Inhibition of the activation and troponin calcium binding of dog cardiac myofibrils by acidic pH.

Abstract

SUMMARY. The aim of experiments described here was to test whether deactivation of cardiac myofibrils in acidic pH is associated with decreases in amounts of calcium bound to myofilament troponin. We determined the amounts of myofibrillar bound calcium attributable to troponin, from measurements of calcium binding to myofibrils and to myosin and from determination of the troponin C content of the myofibrillar preparations (0.40 nmol troponin C/mg protein). In measurements done at 2 mvi free magnesium, 2 imi (magnesium-adenosine triphosphate, ionic strength 0.12, 22°C, the pCa 50 (-log of the half maximally activating molar free calcium) for myofibrillar magnesium-adenosine triphosphatase activity was 5.87 at pH 7.0, 5.49 at pH 6.5, and 5.04 at pH 6.2. This change in calcium sensitivity of myofibrillar magnesium-adenosine triphosphatase activity was present whether or not ethyleneglycol-bis(/3-aminoethyl ether)-N,N'-tetraacetic acid, was used to buffer the free calcium and whether or not myofibrillar troponin I had been phosphorylated by cyclic adenosine 3',5'-monophosphate-dependent protein kinase. However, the change in pCa 50 of myofibrillar adenosine triphosphatase activity induced by acidic pH, was greater when free magnesium was reduced from 2.0 to 0.05 HIM, and less when free magnesium was increased from 2.0 mM to 10 and 15 mM. The change in pCa 50 with acidic pH was less if the ionic strength was reduced from 0.12 to 0.035 M. The magnesium-adenosine triphosphatase activity of troponin/tropomyosin-free myofibrils was independent of pCa and unaffected by a reduction of pH from 7.0 to 6.5. The affinity of myofibrillar troponin C for calcium decreased as pH was reduced from 7.0 to 6.5 and to 6.2 with and without ethyleneglycolbis(/?-aminoethyl ether)-N,7V'-tetraacetic acid, and in a manner predicted from the effect of acidic pH on pCa 50 for myofibrillar activation. Our results are consistent with the idea that at least part of the mechanism responsible for deactivation of the adenosine triphosphatase activity of cardiac myofilaments in acidic pH is a reduction in the affinity of myofibrillar troponin C for calcium. (Circ Res 55: 382-391, 1984)

Influence of Acidosis on Cardiotonic Effects of Colforsin and Epinephrine: A Dose-Response Study

“…These results indicate that the inotropic effects of colforsin are decreased in the severely acidotic heart, but irrespective of catecholamines and PDE III inhibitors increasing colforsin concentration negates the deleterious effect of acidosis on its cardiotonic effect. Acidosis depresses cardiac performance [1][2][3][4][5][6] and the inotropic effect of catecholamines [7][8][9][10][11] . Several factors are considered to play a role in diminished myocardial responses to catecholamines, such as reduction in the numbers of beta-adrenergic receptors 7,8 , reduced affinity for agonists 9 , depressed adenylate cyclase activity 7 , decreased cAMP production 7 , inhibition of calcium ion exchange 20 , and decreased affinity of calcium ions for myofilaments 11,21,22 .…”

“…Acidosis produces a negative inotropic effect on cardiac muscle [1][2][3][4][5][6] and diminishes the inotropic effects of catecholamines [7][8][9][10][11] and of phosphodiesterase isozyme III (PDE III) inhibitor 12 . The inotropic effect of catecholamines and PDE III inhibitor results mainly from increased concentrations of intracellular cyclic adenosine monophosphate (cAMP) generated by stimulating beta-adrenergic receptors and by inhibiting PDE III, respectively.…”

Decrease in internal H + and positive inotropic effect of heptaminol hydrochloride: a 31P n.m.r. spectroscopy study in rat isolated heart

“…The mechanism of depression of the myocardial contractility by acidosis has been extensively examined (Steenbergen et al, 1977;Vogel & Sperelakis, 1977;Poole-Wilson & Langer, 1979;Philipson et al, 1982). Several possibilities have been postulated: intracellular acidosis could (1) decrease inward calcium current (Chesnais et al, 1975;Kohlhardt et al, 1976;Vogel & Sperelakis, 1977;Irisawa & Sato, 1986); (2) modulate calcium-induced calcium release from the sarcoplasmic reticulum (Fabiato & Fabiato, 1978;Fabiato, 1985;Orchard, 1987); (3) change the concentration of calcium stored in the sarcoplasmic reticulum (Fabiato, 1985) and (4) modify the calcium activation of the myofilaments by way of competition for the calcium binding sites on troponin by intracellular hydrogen ions (Williamson et al, 1975;Blanchard & Solaro, 1984;Chapman, 1983).…”

The effect of acidosis on the relationship between Ca2+ and force in isolated ferret cardiac muscle.

“…This decreased response may be due to a decrease in Ca2" binding to troponin (i.e. a decreased sensitivity to Ca2"; Blanchard & Solaro, 1984) or because acidosis decreases maximum force production (Fabiato & Fabiato, 1978), either by decreasing the maximum number of cross-bridges that can be formed, or by decreasing the maximum force developed per cross-bridge.…”