Ceram, a novel second messenger relaxes vascular smooth muscle

Recent findings demonstrate a hormone-responsive enzyme (sphingomyelinase) acts on sphingomyelin (precursor metabolite) to form a putative second messenger, ceramide. We hypothesized that ceramide plays a second messenger function in the cellular events producing vasodilatation. Aoric rings from adult male rats were positioned in a muscle bath for measurement of isometric force generation. A concentration-dependent relaxation response to ceramide (10^-9M to 10^-5 M) was observed in phenylephrine-contracted vessels. At each concentration of ceramide, the dilator response was transient; at 1 μM the duration was approximately 5 minutes. No relaxation was observed in 60 mM KCl-contracted rings. Relaxation to ceramide was partially inhibited (∼50%) by N^ω-nitro-L-arginine (10^-4 M) and methylene blue (10^-5 M) and by mechanical removal of the endothelium (figure). The phosphatase inhibitor, okadaic acid (10 nM) reduced relaxation to the second messenger (1 μM) bv anoroximatelv 50%. These studies define a signaling function of ceramide in vascular smooth muscle relaxation. We conclude that the vasodilator activity of the second messenger is augmented by activating nitric oxide synthase and that its inhibition may be due to stimulation of a ceramidesensitive phosphatase. (Supported by NIH HL-18575).