SR33805, a Ca2+ antagonist with length-dependent Ca2+ -sensitizing properties in cardiac myocytes.
1. This study examined the effects of SR33805, a fantofarone derivative with reported strong Ca(2+) -antagonistic properties, on the contractile properties of intact and skinned rat ventricular myocytes. 2. On intact cells loaded with the Ca(2+)-fluorescent indicator Indo-1, the application of low concentrations of SR33805 enhanced the amplitude of unloaded cell shortening and decreased the duration of cell shortening. Amplitude of the Ca(2+) transient was also decreased. 3. These effects were accompanied with a shortening of the action potential and a dose-dependent blockade of L-type calcium current (IC(50)=2.4 x 10(-8) M). 4. On skinned cardiac cells, the application of a low SR33805 concentration (10(-8) M) induced a significant increase in maximal Ca(2+)-activated force at the two-tested sarcomere lengths (SLs), 1.9 and 2.3 microm. 5. The application of a larger dose of SR33805 (10(-6)-10(-5) M) induced a significant leftward shift of the tension-pCa relation that accounts for Ca(2+)-sensitization of the myofilaments, particularly at 2.3 microm SL. 6. In conclusion, despite its strong Ca(2+)-antagonistic properties SR33805 increases cardiac cell contractile activity as a consequence of its Ca(2+)-sensitizing effects. These effects are attributable to both an increase in the maximal Ca(2+)-activated force and a length-dependent Ca(2+)-sensitization.
INSERM U-390, Unite de Recherches de Physiopathologie Cardiovasculaire, CHU Arnaud de Villeneuve, 371 Avenue du Doyen Gaston Giraud, 34295 Montpellier Cedex 5, France.
Olivier
O
Cazorla
Alain
A
Lacampagne
Jeremy
J
Fauconnier
Guy
G
Vassort
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D002118:Calcium / Q000502:physiology*; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D048429:Cell Size / Q000187:drug effects; D003864:Depression, Chemical; D004305:Dose-Response Relationship, Drug; D006352:Heart Ventricles / Q000166:cytology; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology*; D008297:Male; D009124:Muscle Proteins / Q000187:drug effects / Q000502:physiology; D009200:Myocardial Contraction / Q000187:drug effects*; D032383:Myocytes, Cardiac / Q000187:drug effects*; D018408:Patch-Clamp Techniques; D051381:Rats; D017208:Rats, Wistar; D013450:Sulfones / Q000494:pharmacology*; D016276:Ventricular Function
D002121:Calcium Channel Blockers; D007211:Indoles; D009124:Muscle Proteins; D013450:Sulfones; C084255:SR 33805; D002118:Calcium