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HMR1402, a potassium ATP channel blocker during hyperdynamic porcine endotoxemia: effects on hepato-splanchnic oxygen exchange and metabolism

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Abstract

Objective

To assess the effects of the potassium ATP (KATP) channel blocker HMR1402 (HMR) on systemic and hepato-splanchnic hemodynamics, oxygen exchange and metabolism during hyperdynamic porcine endotoxemia.

Design

Prospective, randomized, controlled study with repeated measures.

Setting

Animal laboratory.

Subjects

Eighteen pigs allocated to receive endotoxin alone (control group, CON, n=10) or endotoxin and HMR (6 mg/kg h−1, n=8).

Interventions

Anesthetized, mechanically ventilated, and instrumented pigs receiving continuous i.v. endotoxin were resuscitated with hetastarch to maintain mean arterial pressure (MAP) >60 mmHg. Twelve hours after starting the endotoxin infusion, they received HMR or its vehicle for another 12 h.

Results

HMR transiently increased MAP by about 15 mmHg, but this effect was only present during the first 1 h of infusion. The HMR decreased cardiac output due to a fall in heart rate, and thereby reduced liver blood flow. While liver O2 delivery and uptake remained unchanged, HMR induced hyperlactatemia [from 1.5 (1.1; 2.0), 1.4 (1.2; 1.8), and 1.2 (0.8; 2.0) to 3.1 (1.4; 3.2), 3.2 (1.6; 6.5), and 3.0 (1.0; 5.5) mmol/l in the arterial, portal and hepatic venous samples, respectively] and further increased arterial [from 8 (3; 13) to 23 (11; 57); p<0.05], portal [from 9 (4; 14) to 23 (14; 39); p<0.05] and hepatic vein [from 7 (0; 15) to 30 (8; 174), p<0.05] lactate/pyruvate ratios indicating impaired cytosolic redox state.

Conclusion

The short-term beneficial hemodynamic effects of KATP channel blockers have to be weighted with the detrimental effect on mitochondrial respiration.

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Acknowledgements

This work was supported by the Centre Hospitalo-Universitaire, Angers, France (P. Asfar), the Deutscher Akademische Austischdienst (Z. Iványi), the Alexander-von-Humboldt-Stiftung (D. Vassilev), the European Society of Intensive Care Medicine (B. Hauser), the Boehringer Ingelheim Fonds (M. Nalos), and Aventis Pharma. HMR1402 was kindly provided by K. Wirth (Aventis Pharma, Germany). We are indebted to W. Siegler, T. Schulz, U. Ehrmann, A. Derr, and M. Miersch for skillful technical assistance.

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Author notes

  1. Pierre Asfar

    Present address: Service de Réanimation Médicale, CHU, 49000, Angers, France

  2. Zsolt Iványi

    Present address: Semmelweis University Department of Anesthesia and Intensive Therapy, Kútvölgyi, Budapest, Hungary

  3. Marek Nalos

    Present address: Anesteziologicko resuscitacni klinika, Karlova Universita, Plzeň, Czech Republic

Authors and Affiliations

  1. Sektion Anästhesiologische Pathophysiologie und Verfahrensentwicklung, Parkstrasse 11, 89073, Ulm, Germany

    Pierre Asfar, Zsolt Iványi, Hendrik Bracht, Balázs Hauser, Antje Pittner, Damian Vassilev, Damian Vassilev, Marek Nalos, Peter Radermacher & Gebhard Fröba

  2. Sektion Chirurgische Forschung, Universitätsklinikum, Ulm, Germany

    Uwe Bernd Brückner

  3. Laboratoire de Bioénergétique Fondamentale et Appliquée, Université Joseph Fourier, Grenoble, France

    Xavier Maurice Leverve

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  1. Pierre Asfar
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Corresponding author

Correspondence to Peter Radermacher.

Additional information

P. Asfar and Z. Iványi equally contributed to this work

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Asfar, P., Iványi, Z., Bracht, H. et al. HMR1402, a potassium ATP channel blocker during hyperdynamic porcine endotoxemia: effects on hepato-splanchnic oxygen exchange and metabolism. Intensive Care Med 30, 957–964 (2004). https://doi.org/10.1007/s00134-004-2258-9

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