Effects of nitric oxide donors on cardiac contractility in wild-type and myoglobin-deficient mice.
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.
Wegener
J W
JW
Pharmakologisches Institut, Universität Mainz, Obere Zahlbacher Str. 67, 55101 Mainz, Germany.
Gödecke
A
A
Schrader
J
J
Nawrath
H
H
D000818:Animals; D004558:Electric Stimulation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006834:Hydrazines / Q000494:pharmacology*; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D009200:Myocardial Contraction / Q000187:drug effects*; D009206:Myocardium / Q000201:enzymology; D009211:Myoglobin / Q000172:deficiency* / Q000235:genetics; D020030:Nitric Oxide Donors / Q000494:pharmacology*; D009589:Nitrogen Oxides; D009603:Nitroso Compounds; D010069:Oxadiazoles / Q000494:pharmacology; D011810:Quinoxalines / Q000494:pharmacology; D026423:S-Nitroso-N-Acetylpenicillamine / Q000494:pharmacology*
C095284:1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one; D004791:Enzyme Inhibitors; D006834:Hydrazines; D009211:Myoglobin; D020030:Nitric Oxide Donors; D009589:Nitrogen Oxides; D009603:Nitroso Compounds; D010069:Oxadiazoles; D011810:Quinoxalines; C094210:2,2'-(hydroxynitrosohydrazono)bis-ethanamine; D026423:S-Nitroso-N-Acetylpenicillamine; C084012:1,1-diethyl-2-hydroxy-2-nitrosohydrazine