Hiromi Sugawara and Masao Endoh (*)
Department of Pharmacology, Yamagata University School of Medicine, 2-2-2
lida-nishi, Yamagata 990-9585, Japan
(*) To whom correspondence should be addressed.
Abstract: EMD 53998 (5-[1-(3,4-dimethoxybenzoyl)
-1,2,3,4-tetrahydro-6-quinolyl]-6-methyl-3,6-dihydro-2H-1,3,4-thiadiazin-2-one),
the racemic mixture of (+)-enantiomer EMD 57033 and (-)-enantiomer EMD 57439,
is a prototype of Ca2+ sensitizers that act via a central and/or
down-stream mechanism in cardiac E-C coupling. In rabbit ventricular cardiomyocytes
loaded with indo-1/AM, EMD 53998 and EMD 57033 shifted the relationship
between Ca2+ transients and cell shortening (systolic function)
to the left to the same extent as compared with that of elevation of [Ca2+]o.
EMD 57439 did not elicit a positive inotropic effect (PIE). The PIE of EMD
57033 was associated with a more pronounced decrease in the diastolic cell
length than that of EMD 53998, whereas the systolic effects of these compounds
were equivalent. These results indicate that weak phosphodiesterase (PDE)
III inhibition may exert a differential action on diastolic and systolic
function. Thus, EMD 57439 antagonizes the Ca2+-sensitizing effect
of EMD 57033 on diastolic function with no effect on systolic function,
which may lead to a decease in diastolic cell length of a lesser extent
with the racemate EMD 53998 compared with (+)-enantiomer EMD 57033.
Keywords: EMD 53998, EMD 57033, Ca2+ transient, Ca2+
sensitizer, Rabbit ventricular cardiomyocyte