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Vasoconstrictor effects in spinal cord of the substance P antagonist [D-Arg, D-Trp7,9 Leu11]-substance P (Spantide) and somatostatin and interaction with thyrotropin releasing hormone

Freedman, J; Post, C; Kåhrström, J; Öhlen, A; Mollenholt, P; Owman, Christer LU ; Alari, L and Hökfelt, T (1988) In Neuroscience 27(1). p.267-278
Abstract
The present study was undertaken to investigate the possible effects of Spantide [D-Arg1, D-Trp7,9 Leu11]-substance P, a substance P antagonist, and of somatostatin on spinal cord blood flow. The experiments were performed with the laser-doppler technique on the L1 spinal cord segment exposed by laminectomy. The effect of Spantide was also studied in the rat with the [14C]iodoantipyrine technique. In addition, experiments were performed on rabbit skeletal muscle in vivo after administration of Spantide to the local vasculature. In the experiments on spinal cord, approximately the same doses were employed as those earlier shown to be "neurotoxic". When the vehicle alone (0.9% saline) was administered intrathecally, a slight decrease of... (More)
The present study was undertaken to investigate the possible effects of Spantide [D-Arg1, D-Trp7,9 Leu11]-substance P, a substance P antagonist, and of somatostatin on spinal cord blood flow. The experiments were performed with the laser-doppler technique on the L1 spinal cord segment exposed by laminectomy. The effect of Spantide was also studied in the rat with the [14C]iodoantipyrine technique. In addition, experiments were performed on rabbit skeletal muscle in vivo after administration of Spantide to the local vasculature. In the experiments on spinal cord, approximately the same doses were employed as those earlier shown to be "neurotoxic". When the vehicle alone (0.9% saline) was administered intrathecally, a slight decrease of brief duration was noted in the blood flow. Spantide, however, caused a dose-dependent decrease, where 2 micrograms caused an immediate drop of the blood flow to approx. 20% of its normal value. A total circulatory arrest was found in several animals. In most cases, the flow was gradually normalized, whereas the effect persisted for up to 60 min in others. Virtually the same effect was exerted by somatostatin. The experiments using the iodoantipyrine technique confirmed the effect of Spantide. Here, the high resolution of this method showed that the gray matter was affected preferentially, with a complete ischemic state or a drastically reduced flow in 4 out of 5 animals 10 min after 2 micrograms of Spantide; one animal was unaffected, and this animal did not show any signs of motor impairment. The vasoconstriction of Spantide was not affected by simultaneous injections with substance P. However, after i.v. pretreatment with thyrotropin-releasing hormone, at a dose that previously has been reported to be protective against the neurodegenerative effects of Spantide, blood flow was markedly increased as compared to Spantide alone. Results from the experiments using intravital microscopy flow studies in the rabbit tenuissimus muscle revealed that Spantide at the doses used had no vasoconstrictor effect in the skeletal muscle of this species. The results suggest that previous demonstrations of motor impairment and "neurotoxic" actions of intrathecally injected substance P antagonists and somatostatin may be related to a marked decrease in spinal cord blood flow. Counteraction of the effect of Spantide by thyrotropin-releasing hormone may be explained by its effect to increase blood flow. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Neuroscience
volume
27
issue
1
pages
267 - 278
publisher
Elsevier
external identifiers
  • pmid:2462190
  • scopus:0023804118
ISSN
1873-7544
DOI
10.1016/0306-4522(88)90236-9
language
English
LU publication?
yes
id
fc56c4dc-6ffd-479d-aa34-38df198d4bc7 (old id 1104443)
date added to LUP
2008-08-08 11:14:47
date last changed
2017-07-30 03:33:32
@article{fc56c4dc-6ffd-479d-aa34-38df198d4bc7,
  abstract     = {The present study was undertaken to investigate the possible effects of Spantide [D-Arg1, D-Trp7,9 Leu11]-substance P, a substance P antagonist, and of somatostatin on spinal cord blood flow. The experiments were performed with the laser-doppler technique on the L1 spinal cord segment exposed by laminectomy. The effect of Spantide was also studied in the rat with the [14C]iodoantipyrine technique. In addition, experiments were performed on rabbit skeletal muscle in vivo after administration of Spantide to the local vasculature. In the experiments on spinal cord, approximately the same doses were employed as those earlier shown to be "neurotoxic". When the vehicle alone (0.9% saline) was administered intrathecally, a slight decrease of brief duration was noted in the blood flow. Spantide, however, caused a dose-dependent decrease, where 2 micrograms caused an immediate drop of the blood flow to approx. 20% of its normal value. A total circulatory arrest was found in several animals. In most cases, the flow was gradually normalized, whereas the effect persisted for up to 60 min in others. Virtually the same effect was exerted by somatostatin. The experiments using the iodoantipyrine technique confirmed the effect of Spantide. Here, the high resolution of this method showed that the gray matter was affected preferentially, with a complete ischemic state or a drastically reduced flow in 4 out of 5 animals 10 min after 2 micrograms of Spantide; one animal was unaffected, and this animal did not show any signs of motor impairment. The vasoconstriction of Spantide was not affected by simultaneous injections with substance P. However, after i.v. pretreatment with thyrotropin-releasing hormone, at a dose that previously has been reported to be protective against the neurodegenerative effects of Spantide, blood flow was markedly increased as compared to Spantide alone. Results from the experiments using intravital microscopy flow studies in the rabbit tenuissimus muscle revealed that Spantide at the doses used had no vasoconstrictor effect in the skeletal muscle of this species. The results suggest that previous demonstrations of motor impairment and "neurotoxic" actions of intrathecally injected substance P antagonists and somatostatin may be related to a marked decrease in spinal cord blood flow. Counteraction of the effect of Spantide by thyrotropin-releasing hormone may be explained by its effect to increase blood flow.},
  author       = {Freedman, J and Post, C and Kåhrström, J and Öhlen, A and Mollenholt, P and Owman, Christer and Alari, L and Hökfelt, T},
  issn         = {1873-7544},
  language     = {eng},
  number       = {1},
  pages        = {267--278},
  publisher    = {Elsevier},
  series       = {Neuroscience},
  title        = {Vasoconstrictor effects in spinal cord of the substance P antagonist [D-Arg, D-Trp7,9 Leu11]-substance P (Spantide) and somatostatin and interaction with thyrotropin releasing hormone},
  url          = {http://dx.doi.org/10.1016/0306-4522(88)90236-9},
  volume       = {27},
  year         = {1988},
}