ROLE OF LYSOPHOSPHATIDIC ACID IN ENDOTHELIN-1-INDUCED 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 hypothesize d that intrathecal ET-1 injection could 1) modify pial arteriolar reac tivity similarly to hematoma; 2) increase CSF lysophosphatidic acid (L PA), a potential contributor to altered cerebrovascular reactivity; an d 3) reduce the level of adenosine 3',5'-cyclic monophosphate (cAMP) i n 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 win dows were implanted. CSF ET was increased from a basal level of 11 fmo l/ml to 18 fmol/ml 4 days after ET-1 injection, whereas CSF cAMP was r educed 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, an d 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. Norepinephri ne-induced constrictions were potentiated in the ET-l-injected group. Dilations to cAMP-dependent (but not independent) vasodilators were at tenuated after ET-1. The concentration of the vasoconstrictor lipid me diator LPA increased approximately fourfold. Thus intrathecal injectio n of ET-1 mimics hematoma-induced modification of cerebral vascular re activity and increase in LPA production. The mechanism(s) of ET-1- and hematoma-induced modifications may involve LPA, which is known to con tribute to the loss of dilator responses by inhibition of cAMP product ion. The present study further suggests that ET-1 together with LPA co uld be causing changes in cerebrovascular reactivity following cerebra l hemorrhage. ET-1 stimulates the release of LPA from brain parenchyma independent of serum so that LPA could serve as a secondary mediator.