Transient relaxation of rat mesenteric microvessels by ceramides.
We have investigated the vasodilating effects of D-erythro-C2-ceramide (C2-ceramide) in methoxamine-contracted rat mesenteric microvessels. C2-ceramide (10 - 100 microM) caused a concentration-dependent, slowly developing relaxation which reached maximum values after approximately 10 min and partially abated thereafter. Endothelium removal or inhibitors of guanylyl cyclase (3 microM ODQ), protein kinase A (10 microM H7, 1 microM H89) and various types of K(+) channels (10 microM BaCl(2), 3 mM tetraethylammonium, 30 nM charybdotoxin, 30 nM iberiotoxin, 300 nM apamine, 10 microM glibenclamide) had only small if any inhibitory effects against C2-ceramide-induced vasodilation, but some of them attenuated vasodilation by sodium nitroprusside or isoprenaline. A combination of ODQ and charybdotoxin almost completely abolished C2-ceramide-induced vasodilation. A second administration of C2-ceramide caused a detectable but weaker relaxation. L-threo-C2-ceramide (100 microM), which should not be a substrate to ceramide metabolism, had no biphasic time course. The ceramidase inhibitor (1S,2R)-D-erythro-2-(N-myristoylamino)-1-phenyl-1-propanol (100 microM) alone caused some vasodilation, indicating vasodilation by endogenous ceramides, and also hastened relaxation by exogenous C2-ceramide. The late-developing reversal of C2-ceramide-induced vasodilation was absent when alpha-adrenergic tone was removed by addition of 10 microM phentolamine. We conclude that C2-ceramide relaxes rat resistance vessels in an endothelium-independent manner which is prevented only by combined inhibition of guanylyl cyclase and charybdotoxin-sensitive K(+) channels. The vasodilation abates with time partly due to desensitization of the ceramide response and partly due to metabolism of C2-ceramide to an inactive metabolite.
Czyborra
Peter
P
Department of Medicine, University of Essen, Essen, Germany.
Saxe
Miriam
M
Fetscher
Charlotte
C
Meyer Zu Heringdorf
Dagmar
D
Herzig
Stefan
S
Jakobs
Karl H
KH
Michel
Martin C
MC
Bischoff
Angela
A
D000818:Animals; D002518:Ceramides / Q000494:pharmacology / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D008297:Male; D008643:Mesentery / Q000098:blood supply / Q000187:drug effects* / Q000502:physiology; D008833:Microcirculation / Q000187:drug effects / Q000502:physiology; D026902:Potassium Channel Blockers / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000494:pharmacology* / Q000502:physiology; D013152:Splanchnic Circulation / Q000187:drug effects / Q000502:physiology; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology; D014665:Vasodilator Agents / Q000494:pharmacology*
D002518:Ceramides; D004791:Enzyme Inhibitors; C064769:N-acetylsphingosine; D026902:Potassium Channel Blockers; D014665:Vasodilator Agents; D013110:Sphingosine