Sphingomyelinase and ceramide analogs induce vasoconstriction and leukocyte-endothelial interactions in cerebral venules in the intact rat brain: Insight into mechanisms and possible relation to brain injury and stroke.
This study was designed to test the hypothesis that the sphingomyelin-ceramide signaling pathway may be important in proinflammatory-like responses in the intact brain. Effects of neutral sphingomyelinase (N-SMase), ceramide analogs, phosphorylcholine and ceramide metabolites were studied on rat brain cerebral (cortical) venule lumen sizes, leukocyte rolling, velocity and endothelial cell wall adhesion, microvessel permeability, microvessel rupture and focal hemorrhages using in vivo high resolution TV microscopy. Perivascular and close intra-arterial administration of N-SMase, C(2)-, C(8)-, and C(16)-ceramide, but not either phosphorylcholine, C(6)-ceramide, nervonic (C(24):1) ceramide, lignoceric (C(24):0) ceramide, C(8)-ceramide-1-phosphate, glucosylceramide or 1-0-acylceramide, resulted in potent, concentration-dependent constriction (and spasm) of cortical venules, followed by increased leukocyte rolling, decreased leukocyte velocities, increased leukocyte-endothelial wall adhesion, increased venular wall permeability, postcapillary venule rupture and, often, micro-hemorrhaging at high concentrations; angiotensin II, serotonin and PGF(2alpha) didn't demonstrate these characteristics. Pretreatment with either one of three different antioxidants, including inhibitors of NF-kappaB activation, or two different Ca(2+) channel blockers either prevented or attenuated the adverse venular effects of N-SMase and the ceramides. Likewise, pretreatment with either a PKCalpha-beta antagonist or a MAP kinase antagonist also attenuated the adverse venular effects. These results suggest that N-SMase and several ceramides can result in potent venular cerebrovasospasm, leukocyte-endothelial chemoattraction, and microvessel wall permeability changes in the intact rat brain. These proinflammatory-like actions suggest that N-SMase and ceramides could produce brain-vascular damage by reperfusion injury triggering lipid peroxidation, release of reactive oxygen species and activation of diverse signaling pathways: PKCalpha-beta isozymes, MAP kinase and NF-kappaB.
Departments of Physiology and Pharmacology, Health Science Center at Brooklyn, State University of New York, Brooklyn, NY 11203, USA.
Burton M
BM
Altura
Asefa
A
Gebrewold
Tao
T
Zheng
Bella T
BT
Altura
D000804:Angiotensin II / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D001930:Brain Injuries / Q000201:enzymology / Q000503:physiopathology; D002199:Capillary Permeability / Q000187:drug effects / Q000502:physiology; D002450:Cell Communication / Q000187:drug effects / Q000502:physiology; D002518:Ceramides / Q000378:metabolism* / Q000494:pharmacology; D002550:Cerebral Veins / Q000187:drug effects / Q000201:enzymology* / Q000503:physiopathology; D015237:Dinoprost / Q000378:metabolism / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004660:Encephalitis / Q000201:enzymology* / Q000503:physiopathology; D004730:Endothelium, Vascular / Q000187:drug effects / Q000201:enzymology* / Q000503:physiopathology; D007962:Leukocytes / Q000187:drug effects / Q000201:enzymology*; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D012701:Serotonin / Q000378:metabolism / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013108:Sphingomyelin Phosphodiesterase / Q000378:metabolism* / Q000494:pharmacology; D013109:Sphingomyelins / Q000378:metabolism; D020521:Stroke / Q000201:enzymology / Q000503:physiopathology; D014661:Vasoconstriction / Q000187:drug effects / Q000502:physiology; D014699:Venules / Q000187:drug effects / Q000201:enzymology* / Q000503:physiopathology
D002518:Ceramides; D013109:Sphingomyelins; D000804:Angiotensin II; D012701:Serotonin; D015237:Dinoprost; D013108:Sphingomyelin Phosphodiesterase