Coronary arterial smooth muscle contraction by a substance released from platelets: evidence that it is thromboxane A2.

When human platelets are aggregated by thrombin, material is released that rapidly contracts strips of spirally cut porcine coronary artery. Prevention of the contraction by indomethacin suggested mediation by a prostaglandin. The contraction produced by aggregating platelets was unlike those produced by prostaglandins E2, F2alpha, G2, or H2, but resembled that evoked by thromboxane A2, which is formed by platelets during aggregation.

Effects of feeding ethyl-dihomo-gamma-linolenate on prostaglandin biosynthesis and platelet aggregation in the rabbit.

1. The ethyl ester of dihomo-gamma-linolenic acid (20:3omega6) (1 g/kg/day) was fed to rabbits for 25 days. Plasma lipids and platelet aggregation were analyzed on day 1, 11, 16, 21 and 26. 2. All plasma lipid classes were greatly enriched with 20:3omega6. Arachidonic acid levels were elevated to a smaller extent. The different platelet phospholipid fractions analyzed were also highly enriched with 20:3omega6, whereas the arachidonic acid content in platelet phospholipids was significantly lower than in control animals. 3. The excretion of 7 alpha-hydroxy-5,11-diketotetranorprostane-1,16-dioic acid, the major urinary metabolite of prostaglandin E1 and E2 was increased 4.6 fold by the treatment. 4. Platelet aggregation in response to ADP, collagen and arachidonic acid did not differ at any time betweeen 20:3omega6 treated rabbits and controls. 5. It is concluded that prostaglandin E biosynthesis can be increased by enriching the prostaglandin precursor pool. Platelet aggregation in vitro is not altered by feeding ethyl 20:3omega6.

Relation between plasma concentration of indomethacin and its effect on prostaglandin synthesis and platelet aggregation in man.

The dose and plasma levels of indomethacin correlated with inhibition of prostaglandin synthesis as measured both by urinary excretion of the major metabolite of prostaglandin E2 (PGE-M) and by the release of prostaglandin E2 from thrombin-stimulated platelets. Considerable intersubject variability was observed in the suppression of PGE-M excretion. In some patients 37.5 mg indomethacin daily, usually considered subtherapeutic, caused suppression. Maximal suppression (greater than 90%) occurred in some after a daily dose of 75 mg, whereas 150 mg was required to achieve this level of inhibition in others. Suppression of the excretion of PGE-M by 60% occurred when the end of the dosage interval plasma levels of indomethacin were in the range 0.05 to 0.3 microgram/ml, which implies that a somewhat higher average steady-state concentration during the dosage interval was required to achieve this effect. A similar degree of inhibition of the release of PGE2 on thrombin-stimulated platelets was associated with the same range of plasma levels. Upon discontinuation of the drug, the levels of indomethacin in plasma decreased exponentially; inhibition of the release of PGE2 from platelets by indomethacin declined linearly with time and in parallel with the logarithm of the diminishing plasma levels.

Increased arachidonate in lipids after administration to man: effects on prostaglandin biosynthesis.

Ethyl arachidonate was administered orally to 4 healthy male volunteers in a dose of 6 gm daily for a 2 to 3 wk period after 10-day control period. The increased intake of this precursor of the dienoic prostaglandins resulted in significant increases in the relative and absolute amount of arachidonate in plasma triglycerides, phospholipids, and cholesteryl esters. Similar changes in lipid composition were noted in platelets. The excretion of 7alpha-hydroxy-5,11-diketotetranoprostane-1,16-dioic acid, the major urinary metabolite of E prostaglandins in man, was increased by an average of 47% in 3 of the 4 volunteers. Platelet reactivity was assessed by determining the threshold concentration of adenosine diphosphate (ADP) necessary to induce secondary, irreversible aggregation of platelet-rich plasma. This threshold concentration dropped significantly in all volunteers (10% to 60% of control values). It is concluded that the biosynthesis and function of prostaglandins can be augmented in man by oral administration of an esterified precursor fatty acid.

Persistent cognitive impairment in climbers after repeated exposure to extreme altitude.

We performed neuropsychological testing in eight world class climbers who had reached summits higher than 8,500 meters without supplementary oxygen. Five had mildly impaired concentration, short-term memory, and ability to shift concepts and control errors. There were no defects in perception or other cognitive activities. The pattern of impairment suggests malfunctioning of bifronto-temporo-limbic structures. Repeated extreme-altitude exposure can cause mild but persistent cognitive impairment.

Urinary leukotriene E(4) levels are not increased prior to high-altitude pulmonary edema.

STUDY OBJECTIVE: To examine whether increased urinary cysteinyl-leukotriene E(4) (LTE(4)) excretion, which has been found to be elevated in patients presenting with high-altitude pulmonary edema (HAPE), precedes edema formation. DESIGN: Prospective studies in a total of 12 subjects with susceptibility to HAPE. SETTING: In a chamber study, seven subjects susceptible to HAPE and five nonsusceptible control subjects were exposed for 24 h to an altitude of 450 m (control day), and exposed for 20 h to 4,000 m after slow decompression over 4 h. In a field study, prospective measurements at low and high altitude were performed in five subjects developing HAPE at 4,559 m. PARTICIPANTS: Mountaineers with a radiographically documented history of HAPE and control subjects who did not develop HAPE with identical high-altitude exposure. INTERVENTIONS: 24-h urine collections. MEASUREMENTS AND RESULTS: In the hypobaric chamber, none of the subjects developed HAPE. The 24-h urinary LTE(4) did not differ between HAPE susceptible and control subjects, nor between hypoxia and normoxic control day. In the field study, urinary LTE(4) was not increased in subjects with HAPE compared to values obtained prior to HAPE at high altitude and during 2 control days at low altitude. CONCLUSIONS: These data do not provide evidence that cysteinyl-leukotriene-mediated inflammatory response is associated with HAPE susceptibility or the development of HAPE within the context of our studies.

Interactions between Hb, Mg, DPG, ATP, and Cl determine the change in Hb-O2 affinity at high altitude.

Ascent to high altitude (HA) causes an increase in erythrocyte 2,3-diphsophoglycerate (DPG) and standard PO2 at 50% O2 saturation, PCO2 40 Torr, and blood pH 7.4 (P50,st). We studied the early phase of acclimatization to HA of mountaineers without and with a history of HA pulmonary edema. Tests were performed before ascent and after arrival at HA (4,559 m), approximately 22 h after the departure from low altitude (HA1) and on the following 3 days at HA (HA2-HA4). We investigated the relation between changes in DPG and P50,st, since at moderate altitude P50,st increases more rapidly than DPG, indicating that other factors may contribute to the change in P50,st. Combined effects of interaction between allosteric effectors of hemoglobin (Hb) (DPG, ATP, Cl) and Mg, which competes with Hb for DPG and ATP binding, might explain that phenomenon. Therefore concentrations of liganded Hb species were calculated from the total erythrocyte concentrations of the ligands by use of published binding constants and were related to changes in Hb-O2 affinity. P50,st increased at HA by approximately 4.5 Torr; the concentration of total DPG and ATP increased by 28 and 19%, respectively. Whereas P50,st reached a plateau already at HA1, the concentration of DPG reached its highest value at HA4. The erythrocyte Cl concentration decreased, whereas cellular Hb and Mg concentrations increased slightly. The sum of concentrations of all liganded Hb species increased, reaching 79% of its total change within 22 h after ascent; this can mainly be attributed to the change in the concentration of Hb[DPG] (+77% of total increase).(ABSTRACT TRUNCATED AT 250 WORDS)

Acute mountain sickness is not related to cerebral blood flow: a decompression chamber study.

To evaluate the pathogenetic role of cerebral blood flow (CBF) changes occurring before and during the development of acute mountain sickness (AMS), peak mean middle cerebral artery flow velocities () were assessed by transcranial Doppler sonography in 10 subjects at 490-m altitude, and during three 12-min periods immediately (SA1), 3 (SA2), and 6 (SA3) h after decompression to a simulated altitude of 4,559 m. AMS cerebral scores increased from 0. 16 +/- 0.14 at baseline to 0.44 +/- 0.31 at SA1, 1.11 +/- 0.88 at SA2 (P < 0.05), and 1.43 +/- 1.03 at SA3 (P < 0.01); correspondingly, three, seven, and eight subjects had AMS. Absolute and relative at simulated altitude, expressed as percentages of low-altitude values (%), did not correlate with AMS cerebral scores. Average % remained unchanged, because % increased in three and remained unchanged or decreased in seven subjects at SA2 and SA3. These results suggest that CBF is not important in the pathogenesis of AMS and shows substantial interindividual differences during the first hours at simulated altitude.

Enhanced exercise-induced rise of aldosterone and vasopressin preceding mountain sickness.

A possible contribution of exercise to the fluid retention associated with acute mountain sickness (AMS) was investigated in 17 mountaineers who underwent an exercise test for 30 min on a bicycle ergometer with a constant work load of 148 +/- 9 (SE) W at low altitude (LA) and with 103 +/- 6 W 4-7 h after arrival at 4,559 m or high altitude (HA). Mean heart rates during exercise at both altitudes and during active ascent to HA were similar. Exercise-induced changes at LA did not differ significantly between the eight subjects who stayed well and the nine subjects who developed AMS during a 3-day sojourn at 4,559 m. At HA, O2 saturation before (71 +/- 2 vs. 83 +/- 2%, P less than 0.01) and during exercise (67 +/- 2 vs. 72 +/- 1%, P less than 0.025) was lower and exercise-induced increase of plasma aldosterone (617 +/- 116 vs. 233 +/- 42 pmol/l, P less than 0.025) and plasma antidiuretic hormone (23.8 +/- 14.4 vs. 3.4 +/- 1.8 pmol/l, P less than 0.05) was greater in the AMS group, whereas exercise-induced rise of plasma atrial natriuretic factor and changes of hematocrit, potassium, and osmolality in plasma were similar in both groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Enhanced fibrin formation in high-altitude pulmonary edema.

Blood coagulation, fibrinolysis, and arterial blood gases were examined in 66 nonacclimatized mountaineers at 4,557 m. Subjects were classified according to a clinical score as healthy (n = 25), having mild acute mountain sickness (AMS) (n = 24), showing severe AMS (n = 13), and suffering from high-altitude pulmonary edema (HAPE) (n = 4). Coagulation times, euglobulin lysis time, and fibrin(ogen) fragment E were normal in all groups without significant changes. Fibrinopeptide A (FPA), a molecular marker of in vivo fibrin formation, was elevated in HAPE to 4.2 +/- 2.7 ng/ml (P less than 0.0001) compared with the other groups showing mean values between 1.6 +/- 0.4 and 1.8 +/- 0.7 ng/ml. FPA was normal in one patient with HAPE, however. Severe AMS was accompanied by a significant decrease in arterial PO2 due to an increase in alveolar-arterial O2 difference, whereas arterial PCO2 did not change significantly. We conclude that activation of blood coagulation is not involved in the pathogenesis of AMS and the impairment of gas exchange in this disease. Fibrin generation occurring in HAPE is probably an epiphenomenon of edema formation.

Blood rheology in acute mountain sickness and high-altitude pulmonary edema.

The role of blood rheology in the pathogenesis of acute mountain sickness and high-altitude pulmonary edema was investigated. Twenty-three volunteers, 12 with a history of high-altitude pulmonary edema, were studied at low altitude (490 m) and at 2 h and 18 h after arrival at 4,559 m. Eight subjects remained healthy, seven developed acute mountain sickness, and eight developed high-altitude pulmonary edema. Hematocrit, whole blood viscosity, plasma viscosity, erythrocyte aggregation, and erythrocyte deformability (filtration) were measured. Plasma viscosity and erythrocyte deformability remained unaffected. The hematocrit level was lower 2 h after the arrival at high altitude and higher after 18 h compared with low altitude. The whole blood viscosity changed accordingly. The erythrocyte aggregation was about doubled 18 h after the arrival compared with low-altitude values, which reflects the acute phase reaction. There were, however, no significant differences in any rheological parameters between healthy individuals and subjects with acute mountain sickness or high-altitude pulmonary edema, either before or during the illness. We conclude that rheological abnormalities can be excluded as an initiating event in the development of acute mountain sickness and high-altitude pulmonary edema.

Unchanged in vivo P50 at high altitude despite decreased erythrocyte age and elevated 2,3-diphosphoglycerate.

We measured hematological and erythrocyte O2 transport parameters in whole blood and density-separated erythrocytes in 11 mountaineers before and during 5 days of exposure to high altitude (4,559 m). We determined the in vivo (arterial pHblood and PCO2) and standard (pHblood = 7.4, PCO2 = 40 Torr) O2 tension at 50% O2 saturation of hemoglobin and (P50,vv and P50,st) and Bohr coefficients (BC) for fixed acid (H+) and CO2 and examined the contribution of the altered average age of circulating erythrocytes due to the stimulation of erythropoiesis on whole blood 2,3-diphosphoglycerate (2,3-DPG) and P50,st. At altitude, whole blood P50,vv remained almost unchanged, whereas P50,st and 2,3-DPG increased significantly (+4 Torr; 3.5 mumol/g hemoglobin). BCCO2 was elevated significantly at altitude. Serum erythropoietin increased transiently fourfold, iron utilization increased, and serum iron decreased by 66%. Reticulocyte counts increased, but other hematological parameters were unchanged. In density-separated erythrocytes, P50,st and 2,3-DPG increased with decreasing cell density but were higher in fractions with comparable reticulocyte counts in cells prepared at altitude than in those from control studies. Our data show that, despite the increase in 2,3-DPG and the decrease in average erythrocyte age, the in vivo hemoglobin-O2 affinity remains unchanged. P50,st values reflect the elevation of 2,3-DPG, and approximately 50% of the increase in both parameters can be ascribed to the increase in the number of reticulocytes and young erythrocytes.

Contact phase of blood coagulation is not activated in edema of high altitude.

To examine whether bradykinin generated by the activation of the contact phase of blood coagulation is involved in the pathogenesis of edema occurring after acute exposure to high altitude, 15 mountaineers were examined at 490 m and 1, 3, and 5 days after arrival at 4,559 m. The clotting activity levels of factor XII, factor XI, plasma prekallikrein, and high-molecular-weight kininogen (HMWK) were measured, and plasma kallikrein-induced proteolytic cleavage of HMWK was assessed by ligand blotting by use of radiolabeled factor XI. After an ascent on foot from 1,170 to 4,559 m in 3 days, three subjects developed high-altitude pulmonary edema, and four subjects presented facial edema. There was no evidence for activation of the contact system in any subject as demonstrated by the lack of proteolytic cleavage of HMWK at high altitude. The absence of contact system activation was further supported by stable plasma levels of the individual factors of contact activation. Therefore, we conclude that bradykinin generated by plasma kallikrein-induced cleavage of HMWK is not involved in the pathogenesis of edema due to acute exposure to high altitude.

Physiological profile of world-class high-altitude climbers.

The functional characteristics of six world-class high-altitude mountaineers were assessed 2-12 mo after the last high-altitude climb. Each climber on one or several occasions had reached altitudes of 8,500 m or above without supplementary O2. Static and dynamic lung volumes and right and left echocardiographic measurements were found to be within normal limits of sedentary controls (SC). Muscle fiber distribution was 70% type I, 22% type IIa, and 7% type IIb. Mean muscle fiber cross-sectional area was significantly smaller than that of SC (-15%) and of long-distance runners (LDR, -51%). The number of capillaries per unit cross-sectional area was significantly greater than that of SC (+ 40%). Total mitochondrial volume was not significantly different from that of SC, but its subsarcolemmal component was equal to that of LDR. Average maximal O2 consumption was 60 +/- 6 ml X kg-1 X min-1, which is between the values of SC and LDR. Average maximal anaerobic power was 28 +/- 2.5 W X kg-1, which is equal to that of SC and 40% lower that that of competitive high jumpers. All subjects were characterized by resting hyperventilation both in normoxia and in moderate (inspired O2 partial pressure = 77 Torr) hypoxia resulting in higher oxyhemoglobin saturation levels in hypoxia. The ventilatory response to four tidal volumes of pure O2 was similar to that of SC. It is concluded that elite high-altitude climbers do not have physiological adaptations to high altitude that justify their unique performance.

Trichosporon capitatum: thrush-like oral infection, local invasion, fungaemia and metastatic abscess formation in a leukaemic patient.

A thrush-like oral infection with subsequent alveolar abscess formation and a positive blood culture due to Trichosporon capitatum developed in a patient with acute myelogenous leukaemia. Later T. capitatum was identified by indirect immunofluorescence in multiple splenic abscesses. The infection was controlled by immediate aggressive treatment with amphotericin B, flucytosine and rifampicin and by splenectomy. This case of systemic T. capitatum infection resembles somewhat the invasive mycosis due to candida.

Effects of feeding ethyl-dihomo-gamma-linolenate on rabbit renomedullary lipid composition and prostaglandin production in vitro.

Feeding the ethyl ester of dihomo-gamma-linolenic acid for 25 days to rabbits resulted in increased PGE1 (20 to 30-fold) and PGE2 (1.5-fold) output by a hormone responsive, in vitro, renal papilla preparation. The relative amount of PGE1 increased from less than 5% of PGE2 in controls to 25-35% of PGE2 in the papillae of 20 : 3 omega 6-supplemented animals. During the study renomedullary tri glycerides in the 20 : 3 omega 6-supplemented animals increased 2.8-fold compared to animals fed an equal amount of a control fatty acid mixture, and in addition to a marked enrichment in 20 : 3 omega 6, also contained increased proportions of 20 : 4 omega 6 and longer chain polyenes. The increase in triglyceride content found in the renal medulla was not seen in the renal cortex or liver. There was no increase in renomedullary phospholipid content during the study, and phopholipids of treated animals contained increased proportions of 20 : 3 omega 6 and 20 : 4 omega 6, but not longer chain polyenes. The results indicate that enriching the prostaglandin precursor pool by feeding 20 : 3 omega 6 can alter the type and amount of prostaglandin released by the renal papilla, at least in vitro. Also, the selective changes in amount and long chain polyene content of renomedullary triglycerides during the study suggest some special functions for this lipid class in prostaglandin precursor metabolism.

Mont Blanc with oxygen: the first rotters.

After a brief outline of some early theories about the effects of thin air, the attempt of Joseph Ch. Hamel on Mont Blanc in 1820 is described. The Russian physician had postulated that lack of oxygen was responsible for muscular weakness at altitude and therefore had planned to study the oxygen content of air and blood on the summit and to administer oxygen to see if it improved performance. During the ascent he observed "pneumatic flatulence," shortness of breath, and fatigue. Shortly before the summit, an avalanche, which killed three of his guides, stopped and terminated the expedition. Although Hamel may have lacked the necessary equipment, he was among the first to try to test his hypothesis on altitude effects by experiments.

Enhanced cerebral blood flow in acute mountain sickness.

Mean blood flow velocity (v) of both middle cerebral arteries (MCA) was assessed by transcranial Doppler sonography (TCD) in 23 subjects at an altitude of 490 m, as well as after a rapid ascent to a high altitude research laboratory at 4559 m, and daily during a continued 72-h stay at this altitude. Relative changes of mean blood flow velocities (v) of both MCA at high altitude were expressed as percentages of low altitude values and correlated with the development of signs and symptoms of acute mountain sickness (AMS) and changes of arterial PO2, PCO2, and hemoglobin. After ascent to 4559 m, overall MCA-v (mean of all measurements obtained in each subject at high altitude) increased significantly to 148 +/- 16% of baseline values in the subjects with AMS (AMS+) and to 127 +/- 24% in the subjects without AMS (AMS-) (mean +/- SD). This v increase was higher in subjects with AMS and reached statistical significance on day 1 (+50 +/- 19%) and on day 2 (+48 +/- 23%) as compared to the healthy subjects (+27 +/- 24% and +21 +/- 26% on days 1 and 2, respectively). The rise of MCA-v correlated inversely with arterial PO2 on days 2 (r = -0.62, p < 0.005), 3 (r = -0.67, p < 0.025) and 4 (r = -0.69, p < 0.025) and from days 1 to 4 (r = -0.51, p < 0.001). MCA-v did not correlate with blood pressure, arterial PCO2 or hemoglobin. Our results suggest that subjects with AMS have a higher MCA-v increase due to a lower arterial PO2 than healthy subjects.

Assessment of acute mountain sickness by different score protocols in the Swiss Alps.

INTRODUCTION: Purpose of the present study was to evaluate the Lake Louise acute mountain sickness (AMS) score questionnaire at different altitudes and to compare it with the currently used clinical score and the environmental symptoms questionnaire AMS-C score. METHODS: We investigated 490 climbers who stayed over night at 4 huts in the Swiss Alps, located at the altitudes of 2850 m, 3050 m, 3650 m, and 4559 m. AMS was assessed using our previously described clinical score, the Lake Louise consensus AMS score questionnaire and the environmental symptoms questionnaire III. RESULTS: Below 4000 m, the prevalence of AMS, defined by symptoms that force a reduction in activity, was 7%; when assessed with the clinical score (score > or = 3) it was 22%; with the AMS-C score (score > or = 0.7) 4% and with the Lake Louise score (score > 4) 8%. At the altitude of 4559 m, the prevalence of AMS was 30%, 38%, 40%, and 39%, respectively. The standardized regression coefficients from multiple regression analysis (adjusted R2 0.65, p < 0.001) were 0.45 (p < 0.001) for the self-reported Lake Louise score, 0.48 (p < 0.001) for the sum of the points assigned in the clinical section of the Lake Louise questionnaire, and 0.05 (p = 0.27) for the AMS-C score. The sensitivity and specificity of the Lake Louise score > 4 was 78% and 93%, respectively. CONCLUSIONS: The Lake Louise consensus score is adequate and, compared with the AMS-C score, more effective for the assessment of acute altitude illness at different altitudes.

Cognitive changes at high altitude in healthy climbers and in climbers developing acute mountain sickness.

We report the cognitive functions of 17 non-acclimatized mountaineers who ascended from low lands to an altitude of 4,559 m in 24 h and were studied there within 6 h. We found that this rapid ascent to high altitude had small, but differential effects upon cognitive performance depending upon the later development of acute mountain sickness (AMS). Subjects who developed AMS within a 24-48-h stay at high altitude were mildly impaired in short term memory, but improved in conceptual tasks, while subjects who remained healthy had a better short term memory performance but no improvement in cognitive flexibility. Possible explanations for these unexpected effects of high altitude are discussed.