gms | German Medical Science

63rd Annual Meeting of the German Society of Neurosurgery (DGNC)
Joint Meeting with the Japanese Neurosurgical Society (JNS)

German Society of Neurosurgery (DGNC)

13 - 16 June 2012, Leipzig

Reversal of cortical spreading ischemia induced vasoconstriction of isolated rat MCA by T-type Ca2+ channel inhibition

Meeting Abstract

  • U. Lindauer - Experimentelle Neurochirurgie und Neurochirurgische Klinik und Poliklinik, Klinikum rechts der Isar, Technische Universität München
  • H. Baumgärtner - Experimentelle Neurochirurgie und Neurochirurgische Klinik und Poliklinik, Klinikum rechts der Isar, Technische Universität München
  • M. Schreiber - Experimentelle Neurochirurgie und Neurochirurgische Klinik und Poliklinik, Klinikum rechts der Isar, Technische Universität München
  • S. Pinkernell - Experimentelle Neurochirurgie und Neurochirurgische Klinik und Poliklinik, Klinikum rechts der Isar, Technische Universität München
  • B. Meyer - Experimentelle Neurochirurgie und Neurochirurgische Klinik und Poliklinik, Klinikum rechts der Isar, Technische Universität München

Deutsche Gesellschaft für Neurochirurgie. Japanische Gesellschaft für Neurochirurgie. 63. Jahrestagung der Deutschen Gesellschaft für Neurochirurgie (DGNC), Joint Meeting mit der Japanischen Gesellschaft für Neurochirurgie (JNS). Leipzig, 13.-16.06.2012. Düsseldorf: German Medical Science GMS Publishing House; 2012. DocDO.01.01

doi: 10.3205/12dgnc018, urn:nbn:de:0183-12dgnc0185

Published: June 4, 2012

© 2012 Lindauer et al.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by-nc-nd/3.0/deed.en). You are free: to Share – to copy, distribute and transmit the work, provided the original author and source are credited.


Outline

Text

Objective: During nitric oxide synthase (NOS) inhibition, cortical spreading depolarisation (CSD) can induce severe vasoconstriction (cortical spreading ischemia, CSI) [1]. CSI can be modeled in the isolated middle cerebral artery (MCA) by application of combined extraluminal ion changes according to changes of the extracellular milieu during CSI [2]. The CSI-associated vasoconstriction can be reverted to vasodilation by L-type Ca2+ channel inhibition with nimodipine. It has recently been shown that dihydropyridine-insensitive calcium currents contribute to cerebrovascular reactivity [3]. We therefore evaluated whether T-type Ca2+ channel inhibition is capable of reverting CSI-related vasoconstriction to vasodilation.

Methods: Rats were anesthetized and decapitated. The MCA was dissected, cannulated and pressurized. Vascular reactivity to CSI induced ion changes was tested under baseline conditions and under NOS inhibition, followed by L-type channel inhibition with nimodipine or by T-type channel inhibition by mibefradil during sustained NOS inhibition.

Results: In response to CSI cocktail the arteries significantly dilated from 75 ± 12 μm to 89 ± 17 μm. During NOS inhibition by L-NNA, CSI cocktail induced vasoconstriction from 54 ± 9 μm to 46 ± 7 μm, and application of the L-type channel antagonist nimodipine (10-7 M) as well as the T-type channel inhibitor mibefradil (10-8 M) reestablished vasodilation to CSI cocktail (nimodipine: baseline: 62 ± 15 μm, CSI cocktail: 72 ± 16 μm; mibefradil: baseline: 95 ± 12 μm, CSI cocktail: 113 ± 11 μm).

Conclusions: Compared with L-type channel inhibition, T-type channel inhibition is equally capable of reverting CSI-related vasoconstriction during NOS inhibition to vasodilation. In animal models of subarachnoid hemorrhage, expression of L-type channels has been shown to be reduced, whereas T-type channels are upregulated [4]. Because T-type channels have a larger role in smaller vessels [3], it has to be further evaluated whether combined block of T and L-type channels may represent an effective approach not only to reverse cerebral vasospasm of larger vessels but also CSD induced ischemic events within the microcirculation [5].


References

1.
Dreier JP, Körner K, Ebert N, Görner A, Rubin I, Back T, Lindauer U, Wolf T, Villringer A, Einhäupl KM, Lauritzen M, Dirnagl U. Nitric oxide scavenging by hemoglobin or nitric oxide synthase inhibition by N-nitro-L-arginine induces cortical spreading ischemia when K+ is increased in the subarachnoid space. J Cereb Blood Flow Metab. 1998 Sep;18(9):978-90. DOI: 10.1097/00004647-199809000-00007 External link
2.
Windmüller O, Lindauer U, Foddis M, Einhäupl KM, Dirnagl U, Heinemann U, Dreier JP. Ion changes in spreading ischaemia induce rat middle cerebral artery constriction in the absence of NO. Brain. 2005 Sep;128(Pt 9):2042-51. DOI: 10.1093/brain/awh545 External link
3.
Kuo IY, Ellis A, Seymour VA, Sandow SL, Hill CE. Dihydropyridine-insensitive calcium currents contribute to function of small cerebral arteries. J Cereb Blood Flow Metab. 2010 Jun;30(6):1226-39. DOI: 10.1038/jcbfm.2010.11 External link
4.
Kuo IY, Wölfle SE, Hill CE. T-type calcium channels and vascular function: the new kid on the block? J Physiol. 2011 Feb 15;589(Pt 4):783-95. DOI: 10.1113/jphysiol.2010.199497 External link
5.
Lauritzen M, Dreier JP, Fabricius M, Hartings JA, Graf R, Strong AJ. Clinical relevance of cortical spreading depression in neurological disorders: migraine, malignant stroke, subarachnoid and intracranial hemorrhage, and traumatic brain injury. J Cereb Blood Flow Metab. 2011 Jan;31(1):17-35. DOI: 10.1038/jcbfm.2010.191 External link