title: Local and systemic vasodilatory effects of low molecular weight S-nitrosothiols.
abstract: S-nitrosothiols (SNOs) such as S-nitroso-L-cysteine (L-cysNO) are endogenous compounds with potent vasodilatory activity. During circulation in the blood, the NO moiety can be exchanged among various thiol-containing compounds by S-transnitrosylation, resulting in SNOs with differing capacities to enter the cell (membrane permeability). To determine whether the vasodilating potency of SNOs is dependent upon membrane permeability, membrane-permeable L-cysNO and impermeable S-nitroso-D-cysteine (D-cysNO) and S-nitroso-glutathione (GSNO) were infused into one femoral artery of anesthetized adult sheep while measuring bilateral femoral and systemic vascular conductances. L-cysNO induced vasodilation in the infused hind limb, whereas D-cysNO and GSNO did not. L-cysNO also increased intracellular NO in isolated arterial smooth muscle cells, whereas GSNO did not. The infused SNOs remained predominantly in a low molecular weight form during first-passage through the hind limb vasculature, but were converted into high molecular weight SNOs upon systemic recirculation. At systemic concentrations of ~0.6 μmol/L, all three SNOs reduced mean arterial blood pressure by ~50%, with pronounced vasodilation in the mesenteric bed. Pharmacokinetics of L-cysNO and GSNO were measured in vitro and in vivo and correlated with their hemodynamic effects, membrane permeability, and S-transnitrosylation. These results suggest local vasodilation by SNOs in the hind limb requires membrane permeation, whereas systemic vasodilation does not. The systemic hemodynamic effects of SNOs occur after equilibration of the NO moiety amongst the plasma thiols via S-transnitrosylation.
authors.affiliation: Department of Pediatrics, Division of Neonatology, Loma Linda University School of Medicine, Loma Linda, CA 92354, USA.
authors.forename: Taiming
authors.initials: T
authors.lastname: Liu
authors.affiliation: Center for Perinatal Biology, Loma Linda University School of Medicine, Loma Linda, CA 92354, USA.
authors.forename: Hobe J
authors.initials: HJ
authors.lastname: Schroeder
authors.affiliation: Center for Perinatal Biology, Loma Linda University School of Medicine, Loma Linda, CA 92354, USA.
authors.forename: Sean M
authors.initials: SM
authors.lastname: Wilson
authors.affiliation: Department of Respiratory Care, Loma Linda University School of Medicine, Loma Linda, CA 92354, USA.
authors.forename: Michael H
authors.initials: MH
authors.lastname: Terry
authors.affiliation: Advanced Microscopy Imaging Core, Loma Linda University School of Medicine, Loma Linda, CA 92354.
authors.forename: Monica
authors.initials: M
authors.lastname: Romero
authors.affiliation: Center for Perinatal Biology, Loma Linda University School of Medicine, Loma Linda, CA 92354, USA.
authors.forename: Lawrence D
authors.initials: LD
authors.lastname: Longo
authors.affiliation: Center for Perinatal Biology, Loma Linda University School of Medicine, Loma Linda, CA 92354, USA.
authors.forename: Gordon G
authors.initials: GG
authors.lastname: Power
authors.affiliation: Department of Pediatrics, Division of Neonatology, Loma Linda University School of Medicine, Loma Linda, CA 92354, USA; Center for Perinatal Biology, Loma Linda University School of Medicine, Loma Linda, CA 92354, USA. Electronic address: ablood@llu.edu.
authors.forename: Arlin B
authors.initials: AB
authors.lastname: Blood
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D003545:Cysteine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000502:physiology; D004353:Drug Evaluation, Preclinical; D008970:Molecular Weight; D009131:Muscle, Smooth, Vascular / Q000166:cytology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000502:physiology; D009569:Nitric Oxide / Q000378:metabolism; D026403:S-Nitrosothiols / Q000494:pharmacology*; D012756:Sheep; D014664:Vasodilation / Q000187:drug effects*; D014665:Vasodilator Agents / Q000494:pharmacology*
chemical_list: D026403:S-Nitrosothiols; D014665:Vasodilator Agents; D009569:Nitric Oxide; C021315:S-nitrosocysteine; D003545:Cysteine
keywords: Membrane permeability; Nitric oxide; S-nitrosothiol; S-transnitrosylation; Vasodilation