ACTIONS OF CP-060S ON VERATRIDINE-INDUCED CA2+ OVERLOAD IN CARDIOMYOCYTES AND MECHANICAL ACTIVITIES IN VASCULAR STRIPS

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.