The effects of digitalis on intracellular calcium transients in mammalian working myocardium as detected with aequorin.
The effects of positive inotropic agents on the amplitude and time course of the light signal and corresponding tension response were studied in cat and human working myocardium microinjected with the bioluminescent Ca2+ indicator aequorin. Distinctive patterns of light and tension responses were identified that are consistent with known actions of the various agents on the release of Ca2+ from intracellular stores, rate of uptake of Ca2+ by the sarcoplasmic reticulum and sensitivity of the myofilaments to Ca2+. In common with most other inotropic drugs, the cardiotonic steroid, acetylstrophanthidin, in doses of 4 X 10(-7) to 2 X 10(-6)M increases the amount of Ca2+ available for excitation-contraction coupling in the heart. However, in contrast to most other agents, acetylstrophanthidin does not affect the time course of the calcium transient. In common with changes in [Ca2+]o, acetylstrophanthidin does not alter the relationship between the amplitude of the aequorin light signal and developed tension, which, in contrast to caffeine and isoproterenol, indicates that the increase in tension is fully accounted for by the increase in systolic free calcium. These findings suggest that the cardiotonic steroids increase loading of intracellular calcium stores without affecting the kinetics of subcellular handling of Ca2+. In doses of 8 X 10(-7) to 2 X 10(-6)M, acetylstrophanthidin produces a calcium-overload state characterized by 'after-contractions' and 'after-glimmers' that are associated with the development of automatic and triggerable dysrhythmias. These studies provide direct evidence that the inotropic and toxic effects of digitalis on animal and human working myocardium are produced by changes in intracellular Ca2+.
D000200:Action Potentials; D000331:Aequorin; D000818:Animals; D001693:Biological Transport, Active / Q000187:drug effects; D002118:Calcium / Q000378:metabolism*; D002415:Cats; D004070:Digitalis; D004285:Dogs; D005260:Female; D006321:Heart / Q000187:drug effects*; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000378:metabolism*; D010946:Plants, Medicinal; D010947:Plants, Toxic; D011817:Rabbits; D013327:Strophanthidin / Q000031:analogs & derivatives / Q000494:pharmacology
D000331:Aequorin; D013327:Strophanthidin; C004681:acetylstrophanthidin; D002118:Calcium