5E- and 5Z-farnesylacetones from Sargassum siliquastrum as novel selective L-type calcium channel blockers

A specific blocker of L-type Ca2 + channels may be useful in decreasing arterial tone by reducing the open-state probability of L-type Ca2 + channels. The aim of the present study was to evaluate the farnesylacetones, which are major active constituents of Sargassum siliquastrum, regarding their vasodilatation efficacies, selectivities toward L-type Ca2 + channels, and in vivo antihypertensive activities. The application of 5E-(farnesylacetone 311) or 5Z-farnesylacetone (farnesylacetone 312) induced concentration-dependent vasodilatation effects on the basilar artery that was pre-contracted with depolarization and showed an ignorable potential role of endothelial-derived nitric oxide. We also tested farnesylacetone 311 or 312 to determine their pharmacological profiles for the blockade of native L-type Ca2 + channels in basilar arterial smooth muscle cells (BASMCs) and ventricular myocytes (VMCs), cloned L- (α1C/β2a/α2δ), N- (α1B/β1b/α2δ), and T-type Ca2 + channels (α1G, α1H, and α1I). Farnesylacetone 311 or 312 showed greater selectivity toward the L-type Ca2 + channels among the tested voltage-gated Ca2 + channels. The ranked order of the potency for farnesylacetone 311 was cloned α1C ≒ L-type (BASMC) ≒ L-type (VMCs) > α1B > α1H > α1I > α1G and that for farnesylacetone 312 was cloned α1C ≒ L-type (BASMCs) ≒ L-type (VMCs) > α1H > α1G > α1B > α1I. The oral administration of the farnesylacetone 311 (80 mg/kg) conferred potent, long-lasting antihypertensive activity in spontaneous hypertensive rats, but it did not alter the heart rate.

Figure optionsDownload high-quality image (223 K)Download as PowerPoint slide