Effects of sphingomyelinase and sphingosine on arterial vasomotor regulation.
The sphingomyelin pathway is an important signal transduction system regulating various cellular functions. However, little is known about the effect of sphingomyelin metabolites on vasomotor function. We examined the vascular effects of sphingomyelin, sphingosine, and sphingomyelinase (SPMase) in vitro. In pig coronary rings precontracted with prostaglandin F2 alpha, sphingosine and SPMase evoked initial contraction and subsequent gradual relaxation; however, sphingomyelin did not influence the tone. The initial contractions in response to either SPMase (40 microU/ml to 0.4 U/ml) or sphingosine (0.5-10 microM) treatment were abolished in rings denuded of endothelium. This initial contraction in response to sphingosine treatment was significantly attenuated by a cyclo-oxygenase inhibitor indomethacin, but not altered by either a nitric oxide synthase inhibitor, N omega-monomethyl-L-arginine (L-NMMA), a protein kinase C (PKC) inhibitor staurosporine, or superoxide dismutase (SOD, 100 U/ml). Incubation of coronary rings with sphingosine (10 microM) or SPMase (0.4 U/ml) for 120 min significantly attenuated subsequent endothelium-dependent relaxation in response to thrombin and A23187, but did not affect endothelium-independent relaxation in response to sodium nitroprusside. In contrast, sphingomyelin (10 microM) did not alter the endothelium-dependent relaxation. In conclusion, in the sphingomyelin pathway, sphingosine induces vasoconstriction in coronary arteries that seems to be mediated by the release of cyclooxygenase-sensitive vasoconstrictor prostanoids from the endothelium. Sphingosine also induced endothelial dysfunction characterized by impaired endothelium-dependent relaxation. Thus, the sphingomyelin pathway may be an important regulator of vascular function.
Murohara
T
T
Division of Cardiology, Kumamoto University School of Medicine, Japan.
Kugiyama
K
K
Ohgushi
M
M
Sugiyama
S
S
Ohta
Y
Y
Yasue
H
H
D000818:Animals; D000001:Calcimycin / Q000494:pharmacology; D003331:Coronary Vessels / Q000187:drug effects* / Q000502:physiology; D015237:Dinoprost / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000502:physiology; D066298:In Vitro Techniques; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000502:physiology; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D013108:Sphingomyelin Phosphodiesterase / Q000494:pharmacology*; D013109:Sphingomyelins / Q000378:metabolism*; D013110:Sphingosine / Q000494:pharmacology*; D013552:Swine; D014666:Vasomotor System / Q000502:physiology*
D013109:Sphingomyelins; D000001:Calcimycin; D015237:Dinoprost; D013108:Sphingomyelin Phosphodiesterase; D013110:Sphingosine; D019331:NG-Nitroarginine Methyl Ester