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275 Calcium and digitalis action on heart muscle
Abstracts of Papers made to explain: (1) the coupling of excitation to contraction in the heart; and (2) the mechanism of the positive inotropic effects of cardiac glycosides.
275 Calcium
Muscle.
and Digitalis Action on Heart i\. E. FARAH and P.S. WITT (U.S.h.).
83
or k-Strophanthin to actomyosin and myosin of skeletai muscle (rabbit and calf) and heart muscle (calf) was investigated. Ultrafiltration with a specially built apparatus and equilibrium dialysis gave the necessary data for the determination of the dissociation constants. ‘The molar binding ratio \vas found to be larger for actomyosin than for serum-albumin. The resulting glycoside--actumyosin complex changes the molecular form of the protein. The fibrous protein with high viscosity and double refraction of flow assumes an ellipsoidal shape after addition of glycoside to the solution (Ostwald viscosimetcr). For many glycosides the change of viscosity is proportional to the biological property of fixation of the glycoside to the heart muscle. The thixotropy of the actomyosin solutions was studied in a rotation viscosimeter. The cocffxcicnt of thixotropic breakdown obtained by application of constant shear shows an interesting correlation with the biological activity (toxic dose in the cat) of various active and inactive cardiac glycosidrs. This may be due to some charge phenomenon along the actomyosin fibre. Cardin-active glycosides were shown to augment binding of potassium and calcium ions to myosin solutions.
Changes in extracellular Ca concentration affect contractility of cardiac muscle. Ca acts on the excitable membrane, on the excitation-contraction coupling mechanism, and on contractile proteins. Digitaiis effects are influenced by changes in Ca concentration. Thus an increase in Ca in the medium increases the toxicity ofdigitalis glycosidcs. The effects of digitalis on cardiac contractiiiit?; arc also related to Ca concentration, howexrer, here the data intticate an additive effect of Ca and digitalis. Ca content of the heart is not measurably changed by therapeutic doses of digitalis glycosides. Uptake I)! “%a by the beating heart muscle is not chang.ed by IO 7 ,\I ouabain, while lOm@hl ouabain sagnificantly increases uptake. The latter is a highl) losic concentration which causes contracture. Indirect evidence indicates that ‘%a efIlux is not significantly changtd by therapeutic amounts of ouabain. Furthermore, there are distinct differences between Ca and digitalis actions on the heart. , Relation of Cations to the Inotroaic and It is unlikely that digitalis in therapeutic dose_; acts AT!77 Metabolic Actions of Cardiac Giicosides. through either increaTing the rate of uptake or K. s. r.EE (U.S.tk). decreasing the rate of loss or changing the total amount of Ca in heart muscle. This does not The levels of ATP, ADP, AAIP, PC and IP; the exclude the possibility that intracellular redistribuQOa: the contractile tension and the Na+, K+ and tion of Ca may be operative, but this has not bren Ca++ content of papillary muscles of cat were meastudied. sured following the administration of ouabain to the Ouabain produces an increase in the rate-depenmedium containing varying amounts of K+ and dent &tropic effects of heart muscle. When the Ca--. increase in contractility at high rates is depressed, (1) ;\t inotropic stag? of ouabain, the QO, ouabain in low concentrations (10 * to 5 X lo-* RI) increased whereas there was no change in either the restores these phenomena. High or toxic concencontent of the phosphate compounds or the issue trations of ouabain depress or eliminate the ratecontent of Na+, K+ and Cat+. dependent positive inotropic rffccts. It is proposed (2) At toxic stage of ouabain, the QO, was markthat therapeutic doses of digitalis act on the mecbedly increased whiie the PC and ATP content were anism that causes the rate-dependent changes in decreased. In addition, the tissue content of I(+ contracriiity. Our results show that positive was decreased whereas that of Na- and Ca+* was inntropic effects due to ouabain as well as Ca are increased. not related to the changes in intracellular ionic (3) Neither excess Ca-+ nor K” lack in the medium composition as proposed by Hajdu.“’ produced the same effect on those paramerers as iSrll,~,nrrr
275 Calcium
Muscle.
and Digitalis Action on Heart i\. E. FARAH and P.S. WITT (U.S.h.).
83
or k-Strophanthin to actomyosin and myosin of skeletai muscle (rabbit and calf) and heart muscle (calf) was investigated. Ultrafiltration with a specially built apparatus and equilibrium dialysis gave the necessary data for the determination of the dissociation constants. ‘The molar binding ratio \vas found to be larger for actomyosin than for serum-albumin. The resulting glycoside--actumyosin complex changes the molecular form of the protein. The fibrous protein with high viscosity and double refraction of flow assumes an ellipsoidal shape after addition of glycoside to the solution (Ostwald viscosimetcr). For many glycosides the change of viscosity is proportional to the biological property of fixation of the glycoside to the heart muscle. The thixotropy of the actomyosin solutions was studied in a rotation viscosimeter. The cocffxcicnt of thixotropic breakdown obtained by application of constant shear shows an interesting correlation with the biological activity (toxic dose in the cat) of various active and inactive cardiac glycosidrs. This may be due to some charge phenomenon along the actomyosin fibre. Cardin-active glycosides were shown to augment binding of potassium and calcium ions to myosin solutions.
Changes in extracellular Ca concentration affect contractility of cardiac muscle. Ca acts on the excitable membrane, on the excitation-contraction coupling mechanism, and on contractile proteins. Digitaiis effects are influenced by changes in Ca concentration. Thus an increase in Ca in the medium increases the toxicity ofdigitalis glycosidcs. The effects of digitalis on cardiac contractiiiit?; arc also related to Ca concentration, howexrer, here the data intticate an additive effect of Ca and digitalis. Ca content of the heart is not measurably changed by therapeutic doses of digitalis glycosides. Uptake I)! “%a by the beating heart muscle is not chang.ed by IO 7 ,\I ouabain, while lOm@hl ouabain sagnificantly increases uptake. The latter is a highl) losic concentration which causes contracture. Indirect evidence indicates that ‘%a efIlux is not significantly changtd by therapeutic amounts of ouabain. Furthermore, there are distinct differences between Ca and digitalis actions on the heart. , Relation of Cations to the Inotroaic and It is unlikely that digitalis in therapeutic dose_; acts AT!77 Metabolic Actions of Cardiac Giicosides. through either increaTing the rate of uptake or K. s. r.EE (U.S.tk). decreasing the rate of loss or changing the total amount of Ca in heart muscle. This does not The levels of ATP, ADP, AAIP, PC and IP; the exclude the possibility that intracellular redistribuQOa: the contractile tension and the Na+, K+ and tion of Ca may be operative, but this has not bren Ca++ content of papillary muscles of cat were meastudied. sured following the administration of ouabain to the Ouabain produces an increase in the rate-depenmedium containing varying amounts of K+ and dent &tropic effects of heart muscle. When the Ca--. increase in contractility at high rates is depressed, (1) ;\t inotropic stag? of ouabain, the QO, ouabain in low concentrations (10 * to 5 X lo-* RI) increased whereas there was no change in either the restores these phenomena. High or toxic concencontent of the phosphate compounds or the issue trations of ouabain depress or eliminate the ratecontent of Na+, K+ and Cat+. dependent positive inotropic rffccts. It is proposed (2) At toxic stage of ouabain, the QO, was markthat therapeutic doses of digitalis act on the mecbedly increased whiie the PC and ATP content were anism that causes the rate-dependent changes in decreased. In addition, the tissue content of I(+ contracriiity. Our results show that positive was decreased whereas that of Na- and Ca+* was inntropic effects due to ouabain as well as Ca are increased. not related to the changes in intracellular ionic (3) Neither excess Ca-+ nor K” lack in the medium composition as proposed by Hajdu.“’ produced the same effect on those paramerers as iSrll,~,nrrr