Effects of nitric oxide donors on cardiac contractility in wild-type and myoglobin-deficient mice

Abstract

1. The effects of the nitric oxide (NO) donors S-nitroso-N-acetylpenicillamine (SNAP), sodium(Z)-1-(N,N-diethylamino)diazen-1-ium-1,2-diolate (DEA-NONOate), and (Z)-1-[N-(2-Aminoethyl)-N-(2-ammonioethyl)amino]diazen-1-ium-1,2-diolate (DETA-NONOate) on force of contraction (F(c)) were studied in atrial and ventricular muscle strips obtained from wild-type (WT) and myoglobin-deficient (myo(-/-)) mice. 2. SNAP slightly reduced F(c) in preparations from WT mice at concentrations above 100 microM; this effect was more pronounced in myo(-/-) mice. 3. DEA-NONOate reduced F(c) in preparations from myo(-/-) mice to a larger extent than those from WT mice. 4. DETA-NONOate reduced F(c) in preparations from myo(-/-) but not from WT mice. 5. Pre-incubation with an inhibitor of the soluble guanylyl cyclase (1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one; 100 microM) prevented the effects of SNAP, DEA-NONOate and DETA-NONOate on F(c) in myo(-/-) mice. 6. It is suggested that, in physiological conditions, myoglobin acts as intracellular scavenger preventing NO from reaching its intracellular receptors in cardiomyocytes, whereas, in myoglobin-deficient conditions, NO is able to reduce contractility via activation of the soluble guanylyl cyclase/cyclic GMP pathway.

Figure 1

Effects of SNAP on F_C in cardiac muscle from WT and myo^−/− mice. (a, b) Original recordings of F_C from atrial preparations of WT (a) and myo^−/− mice (b). Arrows indicate the times at which SNAP (100 μM) or the solvent DMSO (0.5%, v v⁻¹) was added. (c) Bars represent means±s.e.mean (n=6 – 19). Data were obtained 5 min after the addition of SNAP (100 μM) or DMSO. NS indicates the absence of a statistically significant difference. (d) Concentration-response curves of SNAP in atria from WT mice and from myo^−/− mice in the absence and presence of ODQ (100 μM). Symbols represent means±s.e.mean (n=3 – 4).

Figure 2

Effects of DEA-NONOate on F_C in cardiac muscle from WT and myo^−/− mice. (a) Original recordings of F_C from atrial preparations of WT (upper panel) and myo^−/− mice (middle and lower panel). Arrows indicate the times at which DEA-NONOate (100 μM) was added. The bar indicates the presence of ODQ (100 μM). (b) Bars represent means±s.e.mean (n=3 – 14). Data represent the maximal effects of DEA-NONOate (100 μM) which occurred after 2 to 5 min. ODQ (100 μM) was applied 10 min before DEA-NONOate. NS and asterisks indicate the absence and presence of statistically significant differences, respectively. (c) Concentration-response curves of DEA-NONOate in atria from WT and myo^−/− mice in the absence and presence of ODQ (100 μM). Symbols represent means±s.e.mean (n=3 – 6).

Figure 3

Effects of DETA-NONOate on F_C in cardiac muscle from WT and myo^−/− mice. (a) Original recordings of F_C from atrial preparations of WT (upper panel) and myo^−/− mice (middle and lower panel). Arrows indicate the times at which DETA-NONOate (100 μM) was added. The bar indicates the presence of ODQ (100 μM). (b) Bars represent means±s.e.mean (n=3 – 9). Data were obtained 30 min after the addition of DETA-NONOate (100 μM). ODQ (100 μM) was applied 10 min before DETA-NONOate. NS and asterisks indicate the absence and presence of statistically significant differences, respectively. (c) Concentration-response curves of DETA-NONOate in atria from myo^−/− mice in the absence and presence of ODQ (100 μM). Symbols represent means±s.e.mean (n=3 – 5).