Marc M. Berger

Hypoxia induces late preconditioning in the rat heart in vivo.

Background:Although hypoxic late preconditioning (LPC) limits ischemia-reperfusion injury in vitro, its cardioprotective effect is not established in vivo. Methods:In part 1, rats were exposed to 4 h of hypoxia (16%, 12%, 8% oxygen) before 24 h of reoxygenation. In part 2, normoxic rats received early preconditioning with sevoflurane (1 minimum alveolar concentration [MAC] for 3 × 5 min), continuous administration of 1 MAC sevoflurane, or 11 mg · kg · h propofol. Thereafter, all rats underwent 25 min of regional myocardial ischemia and 120 min of reperfusion. After reperfusion, hearts were excised for infarct staining. The expression of protein kinase C (PKC)&agr; and PKC&egr; was assessed by Western blot analysis and the expression of heme oxygenase-1 and vascular endothelial growth factor by reverse transcriptase polymerase chain reaction. Results:In normoxic control rats, infarct size was 62 ± 6% of the area at risk. Hypoxic LPC reduced infarct size (LPC16: 36 ± 11%, LPC12: 38 ± 10%, LPC8: 39 ± 11%; each P < 0.001) to approximately the same magnitude as sevoflurane-preconditioning (40 ± 8%; P < 0.001). Combined LPC16 and sevoflurane preconditioning was not superior to either substance alone. Continuous sevoflurane or propofol was not protective. The PKC inhibitor calphostin C abolished the cardioprotective effects of LPC16. PKC&egr;, but not PKC&agr;, expression was increased 6 and 28 h after hypoxic LPC. Heme oxygenase-1 and vascular endothelial growth factor were transiently up-regulated after 6 h. Conclusion:Hypoxic LPC at 8%, 12%, and 16% oxygen reduces infarct size in the rat heart in vivo. This effect is as powerful as sevoflurane-preconditioning. PKC&egr; is a key player in mediating hypoxic LPC.

Inhaled budesonide does not prevent acute mountain sickness after rapid ascent to 4559 m

Recent studies showed that inhaled budesonide (200u2005µg twice per day) reduced the incidence of acute mountain sickness (AMS) after passive ascent to 3700 and 3900u2005m [1, 2]. These findings raised the possibility that mediators released from the hypoxic lung transmit signals to the brain which contribute to the cerebral processes leading to AMS [3]. Because neither of these studies reflect alpine-style climbing, the present study was performed to test whether inhalation of budesonide at two different doses (200 and 800u2005µg twice per day) prior to active and rapid ascent (<20u2005h) to 4559u2005m prevents AMS in this high-risk setting. Prophylactic inhalation of budesonide does not prevent acute mountain sickness after rapid ascent to high-altitude http://ow.ly/Bc9p30dOz46

Changes in acid-base and ion balance during exercise in normoxia and normobaric hypoxia.

PurposeBoth exercise and hypoxia cause complex changes in acid–base homeostasis. The aim of the present study was to investigate whether during intense physical exercise in normoxia and hypoxia, the modified physicochemical approach offers a better understanding of the changes in acid–base homeostasis than the traditional Henderson–Hasselbalch approach.MethodsIn this prospective, randomized, crossover trial, 19 healthy males completed an exercise test until voluntary fatigue on a bicycle ergometer on two different study days, once during normoxia and once during normobaric hypoxia (12% oxygen, equivalent to an altitude of 4500xa0m). Arterial blood gases were sampled during and after the exercise test and analysed according to the modified physicochemical and Henderson–Hasselbalch approach, respectively.ResultsPeak power output decreased from 287u2009±u20099 Watts in normoxia to 213u2009±u20096 Watts in hypoxia (−26%, Pu2009<u20090.001). Exercise decreased arterial pH to 7.21u2009±u20090.01 and 7.27u2009±u20090.02 (Pu2009<u20090.001) during normoxia and hypoxia, respectively, and increased plasma lactate to 16.8u2009±u20090.8 and 17.5u2009±u20090.9xa0mmol/l (Pu2009<u20090.001). While the Henderson–Hasselbalch approach identified lactate as main factor responsible for the non-respiratory acidosis, the modified physicochemical approach additionally identified strong ions (i.e. plasma electrolytes, organic acid ions) and non-volatile weak acids (i.e. albumin, phosphate ion species) as important contributors.ConclusionsThe Henderson–Hasselbalch approach might serve as basis for screening acid–base disturbances, but the modified physicochemical approach offers more detailed insights into the complex changes in acid–base status during exercise in normoxia and hypoxia, respectively.

Reliability of echocardiographic speckle-tracking derived bi-atrial strain assessment under different hemodynamic conditions

The aim of this study was to assess intra- and inter-observer variability of left (LA) and right atrial (RA) strain indices obtained by two-dimensional speckle-tracking echocardiography (2D-STE) in a healthy group of individuals at low-altitude and after rapid ascent to high-altitude in order to provoke altered systemic and pulmonary hemodynamics otherwise seen in various cardiac diseases. Twenty healthy subjects underwent transthoracic echocardiography during a baseline examination at low-altitude (424xa0m) as well as 7, 20 and 44 h after arrival at high-altitude (4559xa0m). Atrial strain indices (i.e. reservoir, conduit and contractile strain) were determined off-line by two independent observers. Intra- and inter-observer reproducibility of variables was assessed by intra-class correlation coefficients (ICCs), coefficients of variation and Bland Altman plots. Heart rate, systemic blood pressure and pulmonary artery pressure increased significantly from low-altitude to the first examination at high-altitude. Intra-observer ICCs were ≥0.90 except for RA conduit strain with an ICC of 0.86. The mean intra-observer differences were small and limits of agreement of relative differences were narrow for all atrial strain parameters (<3 and <16%, respectively). Inter-observer ICCs (0.80–0.90), mean biases and limits of agreement (<4 and <20%, respectively) were greater than intra-observer results for all parameters. Intra- and inter-obserer ICCs for all atrial strain variables did not differ between low- and high-altitude. 2D-STE-derived bi-atrial strain indices have excellent intra- and moderate inter-observer reproducibility with no effect of high-altitude-induced hemodynamic changes on reliability results.

Intravenous S-ketamine does not inhibit alveolar fluid clearance in a septic rat model.

We previously demonstrated that intratracheally administered S-ketamine inhibits alveolar fluid clearance (AFC), whereas an intravenous (IV) bolus injection had no effect. The aim of the present study was to characterize whether continuous IV infusion of S-ketamine, yielding clinically relevant plasma concentrations, inhibits AFC and whether its effect is enhanced in acute lung injury (ALI) which might favor the appearance of IV S-ketamine at the alveolar surface. AFC was measured in fluid-instilled rat lungs. S-ketamine was administered IV over 6 h (loading dose: 20 mg/kg, followed by 20 mg/kg/h), or intratracheally by addition to the instillate (75 µg/ml). ALI was induced by IV lipopolysaccharide (LPS; 7 mg/kg). Interleukin (IL)-6 and cytokine-induced neutrophil chemoattractant (CINC)-3 were measured by ELISA in plasma and bronchoalveolar lavage fluid. Isolated rat alveolar type-II cells were exposed to S-ketamine (75 µg/ml) and/or LPS (1 mg/ml) for 6 h, and transepithelial ion transport was measured as short circuit current (ISC). AFC was 27±5% (mean±SD) over 60 min in control rats and was unaffected by IV S-ketamine. Tracheal S-ketamine reduced AFC to 18±9%. In LPS-treated rats, AFC decreased to 16±6%. This effect was not enhanced by IV S-ketamine. LPS increased IL-6 and CINC-3 in plasma and bronchoalveolar lavage fluid. In alveolar type-II cells, S-ketamine reduced ISC by 37% via a decrease in amiloride-inhibitable sodium transport. Continuous administration of IV S-ketamine does not affect rat AFC even in endotoxin-induced ALI. Tracheal application with direct exposure of alveolar epithelial cells to S-ketamine decreases AFC by inhibition of amiloride-inhibitable sodium transport.

Who Gets High Altitude Pulmonary Edema And Why

This paper focuses on high altitude pulmonary edema (HAPE) that occurs in individuals who are free of any pre-existing disease. An exaggerated hypoxic pulmonary vasoconstriction (HPV) is a hallmark of susceptibility to HAPE. In addition, a low hypoxic ventilatory response and defective sodium-dependent absorption of water from the alveoli may contribute to HAPE-susceptibility. However, excessive pulmonary artery hypertension appears to be crucial for the development of HAPE, since lowering pulmonary artery pressure by drugs, such as nifedipine or tadalafil (phospho-diesterase-5-inhibitor), will in most cases prevent HAPE. There is increasing evidence that the excessive pulmonary artery pressure response in HAPE-susceptible individuals is due to a reduced NO bioavailability. HAPE-susceptible individuals show an endothelial dysfunc- tion in the systemic circulation in hypoxia. Lower levels of exhaled NO in hypoxia before and during HAPE in susceptible individuals suggest that this abnormality also occurs in the lungs and polymorphisms of the eNOS gene are associated with susceptibility to HAPE in the Indian and Japanese population.

Acid–base balance during muscular exercise: response to Dr. Böning and Dr. Maassen

We appreciate the interest of Böning and Maassen in our article on exercise and acid–base homeostasis previously published in this journal (Lühker et al. 2017). In their comment, the authors postulate that the Henderson–Hasselbalch approach is more appropriate than Stewart’s approach to acid–base balance and pH regulation. The long-lasting controversy about the superiority of the one compared to the other approach has yielded a bulk of literature and pro-con debates including distinguished researchers and clinicians. Currently, there is no clear evidence which of the ‘modern’ approaches, the Stewart approach or the bicarbonate-centred Henderson–Hasselbalch approach, is the most suitable under all circumstances. One criticism regarding the Henderson–Hasselbalch approach is that it depends solely on bicarbonate (HCO3), carbon dioxide (CO2), and the respective dissociation constant. The Stewart approach considers this relationship as important contributor to acid–base balance but expands this description to a total of six physicochemical equations. As addressed by Böning and Maassen, the Henderson–Hasselbalch equation is derived from a chemical equation. We agree that this equation sufficiently describes acid–base changes under a variety of clinical and experimental circumstances. However, the validity of an equation depends on the given situation, and for many acid–base phenomena, the Stewart approach appears to provide deeper insights than the bicarbonate-centred approaches (Story 2004). Our study (Lühker et al. 2017) suggests that exercise during normoxia and hypoxia is one of these phenomena. One major ingredient of the human body is water. Therefore, virtually, all processes take place in an aqueous solution and the dissociation of water is a central element of Stewart’s approach. Water is the almost infinite source of hydrogen ions, whose concentrations define the actual acid–base condition. Böning and Maassen postulate that changes of strong ions cannot be causative for changes in acid–base balance during exercise but rather mirror them in one compartment, while the opposite may happen in the neighbouring one. During exercise, there are, in fact, multiple and simultaneously occurring chemical, physical, and physiological reactions of which ion shifts are an essential part. The assumption that these ion shifts only mirror changes in acid–base homeostasis without affecting other ongoing processes is probably too simplistic. Because both strong and weak ions, as well as CO2, affect the dissociation of water, a change in any of these variables ultimately leads to a change in hydrogen ions and hydroxyl ions (Lindinger and Heigenhauser 2008). The ion movements during exercise follow the laws of mass conservation, mass action, and electroneutrality in an aqueous milieu. Because different compartments are separated by membranes with different permeability coefficients for anions and cations, changes in the strong ion difference (SID) in one compartment are inevitably linked to opposite changes in the adjacent compartment. Böning and Maassen raised the interesting question whether there are also other acids than lactic acid contributing to the exercise-induced acidosis. Indeed, our own results Communicated by Editors-in-Chief Westerterp/Westerblad.

Milrinone-Induced Postconditioning Requires Activation of Mitochondrial Ca2+-sensitive Potassium (mBKCa) Channels

OBJECTIVESnCardioprotection by postconditioning requires activation of mitochondrial large-conductance Ca2+-sensitive potassium (mBKCa) channels. The involvement of these channels in milrinone-induced postconditioning is unknown. The authors determined whether cardioprotection by milrinone-induced postconditioning involves activation of mBKCa channels in the rat heart in vitro.nnnDESIGNnRandomized, prospective, blinded laboratory investigation.nnnSETTINGnExperimental laboratory.nnnPARTICIPANTSnMale Wistar rats.nnnINTERVENTIONSnHearts of male Wistar rats were randomized, placed on a Langendorff system, and perfused with Krebs-Henseleit buffer at a constant pressure of 80 mmHg. All hearts were subjected to 33 minutes of global ischemia and 60 minutes of reperfusion. At the onset of reperfusion, hearts were perfused with different concentrations of milrinone (0.3-100 μM) for determination of a dose-effect curve. In a second set of experiments, 3 μM milrinone was administered in combination with the mBKCa channel inhibitor paxilline (1 μM). Infarct size was determined by triphenyltetrazoliumchloride staining.nnnMEASUREMENTS AND MAIN RESULTSnIn control animals, infarct size was 37 ± 7%. Milrinone at a concentration of 3 μM reduced infarct size to 22 ± 7% (p < 0.05 v control). Higher milrinone concentrations did not confer stronger protection. Paxilline completely blocked milrinone-induced cardioprotection whereas paxilline alone had no effect on infarct size.nnnCONCLUSIONSnThis study shows that activation of mBKCa channels plays a pivotal role in milrinone-induced postconditioning.