Mechanism of Early Contractile Failure During Hypox in Intact Ferret Heart: Evidence for Modulation of Maximal Ca2+-Activated Force by Inorganic Phosphate

• Published in: Circulation research 1986-09, Vol.59 (3), p.270-282
• Main Authors: KUSUOKA, HIDEO, WEISFELDT, MYRON L, ZWEIER, JAY L, JACOBUS, WILLIAM E, MARBAN, EDUARDO
• Format: Article
• Language: English
• ISSN: 0009-7330; 1524-4571

We tested the hypothesis that accumulation of H or inorganic phosphate (Pi) is responsible for the early contractile failure of hypoxia by measuring maximal Ca-activated pressure and P nuclear magnetic resonance spectra in Langendorff-perfused ferret hearts at 30°C. Maximal Ca-activated pressure was identified by the saturation of pressure with respect to [Ca]0 observed during tetani as [Ca*], 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 Ca release from the sarcoplasmic reticulum, and were elicited once a minute to measure maximal Ca-activated pressure during acquisition of nuclear magnetic resonance spectra. An inverse correlation was observed between [Pi] and maximal Ca-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() showed no significant correlation with maximal Ca-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, and maximal Ca-activated pressure. These protocols confirmed the highly significant correlation between [Pi] and maximal Ca-activated pressure, as well as the lack of correlation with pH,. Acidosis induced by NH4CI (20 mM) or by bubbling with 95% O2/5% CO2 was associated with < 20% depression of maximal Ca-activated pressure in the pH, range down to 6.8, but much greater depression at lower pH,. The data are consistent with depression of maximal Ca-activated force during the early phase of hypoxia by Pi but not by H.