Role of lysophosphatidic acid in endothelin-1- and hematoma-induced alteration of cerebral microcirculation.
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) M ET 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 product on. 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.
Yakubu
M A
MA
Department of Physiology and Biophysics, University of Tennessee, Memphis 38163, USA.
Liliom
K
K
Tigyi
G J
GJ
Leffler
C W
CW
D000818:Animals; D000831:Animals, Newborn; D001160:Arterioles / Q000187:drug effects / Q000502:physiology; D002543:Cerebral Hemorrhage / Q000134:cerebrospinal fluid / Q000503:physiopathology*; D002560:Cerebrovascular Circulation / Q000187:drug effects*; D000242:Cyclic AMP / Q000134:cerebrospinal fluid; D019332:Endothelin-1 / Q000494:pharmacology*; D016232:Endothelins / Q000134:cerebrospinal fluid; D006406:Hematoma / Q000134:cerebrospinal fluid / Q000503:physiopathology*; D008246:Lysophospholipids / Q000134:cerebrospinal fluid / Q000502:physiology*; D008833:Microcirculation / Q000187:drug effects; D013552:Swine; D014661:Vasoconstriction; D014665:Vasodilator Agents / Q000494:pharmacology
D019332:Endothelin-1; D016232:Endothelins; D008246:Lysophospholipids; D014665:Vasodilator Agents; D000242:Cyclic AMP