The positive inotropic effect of compound II, a novel analogue of sotalol, on guinea-pig papillary muscles and single ventricular myocytes.
1. Compound II is a novel analogue of sotalol which has been reported to be free of beta-adrenoceptor and L-type calcium channel blocking actions. The effects of compound II on the contraction of guinea-pig papillary muscles (at 2 microM) and single ventricular myocytes (at 100 nM) were investigated. 2. Exposure to compound II caused a significant increase in the contraction of both preparations. 3. Compound II prolonged the action potential of the single myocytes and increased the magnitude of the Ca-activated current which was used as a qualitative indicator of the intracellular calcium transient. 4. The ratio of first/steady state Ca-activated currents evoked by short action potentials was not modified. This may indicate that compound II does not influence the normal functioning of the sarcoplasmic reticulum stores. 5. The observations are consistent with the hypothesis that action potential prolongation by compound II reduces Ca2+ extrusion via the Na-Ca exchange. This in turn allows increased uptake of calcium into the sarcoplasmic reticulum stores so that more calcium is available for release by subsequent action potentials, leading to an increase in intracellular calcium transients and contractions.
White
E
E
University Department of Pharmacology, Oxford.
Connors
S P
SP
Gill
E W
EW
Terrar
D A
DA
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000187:drug effects / Q000378:metabolism; D002316:Cardiotonic Agents / Q000494:pharmacology*; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism; D006168:Guinea Pigs; D006352:Heart Ventricles / Q000166:cytology / Q000187:drug effects; D066298:In Vitro Techniques; D008564:Membrane Potentials / Q000187:drug effects; D009200:Myocardial Contraction / Q000187:drug effects*; D009206:Myocardium / Q000166:cytology / Q000378:metabolism; D010210:Papillary Muscles / Q000187:drug effects; D012519:Sarcoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D013015:Sotalol / Q000031:analogs & derivatives* / Q000494:pharmacology
D015220:Calcium Channels; D002316:Cardiotonic Agents; C084176:1-(4-methanesulfonamidophenoxy)-3-(N-methyl-3,4-dichlorophenylethylamino)-2-propanol; D013015:Sotalol; D002118:Calcium