Cyclic nucleotide regulation of the contractile proteins in mammalian cardiac muscle.

McClellan, George; Winegrad, Saul

doi:10.1085/jgp.75.3.283

Cited by 47 publications

(28 citation statements)

References 22 publications

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“…In muscles thicker than this, the Ca2+-regulated force seemed to be potentiated slightly after the detergent treatment, to an extent that increased with muscle diameter ; this was probably the result of Triton X-100 skinning a small percentage of the cells that were effectively impermeable to Ca 2+ or CaEGTA2-in the EGTA-treated muscle . These results confirm those of McClellan and Winegrad (1980), who found a small but statistically nonsignificant potentiation of force after Triton . On the other hand, we could find no evidence for a marked potentiation of Cat+ -regulated force after the muscles had been superfused with 0.5 AM adrenaline or 1 AM cAMP plus 5 mM theophylline in the presence of 1 % Triton X-100 ( Figs.…”

Section: Discussionsupporting

confidence: 91%

“…In the muscles of diameter <200 Am, potentiation of force was never observed, whether or not drugs were applied with the detergent. The reason for the discrepancy between these results and those of McClellan and Winegrad (1980) is not clear. The only difference between the experimental protocols was that we used an EGTA concentration of 10 mM rather than 3 mM to provide better buffering of Ca21, but in preliminary experiments we used an EGTA concentration of 3 mM and the results were no different from those reported here .…”

Section: Discussioncontrasting

confidence: 58%

“…1 and 2). McClellan and Winegrad (1980) reported increases of force of 173 and 159%, respectively, after treatment of the muscles with these concentrations of adrenaline and cAMP plus theophylline ; these increases were observed without the muscles being stretched or treated with DTT after the superfusion with Triton . In the present experiments, there was some slight potentiation of force in the thicker muscles, but the increase in force was no different from that found after Triton X-100 without drugs.…”

Section: Discussionmentioning

confidence: 93%

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Some characteristics of Ca2+- regulated force production in EGTA-treated muscles from rat heart.

Kentish¹,

Jewell²

1984

The Journal of General Physiology

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McClellan and Winegrad (1980, J. Gen. Physiol., 75:283-295) have reported that in rat ventricular muscles that have reportedly been made "hyperpermeable" to small ions such as Ca2+, CaEGTA2-, and MgATP2- by a soak in EGTA, the maximum Ca2+-regulated force can be permanently increased by a short exposure to positively inotropic drugs, such as epinephrine or cAMP plus theophylline, in the presence of the detergent Triton X-100. The experiments reported here were begun as an attempt to repeat and extend this important observation. However, no evidence could be found for a potentiation of force that was not merely produced by Triton alone. In addition, the thickest muscles used (250-440 microns diameter) exhibited very low values for force per unit cross-sectional area, which suggested that either Ca2+ reached only a fraction of the myofibrils or the myofibrils were in a state of low contractility. The results of further experiments that were designed to test the permeability characteristics of these EGTA-treated muscles indicated that the movement of certain ions into these preparations was restricted, even in thin muscles (80-200 microns diameter). The rate of development of Ca2+-regulated force was slow (t1/2 approximately equal to 1-3 min), but was greatly accelerated after the muscles had been superfused with Triton X-100 (t1/2 approximately equal to 10-20 s). Removal of creatine phosphate (CP) in the presence of MgATP produced a partial rigor contracture in the EGTA-treated muscles. The results were consistent with the suggestion that the EGTA-treated muscles were permeable to some extent to Ca2+ and HCP2- ions but not to CaEGTA2- and MgATP2-. Thus, it would seem unlikely that the [Ca2+], [MgATP2-], and [Mg2+] in the immediate vicinity of the myofibrils in these preparations can be adequately controlled by the solution bathing the muscles.

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Section: Discussionsupporting

confidence: 91%

Section: Discussioncontrasting

confidence: 58%

Section: Discussionmentioning

confidence: 93%

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Some characteristics of Ca2+- regulated force production in EGTA-treated muscles from rat heart.

Kentish¹,

Jewell²

1984

The Journal of General Physiology

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“…The aequorin light signals recorded from mammalian working myocardium appear to reflect predominantly the release and uptake of Ca2+ from the sarcoplasmic reticulum (Morgan & Blinks, 1982 transients . Determination of the relative effects of drugs on the amplitude of the aequorin light signal at similar levels of tension development provides an index for changes in the sensitivity of the contractile apparatus to Ca"+; an index that correlates well with results from experiments in skinned cardiac muscle fibres (Fabiato & Fabiato, 1979;Allen & Kurihara, 1980;McClellan & Winegrad, 1980;Mope et al, 1980;Hess & Wier, 1984 (Allen & Kurihara, 1980;. These results are consistent with the expectation that an increased concentration of intracellular calcium would be reflected at the level of the myofilaments and result in increased activation.…”

Section: Discussionsupporting

confidence: 74%

The effects of milrinone and piroximone on intracellular calcium handling in working myocardium from the ferret

Gwathmey

Morgan

1985

British J Pharmacology

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1 The effects of milrinone and piroximone were compared to those of isoprenaline, dibutyryl adenosine 3':5'-cyclic monophosphate (dibutyryl cyclic AMP), forskolin, isobutylmethylxanthine, increased extracellular calcium ([Ca2"10) and caffeine in ferret right ventricular papillary muscles that were loaded intracellularly with aequorin, a bioluminescent calcium indicator that emits light when it combines with calcium. 2 The positive inotropic action of each drug, except caffeine, was associated with an increase in the peak amplitude of the aequorin light signal (i.e. intracellular Ca2" transient) reflecting an increased amount of calcium available for excitation-contraction coupling; the positive inotropic effect of caffeine appears to occur by other mechanisms. 3 The time courses of the aequorin light signal and corresponding tension response were shortened by isoprenaline, forskolin, isobutylmethylxanthine, dibutyryl cyclic AMP, milrinone and piroximone; unchanged by increased [Ca2+] and prolonged by caffeine, suggesting that the rates of Ca2+ release and uptake by the sarcoplasmic reticulum were respectively increased, unchanged or decreased by these groups of drugs.4 Relative to changes in [Ca2+1L, the ratio of the peak of the aequorin light signal to the peak of the tension response was increased by isoprenaline, milrinone and piroximone, and decreased by caffeine, indicating that the Ca2+-sensitivity of the myofilaments was respectively decreased, and increased by these drugs. 5 The effects of milrinone and piroximone on the amplitude and time course of the aequorin light signal, as they relate to changes in uptake and release of calcium from the sarcoplasmic reticulum and to changes in the sensitivity of the myofilaments to Ca2+, are consistent with the findings that positive inotropic doses of these agents act by increasing intracellular concentrations of cyclic AMP. 6 Higher doses of milrinone and piroximone produced negative inotropic effects that were characterized by diminution of developed tension but no change or an increase in the amplitude of the aequorin light signal, suggesting a decrease in the sensitivity of the contractile elements to Ca2 . 7 Toxic doses of milrinone, piroximone and isoprenaline were associated with development of a Ca2+-overload state characterized by the presence of after-glimmers, after-contractions and dysrhythmias, and by decreased amplitude of both the aequorin light signal and tension response.8 The negative inotropic and toxic effects of milrinone and piroximone can be explained only in part by increased intracellular concentrations of cyclic AMP; we suggest that these drugs may have other cardiac actions.

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“…Ca^"^ sensitivity of troponin C (McClellan andWinegrad, 1980 andRay andEngland, 1976). Thus, changes in the afSnity of the contractile elements for as well as the magnitude of the Ca^"^ transient achieved during a single beat can regulate the force development by a myocyte.…”

Section: +mentioning

confidence: 99%

Utilization of fatigued and non-fatigued isolated guinea-pig papillary muscles and ventricular myocytes on the comparison of inotropic, chronotropic and intracellular calcium changes induced by monensin and digoxin

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Cyclic nucleotide regulation of the contractile proteins in mammalian cardiac muscle.

Cited by 47 publications

References 22 publications

Some characteristics of Ca2+- regulated force production in EGTA-treated muscles from rat heart.

Some characteristics of Ca2+- regulated force production in EGTA-treated muscles from rat heart.

The effects of milrinone and piroximone on intracellular calcium handling in working myocardium from the ferret

Utilization of fatigued and non-fatigued isolated guinea-pig papillary muscles and ventricular myocytes on the comparison of inotropic, chronotropic and intracellular calcium changes induced by monensin and digoxin

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