Role of intracellular sodium in the regulation of intracellular calcium and contractility. Effects of DPI 201-106 on excitation-contraction coupling in human ventricular myocardium.
Experiments were performed to investigate the mechanism of action of DPI 201-106 on human heart muscle. In both control and myopathic muscles, DPI produced concentration-dependent increases in action potential duration, resting muscle tension, peak isometric tension, and duration of isometric tension. These changes were associated with increases in resting intracellular calcium and peak calcium transients as measured by aequorin. At higher concentrations of DPI, a second delayed Ca2+ transient (L') appeared. L' was inhibited by tetrodotoxin and ryanodine, suggesting that DPI acts at both the sarcolemma and the sarcoplasmic reticulum. DPI toxicity was manifested by after-glimmers and after-contractions reflecting a Ca2+-overload state: DPI effects were mimicked by veratridine, a Na+ channel agonist, and reversed by tetrodotoxin, yohimbine, and cadmium, Na+ channel antagonists. These results suggest that DPI acts primarily as a Na+ channel agonist. DPI may produce an increase in intracellular Ca2+ by increasing intracellular Na+ and altering Na+-Ca2+ exchange across the sarcolemma. DPI may also increase intracellular Ca2+ by directly altering sarcoplasmic reticulum Ca2+ handling.
Gwathmey
J K
JK
Charles A. Dana Research Institute, Beth Israel Hospital, Boston, Massachusetts 02215.
Slawsky
M T
MT
Briggs
G M
GM
Morgan
J P
JP
D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester / Q000494:pharmacology; D000331:Aequorin; D000465:Algorithms; D002104:Cadmium / Q000494:pharmacology; D002118:Calcium / Q000502:physiology*; D006321:Heart / Q000187:drug effects; D006801:Humans; D009200:Myocardial Contraction / Q000187:drug effects*; D010879:Piperazines / Q000494:pharmacology*; D012433:Ryanodine / Q000494:pharmacology; D012964:Sodium / Q000502:physiology*; D013779:Tetrodotoxin / Q000494:pharmacology; D014701:Veratridine / Q000494:pharmacology; D015016:Yohimbine / Q000494:pharmacology
D010879:Piperazines; D002104:Cadmium; D012433:Ryanodine; D015016:Yohimbine; D013779:Tetrodotoxin; D000331:Aequorin; D014701:Veratridine; D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; C046261:DPI 201-106; D012964:Sodium; D002118:Calcium