Contractility in Isolated Mammalian Heart Muscle after Acid-Base Changes
TL;DR: In-vitro experiments performed in cat papillary muscles and strips of rat right ventricle suggest that the changes in myocardial contractility that follow acid-base disturbances are not a function of extracellular pH.
Abstract: In-vitro experiments performed in cat papillary muscles and strips of rat right ventricle suggest that the changes in myocardial contractility that follow acid-base disturbances are not a function of extracellular pH. Simultaneous changes in Pco2 and NaHCO3 concentration, with extracellular pH constant, decreased developed tension and maximal rate of rise of the tension (dT/dt) without significant changes in the time to peak tension when the muscle was exposed to the solution with higher Pco2 and NaHCO3 concentration. At an extracellular pH of 7.40, developed tension decreased 0.51 ± 0.13 g/mm2 (P < 0.02) and dT/dt decreased 1.29 ± 0.50 g/sec (P < 0.05) with no significant change in time to peak tension (0.038 ± 0.022 sec). Changes in pH produced by increasing Pco2 at constant NaHCO3 concentration were followed by a significant decrease in contractility. A change of Pco2 from 20 to 90 mm Hg that produced a change in extracellular pH from 7.60 to 7.00 was accompanied by a decrease in developed tension of 0...
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TL;DR: The final amount of force developed by heart muscle during acidosis is the complex sum of these changes, possibly by a direct action on the cross bridges.
Abstract: It has been known for over 100 years that acidosis decreases the contractility of cardiac muscle. However, the mechanisms underlying this decrease are complicated because acidosis affects every step in the excitation-contraction coupling pathway, including both the delivery of Ca2+ to the myofilaments and the response of the myofilaments to Ca2+. Acidosis has diverse effects on Ca2+ delivery. Actions that may diminish Ca2+ delivery include 1) inhibition of the Ca2+ current, 2) reduction of Ca2+ release from the sarcoplasmic reticulum, and 3) shortening of the action potential, when such shortening occurs. Conversely, Ca2+ delivery may be increased by the prolongation of the action potential that is sometimes observed and by the rise of diastolic Ca2+ that occurs during acidosis. This rise, which will increase the uptake and subsequent release of Ca2+ by the sarcoplasmic reticulum, may be due to 1) stimulation of Na+ entry via Na(+)-Ca2+ exchange; 2) direct inhibition of Na(+)-Ca2+ exchange; 3) mitochondrial release of Ca2+; and 4) displacement of Ca2+ from cytoplasmic buffer sites by H+. Acidosis inhibits myofibrillar responsiveness to Ca2+ by decreasing the sensitivity of the contractile proteins to Ca2+, probably by decreasing the binding of Ca2+ to troponin C, and by decreasing maximum force, possibly by a direct action on the cross bridges. Thus the final amount of force developed by heart muscle during acidosis is the complex sum of these changes.
660 citations
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TL;DR: The removal of extracellular calcium, the addition of verapamil, and the measurement of calcium influx indicate that the initial rise in resting tension is not due to an inward movement of calcium from the extracllular phase.
393 citations
TL;DR: It is shown that acute respiratory acidosis equivalent to an arterial carbon dioxide tension of about 54 mm Hg decreases the contractility and endurance time of the diaphragm in human beings.
Abstract: We studied the effects of acute changes in the partial pressure of arterial carbon dioxide on diaphragmatic contractility and performance in four normal men. To study contractility we measured the ability of the diaphragm to generate pressure at a given level of excitation by determining the relation between the electrical activity of the diaphragm and transdiaphragmatic pressure during a voluntary quasi-isometric inspiratory effort carried out at different levels of end-tidal carbon dioxide. Our results show that contractility was reduced with hypercapnia (when end-tidal carbon dioxide was 7.5 per cent or higher), although hypocapnia (end-tidal carbon dioxide, 3 per cent) had no effect on diaphragmatic contractility. We also studied the development of diaphragmatic fatigue before and during carbon dioxide breathing. Subjects were studied at the same diaphragmatic tension-time index, a value analogous to the more familiar myocardial tension-time index, while the same inspiratory flow was maintained. Electromyographic signs of fatigue appeared at a lower tension-time index during hypercapnia than during normocapnia, indicating that endurance is diminished during hypercapnia. These findings show that acute respiratory acidosis equivalent to an arterial carbon dioxide tension of about 54 mm Hg decreases the contractility and endurance time of the diaphragm in human beings.
309 citations
TL;DR: The proportionately greater acidotic depression of submaximum forces that occurred only at 1 mM Mg2+ (cardiac>adductor>soleus) implicates acidotic depressed of Ca2+-activated force as a major cause of decreased cardiac contractility.
Abstract: The effect of acidosis on Ca2+-activated force generation was studied in rabbit soleus, left ventricular, and adductor magnus muscles. Fibers were skinned (sarcolemma peeled off or mechanico-chemically disrupted) to facilitate direct manipulation and standardization of their intracellular ionic milieus according to bathing solution composition. Skinned single skeletal and small bundles of cardiac fibers were mounted in a photodiode force transducer and activated by immersion in buffered-Ca2+ bathing solutions. The magnitude of steady state isometric force at each [Ca2+] was determined at pH 7.0 and 6.5 (paired data) at both 1 mM and 10 mM Mg2+ in order to detect artifacts of errors in calculated [Ca2+]. All bathing solutions contained: 7 mM total EGTA [ethyleneglycol-bis-(β-amino-ethylether)-N,N′ tetra-acetic acid], 70 mM (Na++K+), 2 mM MgATP2− (Mg adenosine triphosphate), 15 mM CP2− (creatine phosphate), 15 units/ml CPK (creatine phosphokinase), imidazole (adjusted ionic strength to 0.15 M), and propionate anion at 23±1° C. Maximum tensions were similar at both [Mg2+]s but less at pH 6.5 than at pH 7.0, with the following order of mean magnitude of acidotic depression adductor>cardiac>soleus. The proportionately greater acidotic depression of submaximum (relative to maximum) forces that occurred only at 1 mM Mg2+ (cardiac>adductor>soleus) implicates acidotic depression of Ca2+-activated force as a major cause of decreased cardiac contractility.
266 citations
Cites background from "Contractility in Isolated Mammalian..."
...Acidosis has a direct, pronounced negative inotropic effect on cardiac muscle [6, 24,28-30, 34] and may be responsible for the early, rapid decline in force generation during myocardial ischemia [44]....
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TL;DR: The effects of respiratory and metabolic acidosis on myocardial contractility and energy production have been investigated in the perfused rat heart and results indicated that respiratory acidosis caused an 80% inhibition of pressure development at pH 6.7.
Abstract: SUMMARYThe effects of respiratory and metabolic acidosis on myocardial contractility and energy production have been investigated in the perfused rat heart. Respiratory acidosis, produced by increasing the Pco2, caused an 80% inhibition of pressure development at pH 6.7. When artificial buffers (plu
261 citations
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TL;DR: Isometric force generation, the result of the interaction of an actively shortening contractile element with a passive series elastic component with a Passive Series elastic component, has been analyzed in heart muscle using a diffusion-gauging apparatus.
Abstract: Isometric force generation, the result of the interaction of an actively shortening contractile element (CE) with a passive series elastic component (SE), has been analyzed in heart muscle using th...
190 citations
TL;DR: The authors cannot distinguish between a mechanism whereby Ca actively transported into a compartment of the microsomal vesicles containing also the binding sites is bound passively to these sites in exchange for Mg, K, and H and another in which ATP selectively increases the affinity of surface-binding sites for Ca.
Abstract: Fragmented sarcoplasmic reticulum isolated from skeletal muscle of the rabbit has a cation-binding capacity of about 350 µeq/g of protein at neutral pH The same binding sites bind Ca, Mg, K, and H ions and, consequently, the selective binding of Ca induced by ATP releases an amount of the other cations equivalent to the Ca taken up At pH values below 62, an increasing number of binding sites are associated with H+, and ATP induces exchange of Ca mostly for H+ At pH values above 62, the binding sites exist in the form of Mg and K, and Ca is bound in exchange for these cations The total bound Ca + Mg + K, expressed in microequivalents of cations bound per gram of protein, is approximately constant at various pCa values, which indicates a stoichiometric exchange of Ca for the other cations To accomplish the same degree of exchange of Ca for other cations bound, in the absence of ATP, concentrations of free Ca++ of about 1000-fold higher than those needed in the presence of ATP are required in the medium We cannot distinguish between a mechanism whereby Ca actively transported into a compartment of the microsomal vesicles containing also the binding sites is bound passively to these sites in exchange for Mg, K, and H and another in which ATP selectively increases the affinity of surface-binding sites for Ca Irrespective of the mechanism of accumulation, the Ca retained does not contribute to the activity of the cation in the membrane fraction Caffeine (10 mM) has no effect on the binding of Ca, but releases a more labile fraction of Ca, which presumably accumulates in excess of the bound Ca Procaine (5 mM) antagonizes the effect of caffeine Acetylcholine and epinephrine have no effect on the binding of Ca
175 citations
TL;DR: The solubility of CO2 in human cerebrospinal fluid (CSF) is 0.0312 mmole/liter·mm Hg at 38 C and the effect of varying Pco2 on pH in vitro at 38°C, expressed as Delta log P co2/DeltapH, is 1.063 ± 0.022.
Abstract: The solubility of CO2 in human cerebrospinal fluid (CSF) is 0.0312 mmole/liter·mm Hg at 38 C. The first dissociation constant (pK1') of carbonic acid at 38 C is 6.130 at pH 7.30 and varies inversel...
130 citations
113 citations
TL;DR: Guinea pig hearts were perfused with a balanced ion solution in which the pH was altered either by changing the CO2 tension of the gas in equilibrium with the solution or by varying the bicarbonate level.
Abstract: Guinea pig hearts were perfused with a balanced ion solution in which the pH was altered either by changing the CO2 tension of the gas in equilibrium with the solution or by varying the bicarbonate...
100 citations