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C2-ceramide induces vasodilation in phenylephrine-induced pre-contracted rat thoracic aorta: role of RhoA/Rho-kinase and intracellular Ca2+ concentration

 Gil-Jin Jang  ;  Duck Sun Ahn  ;  Young-Eun Cho  ;  Kathleen G. Morgan  ;  Young-Ho Lee 
 Naunyn-Schmiedeberg's Archives of Pharmacology, Vol.372(3) : 242-250, 2005 
Journal Title
 Naunyn-Schmiedeberg's Archives of Pharmacology 
Issue Date
Animals ; Aorta, Thoracic ; Calcium/antagonists & inhibitors* ; Calcium/physiology ; Enzyme Inhibitors/pharmacology* ; Intracellular Signaling Peptides and Proteins ; Muscle, Smooth, Vascular/drug effects* ; Phenylephrine/antagonists & inhibitors* ; Phenylephrine/pharmacology ; Protein-Serine-Threonine Kinases/antagonists & inhibitors* ; Protein-Serine-Threonine Kinases/physiology ; Rats ; Rats, Wistar ; Sphingosine/analogs & derivatives* ; Sphingosine/pharmacology ; Tumor Necrosis Factor-alpha/physiology ; Vasoconstriction/drug effects ; Vasodilation/drug effects ; rho-Associated Kinases
[Ca2+]I ; Ceramide ; Phenylephrine ; Rat thoracic aorta ; RhoA/Rho-kinase ; Vasodilation
It is known that ceramide may play an important regulatory role in vascular tone although its effect on vascular tone and the mechanisms involved are controversial. The present study was designed to investigate the effects of ceramide and its key initial regulators, TNF-α and neutral sphingomyelinase (SMase), on vascular tone of isolated rat thoracic aortic rings and elucidate the mechanisms involved in the changes in vascular tone induced by ceramide. Contractile responses and Fura-2 Ca2+ signals were measured in rat thoracic aortic rings or strips. 10−5 M C2-ceramide, 0.1 U/ml neutral sphingomyelinase (SMase), and 5×10−7 g/ml TNF-α had no effect on resting tone in rat thoracic aortic rings. However, in phenylephrine-induced pre-contracted rings, treatment with ceramide, SMase, and TNF-α evoked a gradual but sustained vasodilation. Vasodilation effect in response to 10−5 M C2-ceramide was not significantly changed by the absence or presence of endothelium, a cyclooxygenase pathway inhibitor (10−6 M indomethacin), or PKC inhibitors (10−5 M H-7 & 5×10−7 M calphostin-C). Pretreatment with 1 μM Y-27632, a RhoA/Rho-kinase inhibitor, significantly inhibited the phenylephrine-induced contraction itself as well as the C2-ceramide-induced vasodilation. Pre-treatment with 10−5 M C2-ceramide had no effect on phasic rise in [Ca2+]i and tension evoked by stimulation with 10−8 M phenylephrine, but post-treatment of C2-ceramide significantly reduced the phenylephrine-induced secondary tonic [Ca2+]i and tension plateau. Our results indicate that C2-ceramide induces vasodilation in phenylephrine-induced pre-contracted rat thoracic aorta. Furthermore, inhibition of phenylephrine-induced activation of RhoA/Rho-kinase pathway as well as phenylephrine-induced elevations in [Ca2+]i are clearly a key factors in C2-ceramide-induced vasodilation.
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1. College of Medicine (의과대학) > Dept. of Physiology (생리학교실) > 1. Journal Papers
Yonsei Authors
Ahn, Duk Sun(안덕선) ORCID logo https://orcid.org/0000-0001-9351-6951
Lee, Young Ho(이영호) ORCID logo https://orcid.org/0000-0002-5749-1045
Cho, Young Eun(조영은)
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