasone treatment. These data suggest that Mer plays a cooperative role in leukemogenesis and may be an effective target for biologically based leukemia/lymphoma therapy.

Multiple comparisons: philosophies and illustrations.

Statistical procedures underpin the process of scientific discovery. As researchers, one way we use these procedures is to test the validity of a null hypothesis. Often, we test the validity of more than one null hypothesis. If we fail to use an appropriate procedure to account for this multiplicity, then we are more likely to reach a wrong scientific conclusion-we are more likely to make a mistake. In physiology, experiments that involve multiple comparisons are common: of the original articles published in 1997 by the American Physiological Society, approximately 40% cite a multiple comparison procedure. In this review, I demonstrate the statistical issue embedded in multiple comparisons, and I summarize the philosophies of handling this issue. I also illustrate the three procedures-Newman-Keuls, Bonferroni, least significant difference-cited most often in my literature review; each of these procedures is of limited practical value. Last, I demonstrate the false discovery rate procedure, a promising development in multiple comparisons. The false discovery rate procedure may be the best practical solution to the problems of multiple comparisons that exist within physiology and other scientific disciplines.

Science education partnership between the University of Colorado and a Denver High School.

The authors describe a partnership, begun in 1997, between Manual High School, a school in which about 85% of the students are African, American or Hispanic, and the University of Colorado Health Sciences Center in Denver. There are three partnership goals: help teachers transform a lecture-based curriculum into an inquiry-based curriculum, help students build their science knowledge, and give students opportunities to learn--and become excited--about careers in medicine. The current emphasis of the partnership is at the ninth-grade level. The first unique aspect of the partnership is the Medical Explorers program. One portion of the program begins when a hypothetical teenage car-crash victim arrives at the emergency room; over the next six weeks, practicing health care professionals dramatize their medical responsibilities to this patient and discuss the academic training necessary to fulfill those responsibilities. In addition, the Medical Explorers students travel to the Health Sciences Center, where they tour laboratories and clinics, help conduct experiments, and explore computer-based surgical simulations. The second unique program is a service learning project in which ninth-grade students assist with an activity that gives elementary school students a chance to participate in the process of scientific inquiry and to discover the wonder of real hearts and lungs; the ninth-graders assist with logistics (e.g., they distribute newspapers), and, more important, interact with the younger students by asking thoughtful questions of them. The partnership plans to incorporate the elementary and middle schools that graduate their students to Manual High School in order to encourage the implementation of inquiry-based science curricula and to provide sustained support to teachers throughout the entire K-12 educational pathway. If medical colleges can help teachers provide a consistent classroom draw for student fascination in science and medicine, then the colleges are more likely to help create a rich diversity of students who pursue careers in medicine.

Fundamental concepts in statistics: elucidation and illustration.

Fundamental concepts in statistics form the cornerstone of scientific inquiry. If we fail to understand fully these fundamental concepts, then the scientific conclusions we reach are more likely to be wrong. This is more than supposition: for 60 years, statisticians have warned that the scientific literature harbors misunderstandings about basic statistical concepts. Original articles published in 1996 by the American Physiological Society's journals fared no better in their handling of basic statistical concepts. In this review, we summarize the two main scientific uses of statistics: hypothesis testing and estimation. Most scientists use statistics solely for hypothesis testing; often, however, estimation is more useful. We also illustrate the concepts of variability and uncertainty, and we demonstrate the essential distinction between statistical significance and scientific importance. An understanding of concepts such as variability, uncertainty, and significance is necessary, but it is not sufficient; we show also that the numerical results of statistical analyses have limitations.

Effect of K+ATP channel inhibition on total and regional vascular resistance in guinea pig pregnancy.

Decreased vascular resistance and vasoconstrictor response during pregnancy enables an increase in cardiac output and regional blood flow to the uterine circulation. We sought to determine whether inhibition of vascular smooth muscle ATP-sensitive potassium (K+ATP) channel activity during pregnancy increased systemic and/or regional vascular resistance and resistance response to ANG II. A total of 32 catheterized, awake, pregnant or nonpregnant guinea pigs were treated with either the K+ATP channel inhibitor glibenclamide (3.5 mg/kg) or vehicle (DMSO) (n = 8/group). In nonpregnant and pregnant animals, glibenclamide raised blood pressure and systemic, uterine, and coronary vascular resistance, diminishing cardiac output and organ blood flow. Glibenclamide produced a greater rise in coronary vascular resistance in the pregnant than nonpregnant groups and increased renal and cerebral vascular resistance in the pregnant animals only. ANG II infusion raised blood pressure and systemic and renal vascular resistance and lowered cardiac output and renal blood flow in vehicle-treated animals. Glibenclamide augmented ANG II-induced systemic vasoconstriction in the nonpregnant and pregnant groups and the rise in uteroplacental vascular resistance in the pregnant animals. We concluded that K+ATP channel activity likely modulates systemic, uterine, and coronary vascular resistance and opposes ANG II-induced systemic vasoconstriction in nonpregnant and pregnant guinea pigs. Pregnancy augments K+ATP channel activity in the uterine, coronary, renal, and cerebral vascular beds and the uteroplacental circulation during ANG II infusion. Thus increased K+ATP channel activity appears to influence regional control of vascular resistance during guinea pig pregnancy but cannot account for the characteristic decrease in systemic vascular resistance and ANG II-induced systemic vasoconstrictor response.

An improved statistical methodology to estimate and analyze impedances and transfer functions.

Estimating the mathematical relationship between pulsatile time series (e.g., pressure and flow) is an effective technique for studying dynamic systems. The frequency-domain relationship between time series, often calculated as an impedance (pressure/flow), is known more generally as a frequency-response or transfer function (output/input). Current statistical methods for transfer function analysis 1) assume erroneously that repeated observations on a subject are independent, 2) have limited statistical value and power, or 3) are restricted to use in single subjects rather than in an entire sample. This paper develops a regression model for transfer function analysis that corrects each of these deficiencies. Spectral densities of the input and output time series and the cross-spectral density between them are first estimated from discrete Fourier transforms and then used to obtain regression estimates of the transfer function. Statistical comparisons of the transfer function estimates use a test statistic that is distributed as chi2. Confidence intervals for amplitude and phase can also be calculated. By correctly modeling repeated observations on each subject, this improved statistical approach to transfer function estimation and analysis permits the simultaneous analysis of data from all subjects in a sample, improves the power of the transfer function model, and has broad relevance to the study of dynamic physiological systems.

Hearts, lungs, and children: a physiologist returns to kindergarten.

Scientific illiteracy is a prevalent problem: between kindergarten and high school, most children progressively lose their inherent affinity for science exploration. The correction of this deficiency requires vigorous participation by the scientific community. This paper details my experiences introducing kindergartners to the basics of cardiorespiratory physiology: pulmonary ventilation and circulatory transport of oxygen. More important, my presentation gives children an opportunity to participate in the process of scientific inquiry and to discover and explore the mystique of real hearts and lungs. The children and their teachers truly enjoy the demonstration. In particular, my use of animal organs meets with phenomenal success: the children are enchanted by my inflation and their exploration of pig lungs, and one teacher told me weeks afterward that her students were still "bragging of how they touched a real heart and lung." Young children delight in science exploration and marvel at the wonder inherent to physiology. Armed with an intriguing hands-on presentation and a spirit of adventure and fun, any scientist can return to kindergarten. The rewards are likely to be profound.

Cerebral lactate metabolism in near-term fetal sheep.

The present study was designed to see if lactate can cross the blood-brain barrier of the near-term fetal sheep and replace glucose as an oxidative substrate during normoglycemia and acute insulin-induced hypoglycemia. Cerebral uptake of glucose, oxygen, lactate, and [14C]lactate as well as cerebral production of 14CO2 were measured under three conditions: 1) normoglycemia-normolactemia, 2) acute hypoglycemia-normolactemia, and 3) hypoglycemia-steady-state hyperlactemia. Although uptake of tracer [14C]lactate was consistent, there was no net uptake of unlabeled lactate during either normoglycemia or hypoglycemia. When arterial lactate concentration was raised from 2.2 +/- 0.5 to 3.3 +/- 0.4 (SE) mM by sodium lactate infusion, however, lactate was taken up. Comparison of cerebral [14C]lactate uptake with 14CO2 production indicated that the principal metabolic fate of lactate is oxidation. At increased concentrations, exogenous lactate accounted for approximately 7% of cerebral oxygen consumption. This study demonstrates that lactate crosses the blood-brain barrier of the near-term fetal sheep, is oxidized, and at elevated concentrations can partially replace glucose as an oxidative substrate during acute hypoglycemia.

Hypoxia, hypercapnia, and hypertension: their effects on pulsatile cerebral blood flow.

Pulsatile cerebral blood flow reflects characteristics of arterial blood pressure as well as the structure and mechanical properties of the cerebrovascular network. Although the effects of changes in systemic blood gases and blood pressure on mean cerebral flow are established, their effects on pulsatile cerebral blood flow are unknown. These studies assessed the effects of hypoxia-hypercapnia (combined; both arterial PO2 and PCO2 approximately 55 Torr) and acute hypertension (+30-35 mmHg by aortic occlusion) on pulsatile cerebral blood flow in ketamine-anesthetized rabbits. We characterized the relationship between pulsatile systemic blood pressure (Millar catheter) and cerebral cortical capillary blood-flow (laser-Doppler) by calculating the transfer function, a frequency-domain expression that relates amplitudes and phase angles of flow output to those of the pressure input. During hypoxia-hypercapnia, mean flow increased 17% (P < 0.001), but the amplitude and contour of pulsatile cortical blood flow were unchanged (P > 0.10). Although aortic occlusion, during hypoxia-hypercapnia as well as during normoxia-normocapnia, increased systemic pulse pressure by 40%, the amplitude of cortical flow pulsations was unaffected. Changes in dynamic properties of the cerebral vasculature (P < 0.0001 by analysis of the transfer function) minimized alterations in pulsatile cortical blood flow and thus intrabeat vessel wall stress during acute hypertension; on the basis of analysis of an electrical analogue, we propose that these changes reflect alterations in both resistance and compliance.

Acclimatization to hypoxia alters cerebral convective and diffusive O2 delivery.

Ventilatory acclimatization (VA) to hypoxia alters cerebrovascular responses to arterial blood gas perturbations. For example, after VA, cerebral blood flow (CBF) is elevated, at a given arterial CO2 tension (PaCO2), compared to CBF before VA. This experiment examined the effects of VA to 72 h of normobaric hypoxia [arterial O2 tension (PaO2) approx. 40 mmHg, O2 saturation in arterial blood approx. 50%] on total and regional cerebrovascular resistance (CVR and rCVR) and cerebral O2 extraction fraction (OEF) in 32 conscious sheep. Four different O2-CO2 gas combinations were sequentially administered to each sheep before and after VA. CVR and rCVR were calculated from CBF (radiolabeled microspheres) and arterial and cerebral downstream pressures; OEF was calculated from arterial and cerebral venous O2 contents. After VA, during hyperoxia, CVR and rCVR tended to be lower during both hypocapnia and hypercapnia. During hypoxia, although CVR and rCVR were slightly less during hypocapnia, CVR and rCVR during hypercapnia were surprisingly increased. The post-VA increases in mean CVR and mean rCVR during hypoxic gas combinations differed from the post-VA decreases during hyperoxic gas combinations (0.04 less than or equal to P less than or equal to 0.11). In contrast, although VA decreased OEF during three of four gas combinations (P less than or equal to 0.003), there was a greater mean post-VA decrease in OEF during hypercapnic gas combinations than during hypocapnic gas combinations (P = 0.025); decreases in OEF were correlated with decreases in cerebral O2 consumption. The post-VA CVR responses may reflect altered neurocirculatory control by the arterial chemoreflex; the OEF responses suggest relative cerebral hyperperfusion.(ABSTRACT TRUNCATED AT 250 WORDS)

Regional circulatory contributions to increased systemic vascular conductance of pregnancy.

In pregnancy, maternal systemic vascular conductance increases, a new vascular circuit grows, and the maternal systemic circulation develops a diminished pressor response to angiotensin II (ANG II). However, the quantitative contributions of the latter two circulatory changes to the increased systemic vascular conductance of pregnancy have not been explored. In this experiment, we examined regional circulatory contributions to the increased systemic vascular conductance in conscious, late-gestation guinea pigs. Systemic arterial pressure, cardiac output (dye dilution), and regional blood flows (radiolabeled microspheres) were measured during baseline conditions and progressive ANG II infusion. Systemic and regional conductances were calculated from arterial pressure and cardiac output or regional blood flows. In pregnancy, maternal systemic vascular conductance increased from 3.2 to 5.0 ml.min-1.mmHg-1 (P less than 0.001); increased nonuteroplacental conductance contributed 71% to the increase in whole body conductance. Pregnancy tended to decrease the nonuteroplacental conductance response (P = 0.072), but did not change the uteroplacental conductance response (P greater than or equal to 0.29), to ANG II. The increased uteroplacental blood flow of pregnancy was preserved during ANG II-induced vasoconstriction. We conclude that maternal systemic vascular conductance increased primarily because nonuteroplacental vascular conductance increased.(ABSTRACT TRUNCATED AT 250 WORDS)

Cerebral metabolic and pressure-flow responses during sustained hypoxia in awake sheep.

Conscious sheep (n = 6), exposed to 3.5 h of normobaric hypoxia (arterial PO2 = 40 Torr) while allowed varying arterial PCO2, showed striking early increments of cerebral blood flow (CBF; +200-250%, by radiolabeled microspheres) and decrements of cerebral vascular resistance (CVR) in association with an early temporary elevation of cerebral O2 consumption (CMRO2; +25-60%). After 2 h, CMRO2 returned to normoxic levels, while CBF declined to a lower but still elevated level (+150%). CBF/CMRO2 increased twofold, while cerebral fractional extraction of O2 was unchanged. Mean arterial pressure was unchanged, but cerebral venous pressure rose (+11 mmHg) in a stable fashion such that cerebral perfusion pressure declined by 13%. Cerebral venous hematocrit and hemoglobin concentration were both elevated (+2.2-2.7% Hct units; +1.0-1.3 g/dl, respectively) above the corresponding arterial values between 150 and 210 min of hypoxia, suggesting venous hemoconcentration in possible association with a transcapillary fluid shift. CBF, and especially CVR, were well correlated with arterial O2 content.

Intracranial pressures and O2 extraction in conscious sheep during 72 h of hypoxia.

High-altitude cerebral edema may occur within several days after a rapid ascent to altitude. However, the mechanisms that produce this potentially lethal condition are unclear. This experiment assessed systemic arterial and intracranial pressures (n = 22) and cerebral blood flow per unit cerebral O2 consumption (Qc/cVo2) and cerebral O2 extraction fraction (cEo2) (n = 9) in conscious sheep before and during 72 h of normobaric hypoxia (arterial O2 tension approximately 40 mmHg, oxygen saturation in arterial blood approximately 50%). Qc/cVo2 and cEo2 were calculated from systemic arterial and cerebral venous O2 contents. Wet-to-dry brain weight ratios were calculated during normoxia (n = 4) or after 72 h of hypoxia (n = 5) in additional sheep. Intracranial pressures did not change during hypoxia (+ 1.3 to +1.8 mmHg, P = 1.0); however, estimated intracranial capillary hydrostatic pressure may have increased 1-20 mmHg depending on the arterial-to-downstream resistance ratio. During the 72 h of hypoxia, Qc/cVO2 doubled (P = 0.02) and cEo2 tended to decrease (5% absolute, P = 1.0). Regional wet-to-dry brain weight ratios after 72 h of hypoxia were 4-13% greater than their respective ratios during normoxia (0.001 less than P less than or equal to 0.05); indirect evidence suggests that this increased brain water content was extravascular. The sheep may be an appropriate model for the further study of high-altitude cerebral edema.

Coronary blood flow and thallium 201 uptake in rejecting rat heart transplantations.

The effects of rejection on coronary flow (CAF) in heart allografts are unclear, although previous evidence with cardiac imaging agents indicates impaired flow during advanced rejection. The purpose of this study was to measure CAF in heterotopically placed heart grafts. Lewis rats (LEW) received grafts from either syngeneic Lewis rats (LEW/LEW group) or allogeneic ACI rats (ACI/LEW group). CAF was measured in both the transplanted and native hearts with radiolabeled microspheres. Rejection was measured histologically (grades 0 [absent] to 4+ [severe]). In addition systemic blood pressure and cardiac outputs of the native hearts were determined with microspheres. Different animals were studied during relatively early (4 days) and late (6 days) rejection. Among the 4-day animals a cyclosporine-treated group was included (ACI/LEW CyA). In 6-day rats CAF in allografts was lower (0.56 +/- .06 ml/gm/min) compared with syngeneic grafts (1.72 +/- 0.4 ml/gm/min) (p less than 0.05). The CAF in the native hearts did not differ significantly but was higher than in the grafts in both groups. Heart rates were reduced in allografts (p less than 0.05). It is interesting that arterial pressure and cardiac output were significantly lower in animals bearing allogeneic than syngeneic grafts. In rats studied at 4 days graft CAF was lower than in the native heart in both the LEW/LEW and ACI/LEW groups, but there was no significant difference in behavior between groups. The same was true for a cyclosporine-treated group. Graft heart rates were similar in all 4-day rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Hormonal and electrolyte responses of conscious sheep to 96 h of hypoxia.

Hypoxia alters the relationship of aldosterone secretion to plasma renin activity. The potential role plasma electrolytes play in this modification is not clear. This study analyzed the interrelationships among renin, aldosterone, vasopressin (ADH), and plasma electrolytes during 96 h of normobaric hypoxia. Eight ewes were exposed, in discrete experiments, to hypocapnic hypoxia [arterial O2 tension (PaO2) 37-42 mmHg, arterial CO2 tension (PaCO2) 26-28 mmHg] and eucapnic hypoxia (PaO2 40-43 mmHg, PaCO2 28-31 mmHg) by N2 dilution in an environmental chamber. Urine output (24 h) was measured, and arterial plasma samples were collected during the normoxic control period and at 24-h intervals of hypoxia. Plasma Na+, K+, renin, and ADH levels did not change from the normoxic values during either hypocapnic or eucapnic hypoxia. However, urinary aldosterone excretion [critical significance (alpha) less than 0.046] and K+ excretion (alpha less than 0.046) decreased markedly during each type of hypoxia. All sheep developed a pronounced negative K+ balance by 96 h of hypoxia. These data suggest that plasma K+ concentration is preserved by movement of K+ out of the intracellular compartment; this change in K+ distribution may inhibit aldosterone secretion during hypoxia.