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- Title
Transient relaxation of rat mesenteric microvessels by ceramides.
- Authors
Czyborra, Peter; Saxe, Miriam; Fetscher, Charlotte; Meyer zu Heringdorf, Dagmar; Herzig, Stefan; Jakobs, Karl H.; Michel, Martin C.; Bischoff, Angela
- Abstract
1 We have investigated the vasodilating effects of D-erythro-C2-ceramide (C2-ceramide) in methoxamine-contracted rat mesenteric microvessels. 2 C2-ceramide (10-100 µM) caused a concentration-dependent, slowly developing relaxation which reached maximum values after ≈10 min and partially abated thereafter. 3 Endothelium removal or inhibitors of guanylyl cyclase (3 µM ODQ), protein kinase A (10 µM H7, 1 µM H89) and various types of K[sup +] channels (10 µM BaCl[sub 2], 3 mM tetraethylammonium, 30 nM charybdotoxin, 30 nM iberiotoxin, 300 nM apamine, 10 µM 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. 4 A second administration of C2-ceramide caused a detectable but weaker relaxation. L-threo-C2ceramide (100 µM), 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 µM) alone caused some vasodilation, indicating vasodilation by endogenous ceramides, and also hastened relaxation by exogenous C2-ceramide. The late-developing reversal of C2-ceramideinduced vasodilation was absent when α-adrenergic tone was removed by addition of 10 µM phentolamine. 5 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 charybdotoxinsensitive 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.
- Subjects
MESENTERIC blood vessels; LIPIDS; ENDOTHELIUM
- Publication
British Journal of Pharmacology, 2002, Vol 135, Issue 2, p417
- ISSN
0007-1188
- Publication type
Article
- DOI
10.1038/sj.bjp.0704498