Acetazolamide 125 mg BD is not significantly different from 375 mg BD in the prevention of acute mountain sickness: the prophylactic acetazolamide dosage comparison for efficacy (PACE) trial.

750 mg per day of acetazolamide in the prevention of acute mountain sickness (AMS), as recommended in the meta-analysis published in 2000 in the British Medical Journal, may be excessive and is controversial. To determine if the efficacy of low-dose acetazolamide 125 mg bd (250 mg), as currently used in the Himalayas, is significantly different from 375 mg bd (750 mg) of acetazolamide in the prevention of AMS, we designed a prospective, double-blind, randomized, placebo-controlled trial. The participants were sampled from a diverse population of (non-Nepali) trekkers at Namche Bazaar (3440 m) in Nepal on the Everest trekking route as they ascended to study midpoints (4280 m/4358 m) and the endpoint, Lobuje (4928 m), where data were collected.

Mutagenesis of basic residues R151 and R161 in manganese-stabilizing protein of photosystem II causes inefficient binding of chloride to the oxygen-evolving complex.

Manganese-stabilizing protein of photosystem II, an intrinsically disordered polypeptide, contains a high ratio of charged to hydrophobic amino acid residues. Arg151 and Arg161 are conserved in all known MSP sequences. To examine the role of these basic residues in MSP structure and function, three mutants of spinach MSP, R151G, R151D, and R161G, were produced.

Carbonic anhydrase inhibitors and hypoxic pulmonary vasoconstriction.

Acetazolamide and other related carbonic anhydrase (CA) inhibitors have had a long history of effectiveness in prevention and treatment of acute mountain sickness (AMS) and remain the standard of care for this indication. Despite many decades of CA inhibitor use for AMS, the possibility has never been seriously entertained that these drugs might also afford protection against high altitude pulmonary edema (HAPE). In this paper, I will present our evidence and supporting data of others, that acetazolamide has inhibitory effects on the hypoxic response of the pulmonary circulation that may be useful in HAPE.

Hypercapnic acidosis and mortality in acute lung injury.

Objective: We tested the hypothesis that hypercapnic acidosis is associated with reduced mortality rate in patients with acute lung injury independent of changes in mechanical ventilation.

Design: Secondary analysis of randomized clinical trial data using hypothesis-driven multivariate logistic regression.

Setting: Randomized, multiple-center trial (n = 861) comparing 12 mL/kg to 6 mL/kg predicted body weight tidal volumes previously published by the National Institutes of Health Acute Respiratory Distress Syndrome (ARDS) Network.

An investigation of the role of carbonic anhydrase in aquatic and aerial gas transfer in the African lungfish Protopterus dolloi.

Experiments were performed on bimodally breathing African lungfish Protopterus dolloi to examine the effects of inhibition of extracellular vs total (extracellular and intracellular) carbonic anhydrase (CA) activity on pulmonary and branchial/cutaneous gas transfer. In contrast to previous studies on Protopterus, which showed that the vast majority of CO(2) is excreted into the water through the gill and/or skin whereas O(2) uptake largely occurs via the lung, P. dolloi appeared to use the lung for the bulk of both O(2) uptake (91.

Smad2 and Smad3 play different roles in rat hepatic stellate cell function and alpha-smooth muscle actin organization.

Hepatic stellate cells (HSC) play a central role in the pathogenesis of liver fibrosis, transdifferentiating in chronic liver disease from "quiescent" HSC to fibrogenic myofibroblasts. Transforming growth factor-beta (TGF-beta), acting both directly and indirectly, is a critical mediator of this process. To characterize the function of the TGF-beta signaling intermediates Smad2 and Smad3 in HSC, we infected primary rat HSC in culture with adenoviruses expressing wild-type and dominant negative Smads 2 and 3.

Physiological aspects of high-altitude pulmonary edema.

High-altitude pulmonary edema (HAPE) develops in rapidly ascending nonacclimatized healthy individuals at altitudes above 3,000 m. An excessive rise in pulmonary artery pressure (PAP) preceding edema formation is the crucial pathophysiological factor because drugs that lower PAP prevent HAPE. Measurements of nitric oxide (NO) in exhaled air, of nitrites and nitrates in bronchoalveolar lavage (BAL) fluid, and forearm NO-dependent endothelial function all point to a reduced NO availability in hypoxia as a major cause of the excessive hypoxic PAP rise in HAPE-susceptible individuals.

Nitric oxide (NO) in normal and hypoxic vascular regulation of the spiny dogfish, Squalus acanthias.

Nitric oxide (NO) is a potent vasodilator in terrestrial vertebrates, but whether vascular endothelial-derived NO plays a role in vascular regulation in fish remains controversial. To explore this issue, a study was made of spiny dogfish sharks (Squalus acanthias) in normoxia and acute hypoxia (60 min exposure to seawater equilibrated with 3% oxygen) with various agents known to alter NO metabolism or availability. In normoxia, nitroprusside (a NO donor) reduced blood pressure by 20%, establishing that vascular smooth muscle responds to NO.

HCO3- secretion in the esophageal submucosal glands.

The mammalian esophagus has the capacity to secrete a HCO(3)(-) and mucin-rich fluid in the esophageal lumen. These secretions originate from the submucosal glands (SMG) and can contribute to esophageal protection against refluxed gastric acid. The cellular mechanisms by which glandular cells achieve these secretions are largely unknown.

Summer hypoxia in the northern Gulf of Mexico and its prediction from 1978 to 1995.

An 18-year monitoring record (1978-1995) of dissolved oxygen within a region having hypoxia (dissolved oxygen less than 2 mgl(-1)) in the bottom layer was examined to describe seasonal and annual trends. The monitoring location was near or within a well-described summer hypoxic zone whose size has been up to 20,000 km(2). The monitoring data were used to hindcast the size of the hypoxic zone for before consistent shelfwide surveys started, and to predict it for 1989, when a complete shelfwide survey was not made.

Pulmonary vascular effects of red blood cells containing S-nitrosated hemoglobin.

The role of S-nitrosated hemoglobin (SNO-Hb) in the regulation of blood flow is a central and controversial question in cardiopulmonary physiology. In the present study, we investigate whether intact human red blood cells (RBCs) synthesized to contain high SNO-Hb levels are able to export nitric oxide bioactivity and vasodilate the pulmonary circulation, and whether SNO-Hb dependent vasodilation occurs secondary to an intrinsic oxygen-linked, allosteric function of Hb. RBCs containing supraphysiological concentrations (100-1,000x normal) of SNO-Hb (SNO-RBCs) were synthesized and added to isolated, perfused rat lungs during anoxic or normoxic ventilation, and during normoxic ventilation with pulmonary hypertension induced by the thromboxane mimetic U-46619.

Carbonic anhydrase in mammalian vascular smooth muscle.

Carbonic anhydrase (CA) is ubiquitously expressed and plays a pivotal role in acid-base balance, ion transport, and gas exchange. Limited observations by others, derived from functional, pharmacological, and histochemical studies, suggest that CA is present in vascular smooth muscle and is involved in vasoregulation. The present study, using measurements of bioactivity, inhibition characteristics, and immunohistochemical analysis, was undertaken to more fully evaluate CA in vascular smooth muscle.

Acetazolamide prevents hypoxic pulmonary vasoconstriction in conscious dogs.

Acute hypoxia increases pulmonary arterial pressure and vascular resistance. Previous studies in isolated smooth muscle and perfused lungs have shown that carbonic anhydrase (CA) inhibition reduces the speed and magnitude of hypoxic pulmonary vasoconstriction (HPV). We studied whether CA inhibition by acetazolamide (Acz) is able to prevent HPV in the unanesthetized animal.

Hemorrhage during isoflurane-nitrous oxide anesthesia: effects of endothelin-A or angiotensin II receptor blockade or both.

Background: The objective of this study was to determine whether endothelin-A receptor blockade (ETAB) impairs hemodynamic and hormonal regulation compared with controls and angiotensin II receptor blockade (AT1B) during hypotensive hemorrhage in dogs under isoflurane-nitrous oxide anesthesia.

Methods: Six dogs were studied in four protocols: (1) control experiments (controls); (2) ETA blockade using ABT-627 (ETAB); (3) AT1 blockade using losartan (AT1B); and (4) combined AT1B and ETAB (AT1B + ETAB). After a 30-min awake period, isoflurane-nitrous oxide anesthesia was established (1.

Increased oxidative stress following acute and chronic high altitude exposure.

The generation of reactive oxygen species is typically associated with hyperoxia and ischemia reperfusion. Recent evidence has suggested that increased oxidative stress may occur with hypoxia. We hypothesized that oxidative stress would be increased in subjects exposed to high altitude hypoxia.

A dose-response study of acetazolamide for acute mountain sickness prophylaxis in vacationing tourists at 12,000 feet (3630 m).

The study objective was to determine whether acetazolamide is effective in prophylaxis of acute mountain sickness (AMS) at moderate altitude in ambulatory travelers not undergoing vigorous exercise. Volunteers vacationing in La Paz, Bolivia (3630 m), immediately after arrival from sea level were studied. The design was a double-blind, randomized trial of two doses of acetazolamide (125 mg twice daily, 250 mg twice daily) versus placebo twice daily over a 24-h period.

Inhibitors of hypoxic pulmonary vasoconstriction prevent high-altitude pulmonary edema in rats.

Objective: Rapid ascent to high altitude causes hypoxic pulmonary vasoconstriction (HPV) and leads to high-altitude pulmonary edema (HAPE) in susceptible humans. Vasodilating agents lessen HAPE (as evidenced by radiographic and gas exchange measurements), but data establishing their effectiveness on alveolar protein content and hemorrhage are lacking. This study was designed to assess whether preventing HPV reduces the alveolar-capillary barrier leak characteristic of HAPE.

Carbon dioxide added late in inspiration reduces ventilation-perfusion heterogeneity without causing respiratory acidosis.

We have shown previously that inspired CO2 (3-5%) improves ventilation-perfusion (Va/Q) matching but with the consequence of mild arterial hypercapnia and respiratory acidosis. We hypothesized that adding CO2 only late in inspiration to limit its effects to the conducting airways would enhance Va/Q matching and improve oxygenation without arterial hypercapnia. CO2 was added in the latter half of inspiration in a volume aimed to reach a concentration of 5% in the conducting airways throughout the respiratory cycle.

Altered ion transporter expression in bronchial epithelium in mountaineers with high-altitude pulmonary edema.

Hypoxia inhibits activity and expression of transport proteins of cultured lung alveolar epithelial cells. Here we tested whether hypoxia at high altitude affected the expression of ion transport proteins in tissues obtained from controls and mountaineers with high-altitude pulmonary edema (HAPE) at the Capanna Margherita (4,559 m). Expression was determined by RT-PCR and Western blots from brush biopsies of bronchial epithelium and from leukocytes obtained before and during the stay at high altitude.

A comparative approach to carbonic anhydrase: the work of Thomas H. Maren.

Thomas H. Maren studied carbonic anhydrase (CA) for half a century, venturing into all aspects of this powerful enzyme from active site chemistry to clinical medicine. He was a keen proponent of comparative physiology to illuminate basic principles of the chemistry and biology of CA and spent 47 summers at the Mt.

High altitude pulmonary oedema.

Altitude, speed and mode of ascent and, above all, individual susceptibility are the most important determinants for the occurrence of high altitude pulmonary oedema (HAPE). This illness usually develops only within the first 2-5 days after acute exposure to altitudes above 2500-3000 m. An excessive rise in pulmonary artery pressure preceding oedema formation is the crucial pathophysiological factor.