Regulation of cerebromicrovascular permeability by lysophosphatidic acid.
OBJECTIVE
Lysophosphatidic acid (LPA) increases permeability of cerebral endothelium in culture, but it has been suggested that histamine release is required in vivo.


METHODS
Cerebral venular permeability was measured by using the single-vessel micro-occlusion technique, and fura-2 ratios were used to track changes in endothelial [Ca(2+)].


RESULTS
Topical acute LPA application dose-dependently increased permeability (log EC(50)-9.4; similar to the K(d) of the LPA1 receptor). The calcium response to LPA was similar to histamine, but the permeability response was unaffected by H(2)-histamine receptor antagonism, and was blocked by Ki16425, a LPA1 receptor antagonist. The permeability response was blocked by nitric oxide synthase and free radical scavenging, which were carried out together, but not separately. Intravascular LPA bolus injection increased permeability. Whole serum albumin, or plasma albumin co-applied with LPA, increased permeability, but less potently than LPA itself (log EC(50) 5.1 and 6.1, respectively). Tachyphylaxis of the LPA1 receptor was demonstrated by LPA application for 10 minutes, which resulted in suppression of the response to subsequent applications for the following 15 minutes.


CONCLUSIONS
Lysophosphatidic acid increases cerebrovascular permeability by acting directly on the endothelium and utilizes both nitric oxide and free radical signaling pathways.
Cardiovascular Division, King's College London, School of Medicine, Franklin-Wilkins Building, Stamford Street, London, UK.
Mosharraf H
MH
Sarker
De-En
DE
Hu
Paul A
PA
Fraser
D000818:Animals; D020013:Calcium Signaling / Q000187:drug effects; D002199:Capillary Permeability / Q000187:drug effects* / Q000502:physiology; D002560:Cerebrovascular Circulation / Q000187:drug effects* / Q000502:physiology; D002927:Cimetidine / Q000494:pharmacology; D005260:Female; D005609:Free Radicals / Q000378:metabolism; D006635:Histamine H2 Antagonists / Q000494:pharmacology; D007555:Isoxazoles / Q000494:pharmacology; D008246:Lysophospholipids / Q000494:pharmacology*; D008297:Male; D008833:Microcirculation / Q000187:drug effects / Q000502:physiology; D009569:Nitric Oxide / Q000378:metabolism; D011422:Propionates / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D049368:Receptors, Lysophosphatidic Acid / Q000037:antagonists & inhibitors / Q000378:metabolism; D012709:Serum Albumin / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D013618:Tachyphylaxis
C477898:3-(4-(4-((1-(2-chlorophenyl)ethoxy)carbonyl amino)-3-methyl-5-isoxazolyl) benzylsulfanyl) propanoic acid; D005609:Free Radicals; D006635:Histamine H2 Antagonists; D007555:Isoxazoles; D008246:Lysophospholipids; D011422:Propionates; D049368:Receptors, Lysophosphatidic Acid; D012709:Serum Albumin; D009569:Nitric Oxide; D002927:Cimetidine; C032881:lysophosphatidic acid