K. Tamura et al., ACTIONS OF CP-060S ON VERATRIDINE-INDUCED CA2+ OVERLOAD IN CARDIOMYOCYTES AND MECHANICAL ACTIVITIES IN VASCULAR STRIPS, European journal of pharmacology, 312(2), 1996, pp. 195-202
CP-060S, [2-(3,4-methylenedioxyphenoxy)ethyl]amino]propyl]- 1,3-thiazo
lidin-4-one hydrogen fumarate, is a novel cardioprotective drug which
is designed to prevent Ca2+ overload and cause vasorelaxation. The eff
ects of this compound were evaluated and compared with those of CP-060
R (enantiomer of CP-060S,) and diltiazem(Ca2+ channel antagonist) in a
veratridine-induced model of Ca2+ overload and vasorelaxation. After
5-min superfusion of veratridine (74 mu M), intracellular free calcium
concentrations ([Ca2+](i)) of rat single cardiomyocytes, as measured
with the fura-2 procedure, were greatly elevated, from 44 +/- 5 nM to
3705 +/- 942 nM, and subsequently generated cell contracture. Pretreat
ment of cardiomyocytes with more than 300 nM of CP-060S or CP-060R for
30 min provided almost complete protection against the veratridine-in
duced cell contracture; in CP-060S(1 mu M)-treated myocytes, [Ca2+](i)
were minimal and partially elevated from 42 +/- 5 nM to 72 +/- 14 nM
after 5 min of veratridine superfusion. In comparison, diltiazem showe
d no protection below 1 mu M and only partial protection at 10 mu M. C
P-060S, CP-060R and diltiazem all shifted the concentration-response c
urve for CaCl2 to the right in a competitive manner in depolarized rat
thoracic aorta. The pA(2) values of CP-060S, CP-060R and diltiazem we
re 9.16 +/- 0.18, 8.24 +/- 0.14 and 7.66 +/- 0.09, respectively. Our r
esults indicate that CP-060 behaves stereoselectively as a Ca2+ channe
l antagonist and non-stereoselectively to protect against veratridine-
induced contracture. The latter effect suggests that Ca2+ entry blocka
de is not the mechanism by which CP-060S exerts cardioprotection.