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J Vasc Surg ; 69(6): 1924-1935, 2019 06.
Article in English | MEDLINE | ID: mdl-30777693

ABSTRACT

OBJECTIVE: Previous studies have shown that hydrogen sulfide (H2S) exerts potent proangiogenic properties under in vitro conditions and in rodent models. We sought to determine whether a novel H2S prodrug promotes peripheral revascularization in a swine model of acute limb ischemia (ALI). METHODS: ALI was induced in 17 female miniswine via intravascular occlusion of the external iliac. At day 7 after ALI induction, miniswine (n = 17) were randomized to received placebo or the H2S prodrug, SG-1002 (800 mg per os twice a day), for 35 days. At day 35 SG-1002 increased circulating levels of H2S (5.0 ± 1.2 µmol/L vs 1.8 ± 0.50 µmol/L; P < .05), sulfane sulfur (10.6 ± 2.3 µmol/L vs 2.6 ± 0.8 µmol/L; P < .05), and nitrite (0.5 ± 0.05 µmol/L vs 0.3 ± 0.03 µmol/L; P < .005) compared with placebo. SG-1002 therapy increased angiographic scoring in ischemic limb vessel number (27.6 ± 1.6 vs 22.2 ± 1.8; P < .05) compared with placebo. Treatment with SG-1002 preserved existing capillaries in ischemic limbs (128.3 ± 18.7 capillaries/mm2 vs 79.0 ± 9.8 capillaries/mm2; P < .05) compared with placebo. Interestingly, treatment with SG-1002 also improved coronary vasorelaxation responses to bradykinin and substance P in miniswine with ALI. CONCLUSIONS: Our results suggest that daily administration of the H2S prodrug, SG-1002, leads to an increase in circulating H2S and nitric oxide signaling and preserves vessel number and density in ischemic limbs. Furthermore, SG-1002 therapy improved endothelial-dependent coronary artery vasorelaxation in the setting of ALI. Our data demonstrate that SG-1002 preserves the vascular architecture in ischemic limbs and exerts vascular protective effects in the coronary vasculature in a model of peripheral vascular disease.


Subject(s)
Angiogenesis Inducing Agents/pharmacology , Extremities/blood supply , Hydrogen Sulfide/pharmacology , Ischemia/drug therapy , Neovascularization, Physiologic/drug effects , Peripheral Arterial Disease/drug therapy , Prodrugs/pharmacology , Acute Disease , Angiogenesis Inducing Agents/blood , Angiogenesis Inducing Agents/pharmacokinetics , Animals , Coronary Vessels/drug effects , Coronary Vessels/physiopathology , Disease Models, Animal , Female , Hydrogen Sulfide/blood , Hydrogen Sulfide/pharmacokinetics , Ischemia/blood , Ischemia/physiopathology , Nitric Oxide/blood , Nitrites/blood , Oxidative Stress/drug effects , Peripheral Arterial Disease/blood , Peripheral Arterial Disease/physiopathology , Prodrugs/pharmacokinetics , Regional Blood Flow , Signal Transduction , Swine , Swine, Miniature , Vasodilation/drug effects
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