Farnesyl analogues inhibit vasoconstriction in animal and human arteries

Recent studies have suggested that nonsterol mevalonate-derived metabolites are implicated in the control of vascular tone and blood pressure. Because of the metabolic importance of farnesyl pyrophosphate, a 15-carbon (C-15) intermediate of the cholesterol pathway, the vasoactive properties of the fanesyl moth were investigated. Two farnesyl analogues were used: farnesol, the natural dephosphorylated form of farnesyl pyrophosphate, and N-acetyl-S-trans,trans-farnesyl-1-cysteine (AFC), a synthetic mimic of the carboxyl terminus of farnesylated proteins. Both compounds inhibited NE-induced vasoconstriction in rat aortic rings at micromolar concentration. Their action was rapid, dose dependent, and reversible. Shorter (C-10) and longer (C-20) isoprenols as well as N-acetyl-S-geranyl-L-cysteine (Clo) did not inhibit the response to NE, In contrast, N-acetyl-S-geranylgeranyl-L-cysteine (C-20), exhibited vasoactive properties similar to AFC, It was further demonstrated that AFC and farnesol inhibited KCI and NaF-induced contractions, suggesting a complex action on Ca2+ channels and G protein-dependent pathways, Finally, the effect of farnesol and AFC on the NE response was reproduced in human resistance arteries. In conclusion, mevalonate-derived farnesyl analogues are potent inhibitors of vasoconstriction. The study suggests that farnesyl cellular availability is an important determinant of vascular tone in animals and humans, and provides a basis for exploring farnesyl metabolism in humans with compromised vascular function as well as for using farnesyl analogues as regulators of arterial tone in vivo. (J. Clin. Invest. 1996. 97:2384-2390.)