Role of lysophosphatidic acid in endothelin-1- and hematoma-induced alteration of cerebral microcirculation

Momoh A. Yakubu, Karoly Liliom, Gabor J. Tigyi, Charles W. Leffler

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Cerebral hematoma increases cerebrospinal fluid (CSF) endothelin-1 (ET- 1). Inhibitors of ET-1 synthesis prevent this increment and hematoma-induced modification of cerebral arteriolar reactivity. We hypothesized that intrathecal ET-1 injection could 1) modify pial arteriolar reactivity similarly to hematoma; 2) increase CSF lysophosphatidic acid (LPA), a potential contributor to altered cerebrovascular reactivity; and 3) reduce the level of adenosine 3',5'-cyclic monophosphate (cAMP) in the CSF. Either ET-1 (10-7 M) or artificial CSF was injected over the left parietal cortex of newborn pigs. Four days later, cranial windows were implanted. CSF ET was increased from a basal level of 11 fmol/ml to 18 fmol/ml 4 days after ET-1 injection, whereas CSF cAMP was reduced from 2,700 to 950 fmol/ml. The mean diameter of pial arterioles was reduced 31%. In control animals, 10-12 MET caused dilation, and higher concentrations induced vasoconstriction. Four days after ET-1 injection, topical ET-1 caused constriction instead of dilation at 10-12 M, and constrictions at higher doses were enhanced. Norepinephrine-induced constrictions were potentiated in the ET-1-injected group. Dilations to cAMP-dependent (but not independent) vasodilators were attenuated after ET-1. The concentration of the vasoconstrictor lipid mediator LPA increased approximately fourfold. Thus intrathecal injection of ET-1 mimics hematoma-induced modification of cerebral vascular reactivity and increase in LPA production. The mechanism(s) of ET-1- and hematoma-induced modifications may involve LPA, which is known to contribute to the loss of dilator responses by inhibition of cAMP production. The present study further suggests that ET-1 together with LPA could be causing changes in cerebrovascular reactivity following cerebral hemorrhage. ET-1 stimulates the release of LPA from brain parenchyma independent of serum so that LPA could serve as a secondary mediator.

Original languageEnglish
Pages (from-to)R703-R709
JournalAmerican Journal of Physiology - Regulatory Integrative and Comparative Physiology
Issue number2 42-2
Publication statusPublished - Oct 18 1997



  • Adenosine 3',5'-cyclic monophosphate
  • Phospholipid
  • Piglet

ASJC Scopus subject areas

  • Physiology
  • Physiology (medical)

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