| Autor: |
Goshovska YV; Department of Blood Circulation, Bogomoletz Institute of Physiology, National Academy of Sciences of Ukraine, Kyiv, Ukraine.; Department of Blood Circulation, Bogomoletz Institute of Physiology, National Academy of Sciences of Ukraine, Kyiv, Ukraine., Fedichkina RA; Department of Blood Circulation, Bogomoletz Institute of Physiology, National Academy of Sciences of Ukraine, Kyiv, Ukraine.; Department of Blood Circulation, Bogomoletz Institute of Physiology, National Academy of Sciences of Ukraine, Kyiv, Ukraine., Korkach YP; Department of Blood Circulation, Bogomoletz Institute of Physiology, National Academy of Sciences of Ukraine, Kyiv, Ukraine.; Department of Blood Circulation, Bogomoletz Institute of Physiology, National Academy of Sciences of Ukraine, Kyiv, Ukraine., Sagach VF; Department of Blood Circulation, Bogomoletz Institute of Physiology, National Academy of Sciences of Ukraine, Kyiv, Ukraine.; Department of Blood Circulation, Bogomoletz Institute of Physiology, National Academy of Sciences of Ukraine, Kyiv, Ukraine. |
| Abstrakt: |
The Frank-Starling response of the heart is known to be mediated by nitric oxide (NO) signaling, which is regulated by reduced glutathione (GSH) and hydrogen sulfide (H 2 S). We hypothesized that stimulation of endogenous H 2 S or GSH synthesis would improve the Frank-Starling response. Wistar male rats were injected with propargylglycine (PAG; 11.3 mg/kg, 40 min, n = 12), an inhibitor of H 2 S-producing enzyme (cystationine-γ-lyase), and l-cysteine (121 mg/kg, 30 min, n = 20), a precursor of H 2 S and GSH. Pretreatment with PAG or l-cysteine separately slightly improved the pressure-volume (P-V) dependence of the isolated rat heart, but the combination of PAG and l-cysteine ( n = 12) improved heart contractile activity. H 2 S content, Ca 2+ -dependent NOS activity (cNOS) activity, nitrate reductase activity, and nitrite content increased by 2, 3.83, 2.5, and 1.3 times in cardiac mitochondria, and GSH and oxidized glutathione (GSSG) levels increased by 2.24 and 1.86 times in the heart homogenates of the PAG + l-cysteine group compared with the control (all P < 0.05). Inhibition of glutathione with DL-buthionine-sulfoximine (BSO; 22.2 mg/kg, 40 min, n = 6) drastically decreased Frank-Starling response of the heart and prevented PAG + l-cysteine-induced increase of GSH and GSSG levels (BSO + PAG + l-cysteine, n = 9). Inhibition of NOS, N-nitro-l-arginine-methylester hydrochloride (l-NAME; 40 min, 27 mg/kg) abolished positive inotropy induced by PAG+l-cysteine pretreatment (l-NAME + PAG + l-cysteine, n = 7). Thus, PAG + l-cysteine administration improves the Frank-Starling response by upregulating mitochondrial H 2 S, glutathione, and NO synthesis, which may be a promising approach in the treatment of myocardial dysfunction. |
