Actions of CP-060S on veratridine-induced Ca2+ overload in cardiomyocytes and mechanical activities in vascular strips.

Abstract

CP-060S, (-)-(S)-2-[3,5-bis(1, 1-dimethylethyl)-4-hydroxyphenyl]-3-[3-[N-methyl-N-[2-(3, 4-methylenedioxyphenoxy)ethyl]amino]propyl]-1,3-thiazolidin- 4-one hydrogen fumarate, is a novel cardioprotective drug which is designed to prevent Ca2+ overload and cause vasorelaxation. The effects of this compound were evaluated and compared with those of CP-060R (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 microM), 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. Pretreatment of cardiomyocytes with more than 300 nM of CP-060S or CP-060R for 30 min provided almost complete protection against the veratridine-induced cell contracture; in CP-060S(1 microM)-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 showed no protection below 1 microM and only partial protection at 10 microM. CP-060S, CP-060R and diltiazem all shifted the concentration-response curve for CaCl2 to the right in a competitive manner in depolarized rat thoracic aorta. The pA2 values of CP-060S, CP-060R and diltiazem were 9.16 +/- 0.18, 8.24 +/- 0.14 and 7.66 +/- 0.09, respectively. Our results indicate that CP-060 behaves stereoselectively as a Ca2+ channel antagonist and non-stereo-selectively to protect against veratridine-induced contracture. The latter effect suggests that Ca2+ entry blockade is not the mechanism by which CP-060S exerts cardioprotection.

• Authors: K Tamura, Y Suzuki, T Koga, M Akima, T Kato, H Nabata
• Journal: European journal of pharmacology (Eur J Pharmacol) Vol. 312 Issue 2 Pg. 195-202 (Sep 26 1996) ISSN: 0014-2999 [Print] Netherlands
• PMID: 8894596 (Publication Type: Journal Article)

Chemical References

• CP 060S
• Calcium Channel Blockers
• Thiazoles
• Thiazolidines
• Vasodilator Agents
• Veratridine
• Calcium

Topics

• Animals
• Aorta (drug effects, metabolism)
• Calcium (metabolism)
• Calcium Channel Blockers (pharmacology)
• Drug Interactions
• Heart (drug effects)
• In Vitro Techniques
• Male
• Rats
• Rats, Sprague-Dawley
• Thiazoles (pharmacology)
• Thiazolidines
• Vasodilator Agents (pharmacology)
• Veratridine (pharmacology)