RESUMO
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.
Assuntos
Indutores da Angiogênese/farmacologia , Extremidades/irrigação sanguínea , Sulfeto de Hidrogênio/farmacologia , Isquemia/tratamento farmacológico , Neovascularização Fisiológica/efeitos dos fármacos , Doença Arterial Periférica/tratamento farmacológico , Pró-Fármacos/farmacologia , Doença Aguda , Indutores da Angiogênese/sangue , Indutores da Angiogênese/farmacocinética , Animais , Vasos Coronários/efeitos dos fármacos , Vasos Coronários/fisiopatologia , Modelos Animais de Doenças , Feminino , Sulfeto de Hidrogênio/sangue , Sulfeto de Hidrogênio/farmacocinética , Isquemia/sangue , Isquemia/fisiopatologia , Óxido Nítrico/sangue , Nitritos/sangue , Estresse Oxidativo/efeitos dos fármacos , Doença Arterial Periférica/sangue , Doença Arterial Periférica/fisiopatologia , Pró-Fármacos/farmacocinética , Fluxo Sanguíneo Regional , Transdução de Sinais , Suínos , Porco Miniatura , Vasodilatação/efeitos dos fármacosRESUMO
Although the use of aortoiliac endarterectomy to treat occlusive disease has declined since the advent of endovascular procedures and operative bypass grafting techniques, clinical scenarios still exist in which it can be useful. We present the case of a patient with right lower extremity pain at rest, an anomalous right pelvic kidney, right common iliac artery occlusion, and severe left common iliac artery stenosis. We have demonstrated that aortoiliac endarterectomy should not be considered an outdated surgical technique but a viable alternative for revascularization in a specific subset of patients.
RESUMO
BACKGROUND: Zofenopril, a sulfhydrylated angiotensin-converting enzyme inhibitor (ACEI), reduces mortality and morbidity in infarcted patients to a greater extent than do other ACEIs. Zofenopril is a unique ACEI that has been shown to increase hydrogen sulfide (H2S) bioavailability and nitric oxide (NO) levels via bradykinin-dependent signaling. Both H2S and NO exert cytoprotective and antioxidant effects. We examined zofenopril effects on H2S and NO bioavailability and cardiac damage in murine and swine models of myocardial ischemia/reperfusion (I/R) injury. METHODS AND RESULTS: Zofenopril (10 mg/kg PO) was administered for 1, 8, and 24 hours to establish optimal dosing in mice. Myocardial and plasma H2S and NO levels were measured along with the levels of H2S and NO enzymes (cystathionine ß-synthase, cystathionine γ-lyase, 3-mercaptopyruvate sulfur transferase, and endothelial nitric oxide synthase). Mice received 8 hours of zofenopril or vehicle pretreatment followed by 45 minutes of ischemia and 24 hours of reperfusion. Pigs received placebo or zofenopril (30 mg/daily orally) 7 days before 75 minutes of ischemia and 48 hours of reperfusion. Zofenopril significantly augmented both plasma and myocardial H2S and NO levels in mice and plasma H2S (sulfane sulfur) in pigs. Cystathionine ß-synthase, cystathionine γ-lyase, 3-mercaptopyruvate sulfur transferase, and total endothelial nitric oxide synthase levels were unaltered, while phospho-endothelial nitric oxide synthase(1177) was significantly increased in mice. Pretreatment with zofenopril significantly reduced myocardial infarct size and cardiac troponin I levels after I/R injury in both mice and swine. Zofenopril also significantly preserved ischemic zone endocardial blood flow at reperfusion in pigs after I/R. CONCLUSIONS: Zofenopril-mediated cardioprotection during I/R is associated with an increase in H2S and NO signaling.