C-2-CERAMIDE ATTENUATES PROSTAGLANDIN F-2-ALPHA-INDUCED VASOCONSTRICTION AND ELEVATION OF [CA2-MUSCLE(](I) IN CANINE CEREBRAL VASCULAR SMOOTH)

Sphingolipids have emerged as important components of signal transduct ion pathways involved in a variety of cellular processes. In the prese nt study, we examined the effects of C-2-ceramide, a cell-permeable sp hingolipid, on contraction of canine cerebral vascular smooth muscle a nd intracellular free Ca2+ ([Ca2+](i)). C-2-ceramide (10(-8)-10(-4) M) alone did not elicit any significant changes in either basal tension or resting levels of [Ca2+](i) in canine cerebrovascular muscle. Howev er, C-2- ceramide (10(-7)-10(-4) M) attenuated prostaglandin F-2 alpha (PGF(2 alpha))-induced contractions in isolated canine cerebrovascula r smooth muscle rings. C-2-ceramide (10(-5) M) inhibited the secondary phasic rise of [Ca2+](i) evoked by PGF(2 alpha) in cultured canine ce rebral vascular smooth muscle cells, resulting in decreases in the ele vation in [Ca2+](i). NO inhibitors (L-NNA, L-NMMA), an inhibitor of pr ostanoid synthesis (indomethacin), an inhibitor of opiate actions and several inhibitors of the pharmacologic actions of various vasoactive amines all failed to interfere with the vasorelaxant response of C-2-c eramide. Our results suggest that the sphingomyelin signaling pathway may play an important regulatory role in cerebral arterial wall tone. (C) 1998 Elsevier Science Ireland Ltd. All rights reserved.