Farnesyl analogues inhibit vasoconstriction in animal and human arteries

Jean Baptiste Roullet, Hong Xue, Justin Chapman, Patrick McDougal, Chantal M. Roullet, David A. McCarron

Research output: Contribution to journalArticlepeer-review

31 Scopus citations

Abstract

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 (C15) intermediate of the cholesterol pathway, the vasoactive properties of the farnesyl motif were investigated. Two farnesyl analogues were used: farnesol, the natural dephosphorylated form of farnesyl pyrophosphate, and N-acetyl-S-trans,trans-farnesyl-L-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 (C10) and longer (C20) isoprenols as well as N- acetyl-S-geranyl-L-cysteine (C10) did not inhibit the response to NE. In contrast, N-acetyl-S-geranylgeranyl-L-cysteine (C20), exhibited vasoactive properties similar to AFC. It was further demonstrated that AFC and farnesol inhibited KCl 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.

Original languageEnglish (US)
Pages (from-to)2384-2390
Number of pages7
JournalJournal of Clinical Investigation
Volume97
Issue number10
DOIs
StatePublished - May 15 1996

Keywords

  • G proteins
  • farnesol
  • farnesylation
  • isoprenoids
  • vascular tone

ASJC Scopus subject areas

  • Medicine(all)

Fingerprint Dive into the research topics of 'Farnesyl analogues inhibit vasoconstriction in animal and human arteries'. Together they form a unique fingerprint.

Cite this