Sphingosine-1-phosphate and sphingosylphosphorylcholine constrict renal and mesenteric microvessels in vitro.
Sphingolipids such as sphingosine-1-phosphate (SPP) and sphingosylphosphorylcholine (SPPC) can act both intracellularly and at G-protein-coupled receptors, some of which were cloned and designated as Edg-receptors. Sphingolipid-induced vascular effects were determined in isolated rat mesenteric and intrarenal microvessels. Additionally, sphingolipid-induced elevations in intracellular Ca(2+) concentration were measured in cultured rat aortic smooth muscle cells. SPPC and SPP (0.1-100 micromol l(-1)) caused concentration-dependent contraction of mesenteric and intrarenal microvessels (e.g. SPPC in mesenteric microvessels pEC(50) 5.63+/-0.17 and E(max) 49+/-3% of noradrenaline), with other sphingolipids being less active. The vasoconstrictor effect of SPPC in mesenteric microvessels was stereospecific (pEC(50) D-erythro-SPPC 5.69+/-0.08, L-threo-SPPC 5.31+/-0.06) and inhibited by pretreatment with pertussis toxin (E(max) from 44+/-5 to 19+/-4%), by chelation of extracellular Ca(2+) with EGTA and by nitrendipine (E(max) from 40+/-6 to 6+/-1 and 29+/-6%, respectively). Mechanical endothelial denudation or NO synthase inhibition did not alter the SPPC effects, while indomethacin reduced them (E(max) from 87+/-3 to 70+/-4%). SPP and SPPC caused transient increases in intracellular Ca(2+) concentrations in rat aortic smooth muscle cells in a pertussis toxin-sensitive manner. Our data demonstrate that SPP and SPPC cause vasoconstriction of isolated rat microvessels and increase intracellular Ca(2+) concentrations in cultured rat aortic smooth muscle cells. These effects appear to occur via receptors coupled to pertussis toxin-sensitive G-proteins. This is the first demonstration of effects of SPP and SPPC on vascular tone and suggests that sphingolipids may be an hitherto unrecognized class of endogenous regulators of vascular tone.
Bischoff
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Department of Medicine, University of Essen, 45122 Essen, Germany. angela.bischoff@uni-essen.de
Czyborra
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Fetscher
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Meyer Zu Heringdorf
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Jakobs
K H
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Michel
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MC
D000818:Animals; D002118:Calcium / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004533:Egtazic Acid / Q000494:pharmacology; D066298:In Vitro Techniques; D007213:Indomethacin / Q000494:pharmacology; D008246:Lysophospholipids; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects* / Q000502:physiology; D009568:Nitrendipine / Q000494:pharmacology; D019335:Nitroarginine / Q000494:pharmacology; D037342:Pertussis Toxin; D010767:Phosphorylcholine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D011609:Psychosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D012077:Renal Artery / Q000187:drug effects* / Q000502:physiology; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D014661:Vasoconstriction / Q000187:drug effects*; D014665:Vasodilator Agents / Q000494:pharmacology; D010566:Virulence Factors, Bordetella / Q000494:pharmacology
D008246:Lysophospholipids; D014665:Vasodilator Agents; D010566:Virulence Factors, Bordetella; C005356:sphingosine phosphorylcholine; D010767:Phosphorylcholine; D019335:Nitroarginine; D011609:Psychosine; C060506:sphingosine 1-phosphate; C035742:sphingosyl beta-glucoside; D004533:Egtazic Acid; D009568:Nitrendipine; D037342:Pertussis Toxin; D013110:Sphingosine; D002118:Calcium; D007213:Indomethacin