Novel marine-derived halogen-containing gramine analogues induce vasorelaxation in isolated rat aorta.

We examined the effects of 2,5,6-tribromo-1-methylgramine (TBG), isolated from bryozoan, and its derivative, 5,6-dibromo-1,2-dimethylgramine (DBG), on the contraction of rat aorta. TBG and DBG decreased the high-K(+)-induced increase in muscle contraction and cytosolic Ca(2+) level ([Ca(2+)](i)), respectively. The inhibitory effects of TBG and DBG on high-K(+)-induced contraction were antagonized by increasing the external Ca(2+) concentration or by 1,4-dihydro2,6-dimethyl-5-nitro-4-[2-(trifluoromethyl)phenyl]pyridine-3-carboxylic acid (Bay k8644). The high-K(+)-induced increase of Mn(2+) influx was completely blocked by 10 microM TBG or 10 microM DBG. In the Ca(2+)-free solution, 30 microM TBG or 30 microM DBG inhibited the phenylephrine-induced transient increase in [Ca(2+)](i) and muscle tension, while scarcely affecting caffeine-induced transient changes. TBG and DBG significantly increased the cyclic AMP content at 30 microM, but not at 10 microM. These results suggest that TBG and DBG inhibit the smooth muscle contraction by inhibiting Ca(2+) entry, and at higher concentrations, the increase in intracellular cyclic AMP content also contributes to their inhibitory effect.