Effects of a novel hydrogen sulfide prodrug in a porcine model of acute limb ischemia.

Abstract

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). 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. 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.