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Omapatrilat: penetration across the blood–brain barrier and effects on ischaemic stroke in rats

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Abstract

Omapatrilat (OMA), which simultaneously inhibits the angiotensin-converting enzyme (ACE) and the neutral endopeptidase (neprilysin (NEP)), is widely used in experimental protocols related to hypertension and heart failure. The penetration of OMA across the blood–brain barrier (BBB) and the effects of ACE/NEP inhibition on the recovery from ischaemic stroke have not yet been investigated. Angiotensin (Ang) I injected intracerebroventricularly (ICV) or intravenously (IV) is converted to Ang II by ACE and induces an immediate increase in blood pressure. The pressor responses to OMA administered ICV, orally or IV were studied in male Wistar rats instrumented with an ICV and arterial and venous catheters. OMA infused ICV rapidly appeared in the systemic circulation and more effectively attenuated the systemic than the central pressor responses to Ang I. OMA administered orally (5, 25, 100 μmol/kg body weight) or IV (0.5, 1, 5, 25 μmol/kg body weight) completely abolished increases in blood pressure to IV Ang I up to 2 h after treatment. The pressor responses to ICV Ang I were not altered, indicating that systemically administered OMA does not cross the BBB. To study the effects of ACE and NEP inhibition in the brain on the recovery from ischaemic stroke, OMA was infused ICV over a 5-day period before and 24 h after the occlusion of the middle cerebral artery (MCAO) for 90 min. ICV application of OMA had no effect on infarction volume and marginally improved neurological outcome. We demonstrate for the first time that simultaneous inhibition of ACE and NEP in the brain tissue does not alter the recovery from ischaemic stroke.

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Acknowledgments

The authors would like to thank laboratory technicians Mr. Jan Brdon and Ms. B. Schwarten for the implantation of osmotic minipumps.

Compliance with Ethical Standards

This research was not supported by specific grant from any funding agency in the public, commercial or not-for-profit sectors. The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Institute of Experimental and Clinical Pharmacology, University Hospital of Schleswig-Holstein, Campus Kiel, Hospitalstrasse 4, 24105, Kiel, Germany

    Wenke Schmedt auf der Günne, Peter Gohlke & Juraj Culman

  2. Department of Nuclear Medicine, Molecular Imaging, Diagnostics and Therapy, University Hospital of Schleswig-Holstein, Campus Kiel, 24105, Kiel, Germany

    Yi Zhao

  3. Institute of Medical Informatics and Statistics, University Hospital of Schleswig-Holstein, Campus Kiel, 24105, Kiel, Germany

    Jürgen Hedderich

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  1. Wenke Schmedt auf der Günne
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  2. Yi Zhao
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Correspondence to Juraj Culman.

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Schmedt auf der Günne, W., Zhao, Y., Hedderich, J. et al. Omapatrilat: penetration across the blood–brain barrier and effects on ischaemic stroke in rats. Naunyn-Schmiedeberg's Arch Pharmacol 388, 939–951 (2015). https://doi.org/10.1007/s00210-015-1126-1

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  • DOI: https://doi.org/10.1007/s00210-015-1126-1

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