title: The effects of tadalafil on cold-induced vasoconstriction in patients with Raynaud's phenomenon.
abstract: Raynaud's phenomenon (RP) is a disorder characterized by episodic periods of vasoconstriction typically provoked by exposure to cold. Phosphodiesterase 5 (PDE5) inhibitors may improve digital blood flow and clinical symptoms in patients with RP, but the mechanisms are unknown. We examined the hypothesis that a PDE5 inhibitor, tadalafil, attenuates cold-induced vasoconstriction. Additionally, we examined whether tadalafil reduced vascular dysfunction following ischemia, thus altering the response to repeated cooling. We conducted a double-blind, placebo-controlled crossover study in 20 subjects with RP on two separate study days, when subjects received either placebo or tadalafil (10 mg). Digital blood flow (flux) was measured by laser Doppler flowmetry at rest and during two graduated local heat and cold exposure cycles. Temperature-response curves were evaluated by E(max) (maximal flux during heating), E(min) (minimal flux during cooling), and ET(50) and ET(90) (the local temperature at which flux decreased by 50% and 90% of E(max)-E(min), respectively). Tadalafil did not increase baseline flux (81.0+/-73.0 vs 91.3+/-114.0 arbitrary unit (AU), P=0.57), E(max) (280.0+/-107.6 vs 279.5+/-119.8 AU, P=0.94), ET(50) (25.4+/-4.4 vs 26.6+/-5.7 degrees C, P=0.62), or ET(90) (21.2+/-3.9 vs 21.8+/-5.0 degrees C, P=0.78), (cycle 1 values presented). There were no differences between cycles on either study day. In conclusion, in patients with RP, single-dose tadalafil does not increase digital blood flow at baseline or in response to heating, nor does it attenuate cold-induced vasoconstriction. Furthermore, it does not precondition the endothelium to resist a second cooling challenge. The clinical benefit in patients with RP treated with PDE5 inhibitors probably involves mechanisms other than acute inhibition of cold-induced vasoconstriction.
authors.affiliation: 1Division of Clinical Pharmacology, Department of Medicine,Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
authors.forename: E A
authors.initials: EA
authors.lastname: Friedman
authors.forename: P A
authors.initials: PA
authors.lastname: Harris
authors.forename: A J J
authors.initials: AJ
authors.lastname: Wood
authors.forename: C M
authors.initials: CM
authors.lastname: Stein
authors.forename: D
authors.initials: D
authors.lastname: Kurnik
mesh_terms: D015106:3',5'-Cyclic-GMP Phosphodiesterases / Q000378:metabolism; D000328:Adult; D002243:Carbolines / Q000009:adverse effects / Q000494:pharmacology*; D003080:Cold Temperature; D018592:Cross-Over Studies; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008297:Male; D010726:Phosphodiesterase Inhibitors / Q000009:adverse effects / Q000494:pharmacology*; D011928:Raynaud Disease / Q000503:physiopathology*; D012039:Regional Blood Flow / Q000187:drug effects / Q000502:physiology; D012867:Skin / Q000098:blood supply / Q000187:drug effects; D012881:Skin Temperature / Q000187:drug effects / Q000502:physiology; D000068581:Tadalafil; D014661:Vasoconstriction / Q000187:drug effects*
chemical_list: D002243:Carbolines; D010726:Phosphodiesterase Inhibitors; D000068581:Tadalafil; D015106:3',5'-Cyclic-GMP Phosphodiesterases; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; C517381:PDE5A protein, human