Abstract 19028: The Novel H2S Pro-Drug, SG-1002, Preserves Coronary Artery Vascular Reactivity in the Setting of Critical Limb Ischemia in Swine
Introduction: Peripheral artery disease (PAD) including critical limb ischemia (CLI) leads to increased risk of myocardial infarction even in the absence of coronary artery disease (CAD). It has been postulated that the CLI muscles release substances systemically that lead to coronary artery endothelial dysfunction and reduced nitric oxide (NO) bioavailability. We have recently shown that administration of the hydrogen sulfide (H2S) prodrug, SG-1002, increases NO bioavailability in normal and heart failure patients.
Hypothesis: We investigated the effects of SG-1002 on coronary artery vascular function in a clinically relevant swine model of CLI.
Methods: CLI was generated in Yucatan miniswine by placement of an Amplatzer vascular plug deployed within a Viabahn stent in the proximal external iliac artery. Treatment with placebo (n=7) or SG-1002 (1600 mg PO, n=7) was initiated at 7 days post-CLI and continued for 35 days. On days 0 and 42 circulating levels of NO and H2S measured as nitrite (NO2) and sulfane sulfur (SS) were determined. On day 42, left circumflex (LCX) and right coronary arteries (RCA) were isolated to evaluate the relaxation response to endothelial-dependent substance P (SUB P, 0.01-10 nM) and endothelial-independent sodium nitroprusside (SNP, 0.01-10 μM) following preconstriction with prostaglandin (PGF2α). Half maximal effective concentrations (EC50) were calculated.
Results: Plasma levels of NO2 were increased in SG-1002 treated swine (p < 0.05) as compared to placebo. SS levels were also increased in SG-1002 treated group compared to baseline (p < 0.001). SG-1002 treatment improved SUB P relaxation responses of the LCX (EC50: 0.066 vs 0.141 nM, p < 0.001) and the RCA (EC50: 0.113 vs 0.176 nM, p = 0.06). SG-1002 treatment also improved SNP relaxation responses of the LCX (EC50: 0.381 vs 0.805 μM, p < 0.0001) and the RCA (0.453 vs 0.88 μM, p < 0.0001) compared to placebo.
Conclusions: Oral administration of a novel long-acting H2S prodrug improves coronary artery vascular reactivity by an NO-dependent mechanism in the setting of CLI.
Author Disclosures: E. Donnarumma: None. A.M. Rushing: None. S.F. Boisvert: None. A.L. Scarborough: None. D.J. Polhemus: None. R.K. Trivedi: None. D.J. Lefer: None. T.T. Goodchild: None.
- © 2016 by American Heart Association, Inc.