L. Sandirasegarane et J. Diamond, The nitric oxide donors, SNAP and DEA/NO, exert a negative inotropic effect in rat cardiomyocytes which is independent of cyclic GMP elevation, J MOL CEL C, 31(4), 1999, pp. 799-808
The role of guanosine 3',5'-cyclic monophosphate (cGMP) in the regulation o
f cardiac contractility remains controversial. The present study has examin
ed the effects of high concentrations of the nitric oxide (NO) donors, S-ni
troso-N-acetylpenicillamine (SNAP) and 1,1-diethyl-2-hydroxy-2-nitroso-hydr
azine (DEA/NO), on cGMP levels and isoproterenol-induced increases in contr
actility in rat cardiomyocytes before and after selective inhibition of sol
uble guanylyl cyclase with 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ
). In control myocytes, 100 mu M SNAP or 100 mu M DEA/NO increased cGMP lev
els by more than 15-fold at 2 and 6 min and produced marked attenuations of
isoproterenol-mediated increases in maximal cell shortening over the same
time period. The NO donors had no significant effect on basal cell shorteni
ng (in the absence of isoproterenol). Pretreatment of myocytes with 25 mu M
ODQ for 30 min resulted in a complete blockade of the SNAP- or DEA/NO-indu
ced increases in cGMP with no reversal of negative inotropy. ODQ did not af
fect basal contractility, basal cGMP levels or isoproterenol-induced increa
ses in cell shortening. Furthermore, myocytes exposed to the cGMP analog, 8
-bromo-cGMP (100 mu M), did not exhibit significant differences in basal co
ntractility or isoproterenol-induced increases in cell shortening These res
ults suggest that attenuation of cardiac contractility by NO donors in rat
cardiomyocytes occurs by a mechanism independent of increases in cGMP level
s. (C) 1999 Academic Press.