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 journalArticle

30 Citations (Scopus)

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
StatePublished - May 15 1996

Fingerprint

Farnesol
Vasoconstriction
Blood Vessels
Mevalonic Acid
Arteries
GTP-Binding Proteins
Cysteine
Carbon
Cholesterol
Blood Pressure
Proteins
farnesyl pyrophosphate

Keywords

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

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Roullet, J-B., Xue, H., Chapman, J., McDougal, P., Roullet, C. M., & McCarron, D. A. (1996). Farnesyl analogues inhibit vasoconstriction in animal and human arteries. Journal of Clinical Investigation, 97(10), 2384-2390.

Farnesyl analogues inhibit vasoconstriction in animal and human arteries. / Roullet, Jean-Baptiste; Xue, Hong; Chapman, Justin; McDougal, Patrick; Roullet, Chantal M.; McCarron, David A.

In: Journal of Clinical Investigation, Vol. 97, No. 10, 15.05.1996, p. 2384-2390.

Research output: Contribution to journalArticle

Roullet, J-B, Xue, H, Chapman, J, McDougal, P, Roullet, CM & McCarron, DA 1996, 'Farnesyl analogues inhibit vasoconstriction in animal and human arteries', Journal of Clinical Investigation, vol. 97, no. 10, pp. 2384-2390.
Roullet J-B, Xue H, Chapman J, McDougal P, Roullet CM, McCarron DA. Farnesyl analogues inhibit vasoconstriction in animal and human arteries. Journal of Clinical Investigation. 1996 May 15;97(10):2384-2390.
Roullet, Jean-Baptiste ; Xue, Hong ; Chapman, Justin ; McDougal, Patrick ; Roullet, Chantal M. ; McCarron, David A. / Farnesyl analogues inhibit vasoconstriction in animal and human arteries. In: Journal of Clinical Investigation. 1996 ; Vol. 97, No. 10. pp. 2384-2390.
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