Mechanism of early contractile failure during hypoxia in intact ferret heart: Evidence for modulation of maximal Ca2+-activated force by inorganic phosphate

H. Kusuoka, Myron Weisfeldt, J. L. Zweier, W. E. Jacobus, E. Marban

Research output: Contribution to journalArticle

Abstract

We tested the hypothesis that accumulation of H+ or inorganic phosphate (Pi) is responsible for the early contractile failure of hypoxia by measuring maximal Ca2+-activated pressure and 31P nuclear magnetic resonance spectra in Langendorff-perfused ferret hearts at 30°C. Maximal Ca2+-activated pressure was identified by the saturation of pressure with respect to [Ca2+](o) observed during tetani as [Ca2+](o) was increased to 15 mM in HEPES-buffered, 100% O2-bubbled perfusate and during hypoxia induced by bubbling with room air or with 100% N2. Tetani were produced by pacing at 8-12 Hz following exposure to ryanodine (1-5 μM), an inhibitor of Ca2+ release from the sarcoplasmic reticulum, and were elicited once a minute to measure maximal Ca2+-activated pressure during acquisition of nuclear magnetic resonance spectra. An inverse correlation was observed between [Pi] and maximal Ca2+-activated pressure (r = 0.87 mean, n = 12), with an average decline of 8.6% in pressure per 1 μmol/g wet wt. increase in [Pi]. Intracellular pH (pH(i)) showed no significant correlation with maximal Ca2+-activated pressure (r = 0.49 mean, n = 12). Two other protocols, 1) pacing at variable rates and 2) gated measurements at two different times during the tetanus, were also used to correlate [Pi], pH(i), and maximal Ca2+-activated pressure. These protocols confirmed the highly significant correlation between [Pi] and maximal Ca2+-activated pressure, as well as the lack of correlation with pH(i). Acidosis induced by NH4Cl (20 mM) or by bubbling with 95% O2/5% CO2 was associated with <20% depression of maximal Ca2+-activated pressure in the pH(i) range down to 6.8, but much greater depression at lower pH(i). The data are consistent with depression of maximal Ca2+-activated force during the early phase of hypoxia by Pi but not by H+.

Original languageEnglish (US)
Pages (from-to)270-282
Number of pages13
JournalCirculation Research
Volume59
Issue number3
StatePublished - 1986

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Ferrets
Phosphates
Pressure
Tetanus
Magnetic Resonance Spectroscopy
Hypoxia
HEPES
Ryanodine
Sarcoplasmic Reticulum
Acidosis
Air

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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Mechanism of early contractile failure during hypoxia in intact ferret heart : Evidence for modulation of maximal Ca2+-activated force by inorganic phosphate. / Kusuoka, H.; Weisfeldt, Myron; Zweier, J. L.; Jacobus, W. E.; Marban, E.

In: Circulation Research, Vol. 59, No. 3, 1986, p. 270-282.

Research output: Contribution to journalArticle

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abstract = "We tested the hypothesis that accumulation of H+ or inorganic phosphate (Pi) is responsible for the early contractile failure of hypoxia by measuring maximal Ca2+-activated pressure and 31P nuclear magnetic resonance spectra in Langendorff-perfused ferret hearts at 30°C. Maximal Ca2+-activated pressure was identified by the saturation of pressure with respect to [Ca2+](o) observed during tetani as [Ca2+](o) was increased to 15 mM in HEPES-buffered, 100{\%} O2-bubbled perfusate and during hypoxia induced by bubbling with room air or with 100{\%} N2. Tetani were produced by pacing at 8-12 Hz following exposure to ryanodine (1-5 μM), an inhibitor of Ca2+ release from the sarcoplasmic reticulum, and were elicited once a minute to measure maximal Ca2+-activated pressure during acquisition of nuclear magnetic resonance spectra. An inverse correlation was observed between [Pi] and maximal Ca2+-activated pressure (r = 0.87 mean, n = 12), with an average decline of 8.6{\%} in pressure per 1 μmol/g wet wt. increase in [Pi]. Intracellular pH (pH(i)) showed no significant correlation with maximal Ca2+-activated pressure (r = 0.49 mean, n = 12). Two other protocols, 1) pacing at variable rates and 2) gated measurements at two different times during the tetanus, were also used to correlate [Pi], pH(i), and maximal Ca2+-activated pressure. These protocols confirmed the highly significant correlation between [Pi] and maximal Ca2+-activated pressure, as well as the lack of correlation with pH(i). Acidosis induced by NH4Cl (20 mM) or by bubbling with 95{\%} O2/5{\%} CO2 was associated with <20{\%} depression of maximal Ca2+-activated pressure in the pH(i) range down to 6.8, but much greater depression at lower pH(i). The data are consistent with depression of maximal Ca2+-activated force during the early phase of hypoxia by Pi but not by H+.",
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