Toshishige Shibamoto

Dexamethasone in the Treatment of Acute Mountain Sickness

Cerebral edema occurs in fatal cases of acute mountain sickness. Dexamethasone, commonly used to treat cerebral edema due to other causes, also reduces the symptoms of acute mountain sickness when given prophylactically. However, the efficacy of dexamethasone in the treatment of established acute mountain sickness remains uncertain. To investigate this question, we exposed six men in a hypobaric chamber to a simulated altitude of 3700 m (barometric pressure, 64 kPa [481 mm Hg]) for 48 hours on two occasions. Acute mountain sickness was diagnosed with use of a symptoms questionnaire, and dexamethasone (4 mg every six hours) or placebo was then given in a randomized, double-blind, crossover fashion. Dexamethasone reduced the symptoms of acute mountain sickness by 63 percent (P less than 0.05), whereas placebo had a minimal effect (reduction by 23 percent; P not significant). In spite of this response, one subject had mild cerebral edema on brain CT after both placebo and dexamethasone. Dexamethasone had no effect on fluid shifts, oxygenation, sleep apnea, urinary catecholamine levels, the appearance of chest radiographs or perfusion scans, serum electrolyte levels, hematologic profiles, or the results of psychometric tests. Dexamethasone treatment was complicated by mild hyperglycemia in all subjects (mean [+/- SE] glucose level, 7.3 +/- 1.3 mmol per liter [132 +/- 23 mg per deciliter]). We conclude that dexamethasone effectively reduces the symptoms of acute mountain sickness. However, it did not improve objective physiologic abnormalities related to exposure to high altitudes. We therefore recommend that dexamethasone be used only when descent is impossible, or to facilitate cooperation in evacuation efforts.

Endothelin-1 selectively contracts portal vein through both ETA and ETB receptors in isolated rabbit liver.

We determined the constrictive effects of endothelin (ET)-1 on the hepatic vascular resistance distribution and the receptor subtype responsible for the effect in isolated rabbit livers perfused via the portal vein with 5% albumin-Krebs solution. The sinusoidal pressure was estimated using the double vascular occlusion pressure. The basal portal venous resistance comprised 59% of the total portal-hepatic venous resistance. In response to a bolus injection of ET-1 (0.05-5 micrograms), which led to a final concentration of 0.1-10 nM in the recirculating perfusate, the portal venous resistance increased in a dose-dependent manner, whereas the hepatic venous resistance did not change significantly at any concentration. This hepatic vasoconstriction was associated with liver weight loss. The selective portal venous constriction induced by ET-1 was confirmed in livers perfused retrogradely from the hepatic vein to the portal vein. The ET-1-induced hepatic vasoconstriction was significantly attenuated by the selective ETA receptor antagonist BQ-123 (1 microM). The ETB receptor antagonist BQ-788 (1 microM) also attenuated the constriction at ET-1 concentrations less than 10 nM. The combination of BQ-123 and BQ-788 tended to inhibit the hepatic vasoconstriction more effectively than BQ-123 alone. These results suggest that ET-1 selectively constricts the portal vein via both ETA and ETB receptors, with predominance of ETA receptor in isolated albumin-Krebs-perfused rabbit livers.We determined the constrictive effects of endothelin (ET)-1 on the hepatic vascular resistance distribution and the receptor subtype responsible for the effect in isolated rabbit livers perfused via the portal vein with 5% albumin-Krebs solution. The sinusoidal pressure was estimated using the double vascular occlusion pressure. The basal portal venous resistance comprised 59% of the total portal-hepatic venous resistance. In response to a bolus injection of ET-1 (0.05-5 μg), which led to a final concentration of 0.1-10 nM in the recirculating perfusate, the portal venous resistance increased in a dose-dependent manner, whereas the hepatic venous resistance did not change significantly at any concentration. This hepatic vasoconstriction was associated with liver weight loss. The selective portal venous constriction induced by ET-1 was confirmed in livers perfused retrogradely from the hepatic vein to the portal vein. The ET-1-induced hepatic vasoconstriction was significantly attenuated by the selective ETA receptor antagonist BQ-123 (1 μM). The ETB receptor antagonist BQ-788 (1 μM) also attenuated the constriction at ET-1 concentrations less than 10 nM. The combination of BQ-123 and BQ-788 tended to inhibit the hepatic vasoconstriction more effectively than BQ-123 alone. These results suggest that ET-1 selectively constricts the portal vein via both ETA and ETB receptors, with predominance of ETA receptor in isolated albumin-Krebs-perfused rabbit livers.

Thromboxane A2 analogue contracts predominantly the hepatic veins in isolated canine liver.

Thromboxane A2 (TxA2) is a potent vasoconstrictor and has been implicated as a mediator of liver diseases such as ischemic-reperfusion injury. We determined the effects of TxA2 and the well-known hepatic venoconstrictor histamine, on the vascular resistance distribution and liver weight in isolated canine livers perfused with blood via the portal vein. The stable TxA2 (STA2; 20 micrograms, n = 5) and histamine (5 micrograms, n = 6) similarly increased the hepatic total vascular resistance, 2.5- and 2.4-fold, respectively. The increase in the hepatic venous resistance was significantly greater than that of the portal resistance (threefold vs. 1.9-fold for STA2; threefold vs. 1.8-fold for histamine). Predominant hepatic venoconstriction induced by both agents was confirmed in livers perfused in a reverse direction from the hepatic vein to the portal vein, as shown by marked precapillary vasoconstriction. STA2 transiently increased liver weight loss (-3.6 g/100 g liver weight), followed by a gradual weight gain (9.0 g/100 g). Histamine caused a progressive weight gain (9.1 g/100 g). In conclusion, similar to histamine, TxA2 constricts predominantly the hepatic vein in isolated canine livers.

Contribution of baroreceptor reflexes to blood pressure and sympathetic responses to cholecystokinin and vasoactive intestinal peptide in anesthetized dogs.

The effects of synthetic vasoactive intestinal peptide (VIP) and cholecystokinin (CCK) on systemic blood pressure and renal nerve activity were studied before and after cervical vagotomy, and sino-aortic denervation with vagotomy in anesthetized dogs. Intravenous injection of VIP (5 micrograms/kg) in animals with an intact neuraxis produced a significant decrease in systemic blood pressure and a significant increase in renal nerve activity. These responses to VIP did not change after vagotomy and after complete denervation, VIP did not cause any change in renal nerve activity, even during hypotension. The level of hypotension after complete denervation was greater than that under other conditions. These results indicate that the cardiovascular effects of VIP are reduced by activation of the systemic baroreceptors. Intravenous injection of CCK (10 micrograms/kg) in animals with an intact neuraxis produced significant decreases in blood pressure and renal nerve activity. These responses to CCK were abolished in animals with cervical vagotomy only. However, following complete denervation of the carotid sinus and total section of the vagal nerves, CCK caused a significant increase in blood pressure and renal sympathetic nerve activity. These results indicate that the sympathetic depressor effect of CCK may be mediated by activation of the vagal afferents, and that the sympathetic pressor effect may be due to a direct action of CCK on the central nervous system. Thus, each gastrointestinal peptide may regulate the cardiovascular system through a different mechanism.

EFFECT OF ONO-5046, A SPECIFIC NEUTROPHIL ELASTASE INHIBITOR, ON THE PHORBOL MYRISTATE ACETATE-INDUCED INJURY IN ISOLATED DOG LUNG

Phorbol myristate acetate (PMA) activates neutrophils and causes acute lung injury. We determined the effect of ONO-5046, a specific neutrophil elastase inhibitor, on the increase in microvascular permeability induced by PMA in isolated dog lung perfused with autologous blood at a constant perfusion flow. The vascular permeability was assessed by the capillary filtration coefficient (Kf, c) and the solvent-drag reflection coefficient (sigma f). PMA (13.3 micrograms) increased vascular permeability, as evidenced by an increase in Kf, c from 0.18 +/- 0.02 to 0.92 +/- 0.14 mL/min/cmH2O/100 g and a decrease in sigma f to 0.35 +/- 0.01 as compared to control values of 0.69 +/- 0.06. The PMA-induced changes in Kf, c and sigma f were dose-dependently attenuated by pretreatment with ONO-5046 (2-20 mg). We conclude that ONO-5046 can effectively attenuate the PMA-induced injury in the isolated blood-perfused dog lungs.

Lecithinized superoxide dismutase attenuates phorbol myristate acetate-induced injury in isolated dog lung

Lecithinized superoxide dismutase, a lecithin derivative bound to recombinant human CuZn superoxide dismutase, has a higher affinity for cells such as polymorphonuclear leukocytes and endothelial cells than recombinant human CuZn superoxide dismutase has. We determined the protective effects of lecithinized superoxide dismutase on the increased microvascular permeability induced by phorbol myristate acetate (PMA) in isolated dog lungs. Microvascular permeability was assessed by the capillary filtration coefficient (Kf,c) and solvent drag reflection coefficient (sigma(f)). PMA (13.3 microg) increased microvascular permeability, as evidenced by an increase in Kf,c and the small sigma(f) value. Lecithinized superoxide dismutase at both low (4800 U) and high doses (48,000 U) inhibited the PMA-induced increase in Kf,c, but only the high dose of lecithinized superoxide dismutase attenuated the decrease in sigma(f). Recombinant human CuZn superoxide dismutase did not affect the PMA-induced increase in vascular permeability at either a low (4800 U) or a high dose (48,000 U). These findings suggest that lecithinized superoxide dismutase has a protective effect against oxygen radical-induced lung injury in isolated dog lungs.

rBPI23 attenuates endotoxin-induced cardiovascular depression in awake rabbits.

We determined the effect of a recombinant N-terminal fragment of bactericidal/permeability-increasing protein (rBPI23) on hemodynamic and renal sympathetic responses to lethal endotoxemia in unanesthetized rabbits. Endotoxin was continuously infused intravenously (200 micrograms/kg/h) over 120 min with simultaneous infusion of either rBPI23 (3 mg/kg bolus followed by 6 mg/kg/h over 120 min; n = 6) or thaumatin (the same dose as rBPI23), a control cationic protein with a molecular weight and isoelectric point similar to that of rBPI23 (n = 9). Tissue blood flow was also determined using colored microspheres to the left ventricle, renal cortex, liver, and skeletal muscle. Seven of nine animals treated with endotoxin and thaumatin died between 45 and 120 min after start of the infusion, whereas all animals with rBPI23 treatment were alive throughout the entire 2 h experimental period. A transient increase in renal sympathetic nerve activity was observed in the thaumatin-treated animals followed by sympathoinhibition with concomitant decreases in heart rate, blood pressure, and cardiac output. Tissue blood flow to all measured organs gradually decreased in animals receiving endotoxin and thaumatin. However, rBPI23 abolished all these deleterious responses to endotoxin. In conclusion, rBPI23 attenuates the acute lethal sympathoinhibitory and hemodynamic effects of endotoxemia in awake rabbits.

Endothelin receptor blockade attenuates air embolization-induced pulmonary hypertension in sheep

We investigated the effects of two types of endothelin receptor antagonists on pulmonary hypertension induced by pulmonary air embolization in awake sheep. We prepared awake sheep with indwelling catheters inserted in blood vessels for continuous monitoring of pulmonary artery pressure, left atrial pressure and systemic arterial pressure. Cardiac output was measured every 30 min. The study consisted of two experiments, one with FR139317 (100 microg/kg/min; (R)2-[(R)-2-[(S)-2-[1-(hexahydro-1H-azepinyl)]-carbonyl]amino-4-++ +methy l-pentanoyl]amino-3-[3-(1-methyl-1H-indolyl)]propionyl)amino-3-(2-pyr idyl)propionic acid), a selective endothelin ET(A) receptor antagonist, and the other with TAK-044 (100 microg/kg/h; cyclo[D-alpha-aspartyl-3-[(4-phenylpiperazin-yl)carbonyl]-L-alanyl -L- alpha- aspartyl-D-2-(2-thienyl) glycyl-L-leucyl-D-tryptophyl] disodium salt), an endothelin ET(A) and ET(B) receptor antagonist. In the paired experiments, air was continuously (4.06 ml/min) infused into the main pulmonary artery for 3 h after the baseline pressures were stabilized. Sheep were treated or not treated with FR139317 or TAK-044. Pulmonary artery pressure was significantly higher than the baseline pressure after the start of air infusion. Both FR139317 and TAK-044 significantly attenuated the increase in pulmonary artery pressure during air embolization. Plasma endothelin -1 levels in both pulmonary and systemic arteries were equally and significantly increased after the start of air infusion. The results indicate that endothelin-1 release is attributable to the development of pulmonary hypertension during the course of air embolization in awake sheep.

The role of endogenous nitric oxide in the sympathetic and hemodynamic response to platelet activating factor-induced hypotension in anesthetized dogs

We previously demonstrated that platelet-activating factor (PAF) when injected intravenously decreases renal sympathetic nerve activity in anesthetized dogs. Recently, nitric oxide (NO) has been shown to inhibit renal sympathetic nerve activity. The present study was designed to determine, using the NO synthase inhibitor NG-nitro-L-arginine methyl ester (L-NAME), whether endogenous NO contributes to the PAF-induced renal sympathoinhibition in anesthetized dogs. We also determined the role of NO in systemic and pulmonary hemodynamics during PAF-induced hypotension. In response to PAF (10 μg · kg−1, intravenously), renal sympathetic nerve activity showed similar responses in animals pretreated with L-NAME (n = 7; 20 mg · kg−1 bolus and .05 mg · kg−1 · min−1), D-NAME (n = 7), and phenylephrine (n = 7), as characterized by an initial increase (230%) followed by a decrease (56%). The depressor response to PAF was also similar as early as 10 min after injection in all PAF-injected groups. In contrast, L-NAME pretreatment potentiated PAF-induced pulmonary hypertension. Pulmonary arterial pressure 10 min after PAF in the L-NAME group (25 ± 2 mmHg) was significantly greater than that in the D-NAME group (12 ± 3 mmHg). In conclusion, endogenously produced NO is not involved in PAF-induced renal sympathetic nerve response or hypotension but attenuates PAF-induced pulmonary hypertension at the early stage in anesthetized dogs.

Lung lymph response to overinfusion with hydroxyethyl starch in sheep : Comparative studies of high and low molecular weight compounds

Background: Several hydroxyethyl starch (HES) solutions are available clinically. We performed comparative studies of low and high molecular weight HES to evaluate the effects on lung lymph flow in sheep, to see the difference in the types of HES.