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Pharmacological Investigations of Excitation‐Contraction Coupling

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Abstract

The sections in this article are:

1 Excitation‐Contraction Coupling Phenomena
1.1 Active State
1.2 Regulation of Calcium Release
1.3 Mechanically Effective Period
1.4 Contractile Threshold
1.5 Potassium Contracture
1.6 Tension Development With Voltage Clamp
1.7 Calcium Indicators
1.8 Calcium‐Induced Calcium Release
1.9 Depolarization‐Induced Calcium Release
1.10 Membrane Potential Changes at SR Level
2 Pharmacological and Experimental Modifications of ECC
2.1 Effect of Extracellular Calcium
2.2 Effect of Hypertonic Solutions
2.3 Transverse‐Tubule Disrupture (Glycerol Treatment)
2.4 Effects of Anions
2.5 Effects of Cations
2.6 Drugs That Activate or Potentiate Contraction
2.7 Drugs That Depress Contraction
2.8 Other Treatment
Figure 1. Figure 1.

Simultaneous recording of electrical and contractile responses of frog single muscle fiber in hypertonic (A) and normal (B) Ringer's solution. Action potentials (a and c) were recorded with an intracellular microelectrode; a transducer measured twitch tension (b and d). While immersed in hypertonic fluid of 270 mM NaCl (instead of 120 mM), fiber resting potential was slightly increased, action potential basically not modified, and twitch tension completely inhibited (a and b). This effect on twitch tension is rapidly reversed when fiber is exposed to normal Ringer's solution (d). Fiber diameter, 140 μm; 20°C. [From Hodgkin and Horowicz .]

Figure 2. Figure 2.

Time courses of isometric tension, active state, and aequorin light signal during twitch of frog single muscle fiber at 5°C. Force trace records single muscle fiber from Rana pipiens; light‐response trace redrawn from ref. and scaled for twitch time course. Active‐state trace combines ideas and results of Hill and Edman and Kiessling .

Figure 3. Figure 3.

Role of action potential in ECC with different contractile potentiators. Voltage and temporal features are typical for frog muscle fibers at 20°C. A: how contractile potentiators of type A (nitrate or caffeine) prolong the mechanically effective period (arrowed bars), by lowering contractile threshold from −50 mV to about −64 mV. Dashed line at about −20 mV represents the level of mechanical saturation. B: extent that type B potentiators (zinc and uranyl ions) prolong the action potential and thus the mechanically effective period. [From Sandow et al. .]

Figure 4. Figure 4.

Time course of K contractures of single muscle fiber tested with K concentrations (values with corresponding membrane potential). Before inducing contractures, fiber was exposed to a Na‐free, choline solution to avoid twitching. [From Hodgkin and Horowicz .]

Figure 5. Figure 5.

Relationship between peak tension as a fraction of maximum tension and membrane potential of muscle fibers under voltage‐clamp conditions. Symbols, results from 5 different fibers of m. lumbricalis IV digiti of frog that were approximately 1.5 mm long and voltage clamped with 2 microelectrodes inserted in their middles. Holding potential, −100 mV; depolarizing pulse, ≥ s; 20°C–22°C. [From Caputo and de Bolanos .]

Figure 6. Figure 6.

Effect of caffeine on contractile‐activation and contractile‐repriming curves. A: relationship between peak contracture tension as fraction of maximum value and external K concentration or corresponding membrane potential in the absence (open symbols) and presence (filled symbols) of caffeine (1.5 mil) at 22°C–23°C. Symbols correspond to 3 different single fibers. As in Fig. , caffeine lowers contractile threshold. B: how external K concentration in the recovery medium after 1st contracture affects steady‐state re‐priming for 2nd contracture. Contractures induced with 190 mM K medium at 21°C–23°C. Results in absence (open symbols) and presence (filled symbols) of 1.5 mM caffeine. Symbols correspond to different single fibers. [From Lüttgau and Oetliker .]

Figure 7. Figure 7.

Changes in the onset and time course of relaxation of K contractures of single muscle fibers produced by different concentrations of tetracaine and at a low Ca concentration (⋍10 μM free Ca). Contractures at 3°C have a prolonged time course. Tetracaine speeds up onset of relaxation; sudden repolarization of fiber causes faster relaxation. Fiber diameter, 81 μm. [From Caputo .]

Figure 8. Figure 8.

Time course of Ca release during a K contracture. A: membrane potential. B and C: time courses of activation and inactivation processes of mechanism that controls Ca release. D: time course of Ca release. Dashed lines, result of sudden changes in membrane potential caused by K‐con‐centration changes as in Fig. F. [From Caputo .]

Figure 9. Figure 9.

Comparison between time courses of aequorin luminescence signals and mechanical responses during K contractures of single muscle fiber at 15°C with different K concentrations. Note different calibrations for light signals. [From Blinks et al. .]

Figure 10. Figure 10.

Voltage dependence of Ca transients and intramembrane charge movement of a cut muscle fiber segment under voltage‐clamp conditions at 3°C. A: average of 6 determinations of light absorbance changes of antipyrylazo III at 720 nm for 100‐ms pulses of different amplitude. Fiber had holding potential of −100 and was depolarized to values shown near each record. Calibration, ratio of A720/A550 of 1.4 × 10−2. B: intramembrane charge‐movement currents for same pulses. Vertical calibration for charge movement, 3.2 μA μF−1; horizontal calibration, 30 ms. Fiber stretched 3.46 μm per sarcomere to diminish movement artifacts.

From Kovacs et al. . Reprinted by permission from Nature, copyright 1979, Maemillan Journals Ltd
Figure 11. Figure 11.

Effect of on twitch tension in a single muscle fiber during rapid solution changes. A: small artifact caused by sudden flow of solution. B: effectiveness of solution change system in abolishing twitch tension when normal Ringer's solution is substituted with Na‐free, choline solution. Abrupt loss of twitch indicates effectiveness of solution change. C, D, and E: time course of twitch potentiator and decay of potentiation when Ringer's solution is flushed into and out of chamber. In C fiber was stimulated at 1.56 Hz and in D and E at 0.78 Hz. Exponential time constant for ON effect, 3–4 s; for OFF effect, 2–3 s; fiber diameter, 122 μn; 19°C. [From Hodgkin and Horowicz .]

Figure 12. Figure 12.

Effect of caffeine at different concentrations on single muscle fibers at 21°C–23°C. A: effects of 2, 3, and 5 mM caffeine on twitch tension of fiber 109 μm in diameter. B: contractures obtained with 4, 8, and 3 mM caffeine and a fiber 145 μm in diameter, either polarized or depolarized. [From Lüttgau and Oetliker .]

Figure 13. Figure 13.

Effect of nicotine (10 mM) on time course of K contracture of single muscle fiber. NR, normal Ringer's solution. At this concentration nicotine did not cause a contracture even after 8‐min exposure. The time course of maximal K contractures, however, was markedly prolonged, consistent with an effect on inactivation mechanism for Ca release shown in Fig. . Nicotine effect appears partially reversible.

From C. Caputo, unpublished experiment
Figure 14. Figure 14.

Effect of 5 mM tetracaine charge movement and antipyrylazo III absorbance signal associated with voltage pulses to −20 mV. Voltage‐clamped cut single muscle fiber of Rana catesbeiana . Left: controls. Right: obtained after addition of drug. Charge movement trace obtained by subtracting 4 traces associated with voltage steps of P/4 amplitude (applied from holding potential of −130 mV) from trace generated by voltage step of amplitude P (applied from holding potential of −100 mV). Charge movement records normalized with membrane capacity calculated by integration of current records of long duration and small amplitude. Arrow, absorbance increase of 0.03 or 0.015, referred to ΔA/A = (ΔA710 − ΔA790)/A550. Temperature, 9°C.

From J. Vergara and C. Caputo, unpublished observations


Figure 1.

Simultaneous recording of electrical and contractile responses of frog single muscle fiber in hypertonic (A) and normal (B) Ringer's solution. Action potentials (a and c) were recorded with an intracellular microelectrode; a transducer measured twitch tension (b and d). While immersed in hypertonic fluid of 270 mM NaCl (instead of 120 mM), fiber resting potential was slightly increased, action potential basically not modified, and twitch tension completely inhibited (a and b). This effect on twitch tension is rapidly reversed when fiber is exposed to normal Ringer's solution (d). Fiber diameter, 140 μm; 20°C. [From Hodgkin and Horowicz .]



Figure 2.

Time courses of isometric tension, active state, and aequorin light signal during twitch of frog single muscle fiber at 5°C. Force trace records single muscle fiber from Rana pipiens; light‐response trace redrawn from ref. and scaled for twitch time course. Active‐state trace combines ideas and results of Hill and Edman and Kiessling .



Figure 3.

Role of action potential in ECC with different contractile potentiators. Voltage and temporal features are typical for frog muscle fibers at 20°C. A: how contractile potentiators of type A (nitrate or caffeine) prolong the mechanically effective period (arrowed bars), by lowering contractile threshold from −50 mV to about −64 mV. Dashed line at about −20 mV represents the level of mechanical saturation. B: extent that type B potentiators (zinc and uranyl ions) prolong the action potential and thus the mechanically effective period. [From Sandow et al. .]



Figure 4.

Time course of K contractures of single muscle fiber tested with K concentrations (values with corresponding membrane potential). Before inducing contractures, fiber was exposed to a Na‐free, choline solution to avoid twitching. [From Hodgkin and Horowicz .]



Figure 5.

Relationship between peak tension as a fraction of maximum tension and membrane potential of muscle fibers under voltage‐clamp conditions. Symbols, results from 5 different fibers of m. lumbricalis IV digiti of frog that were approximately 1.5 mm long and voltage clamped with 2 microelectrodes inserted in their middles. Holding potential, −100 mV; depolarizing pulse, ≥ s; 20°C–22°C. [From Caputo and de Bolanos .]



Figure 6.

Effect of caffeine on contractile‐activation and contractile‐repriming curves. A: relationship between peak contracture tension as fraction of maximum value and external K concentration or corresponding membrane potential in the absence (open symbols) and presence (filled symbols) of caffeine (1.5 mil) at 22°C–23°C. Symbols correspond to 3 different single fibers. As in Fig. , caffeine lowers contractile threshold. B: how external K concentration in the recovery medium after 1st contracture affects steady‐state re‐priming for 2nd contracture. Contractures induced with 190 mM K medium at 21°C–23°C. Results in absence (open symbols) and presence (filled symbols) of 1.5 mM caffeine. Symbols correspond to different single fibers. [From Lüttgau and Oetliker .]



Figure 7.

Changes in the onset and time course of relaxation of K contractures of single muscle fibers produced by different concentrations of tetracaine and at a low Ca concentration (⋍10 μM free Ca). Contractures at 3°C have a prolonged time course. Tetracaine speeds up onset of relaxation; sudden repolarization of fiber causes faster relaxation. Fiber diameter, 81 μm. [From Caputo .]



Figure 8.

Time course of Ca release during a K contracture. A: membrane potential. B and C: time courses of activation and inactivation processes of mechanism that controls Ca release. D: time course of Ca release. Dashed lines, result of sudden changes in membrane potential caused by K‐con‐centration changes as in Fig. F. [From Caputo .]



Figure 9.

Comparison between time courses of aequorin luminescence signals and mechanical responses during K contractures of single muscle fiber at 15°C with different K concentrations. Note different calibrations for light signals. [From Blinks et al. .]



Figure 10.

Voltage dependence of Ca transients and intramembrane charge movement of a cut muscle fiber segment under voltage‐clamp conditions at 3°C. A: average of 6 determinations of light absorbance changes of antipyrylazo III at 720 nm for 100‐ms pulses of different amplitude. Fiber had holding potential of −100 and was depolarized to values shown near each record. Calibration, ratio of A720/A550 of 1.4 × 10−2. B: intramembrane charge‐movement currents for same pulses. Vertical calibration for charge movement, 3.2 μA μF−1; horizontal calibration, 30 ms. Fiber stretched 3.46 μm per sarcomere to diminish movement artifacts.

From Kovacs et al. . Reprinted by permission from Nature, copyright 1979, Maemillan Journals Ltd


Figure 11.

Effect of on twitch tension in a single muscle fiber during rapid solution changes. A: small artifact caused by sudden flow of solution. B: effectiveness of solution change system in abolishing twitch tension when normal Ringer's solution is substituted with Na‐free, choline solution. Abrupt loss of twitch indicates effectiveness of solution change. C, D, and E: time course of twitch potentiator and decay of potentiation when Ringer's solution is flushed into and out of chamber. In C fiber was stimulated at 1.56 Hz and in D and E at 0.78 Hz. Exponential time constant for ON effect, 3–4 s; for OFF effect, 2–3 s; fiber diameter, 122 μn; 19°C. [From Hodgkin and Horowicz .]



Figure 12.

Effect of caffeine at different concentrations on single muscle fibers at 21°C–23°C. A: effects of 2, 3, and 5 mM caffeine on twitch tension of fiber 109 μm in diameter. B: contractures obtained with 4, 8, and 3 mM caffeine and a fiber 145 μm in diameter, either polarized or depolarized. [From Lüttgau and Oetliker .]



Figure 13.

Effect of nicotine (10 mM) on time course of K contracture of single muscle fiber. NR, normal Ringer's solution. At this concentration nicotine did not cause a contracture even after 8‐min exposure. The time course of maximal K contractures, however, was markedly prolonged, consistent with an effect on inactivation mechanism for Ca release shown in Fig. . Nicotine effect appears partially reversible.

From C. Caputo, unpublished experiment


Figure 14.

Effect of 5 mM tetracaine charge movement and antipyrylazo III absorbance signal associated with voltage pulses to −20 mV. Voltage‐clamped cut single muscle fiber of Rana catesbeiana . Left: controls. Right: obtained after addition of drug. Charge movement trace obtained by subtracting 4 traces associated with voltage steps of P/4 amplitude (applied from holding potential of −130 mV) from trace generated by voltage step of amplitude P (applied from holding potential of −100 mV). Charge movement records normalized with membrane capacity calculated by integration of current records of long duration and small amplitude. Arrow, absorbance increase of 0.03 or 0.015, referred to ΔA/A = (ΔA710 − ΔA790)/A550. Temperature, 9°C.

From J. Vergara and C. Caputo, unpublished observations
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Carlo Caputo. Pharmacological Investigations of Excitation‐Contraction Coupling. Compr Physiol 2011, Supplement 27: Handbook of Physiology, Skeletal Muscle: 381-415. First published in print 1983. doi: 10.1002/cphy.cp100114