Mechanisms of hypoxia-induced decrease of load dependence of relaxation in cat papillary muscle.

Relaxation of mammalian cardiac muscle is very sensitive to the prevailing load, but becomes largely load-independent during hypoxia. This effect was previously ascribed to a delayed removal of activating myoplasmic calcium. To further elucidate the underlying mechanisms of this effect of hypoxia, relaxation was now studied in 26 cat papillary muscles, in which hypoxia-induced decrease of load dependence of relaxation was compared with the effects of low [Ca2+]o (1.0, 0.5, 0.375 mM), verapamil (1 microM) and nifedipine (0.1 microM). Load dependence of relaxation was quantified by comparing force and time coordinates at the onset of the isometric relaxation phase in several after-loaded isotonic twitch contractions with the relaxation of the isometric control contraction. Hypoxia, low [Ca2+]o, verapamil and nifedipine decreased load dependence of relaxation. Although low [Ca2+]o, verapamil and nifedipine had a more marked negative inotropic effect on the contraction phase than hypoxia, the decrease of load dependence with hypoxia was significantly more pronounced and it included two phases: an early and fast drop, followed by a slower and longer-lasting decrease. The early fast phase was neutralized in low [Ca2+]o and also diminished after administration of verapamil or nifedipine. An impaired calcium reuptake by the sarcoplasmic reticulum would underly only the second phase of decreased load dependence. The first phase on the other hand originated mainly from changes in the isometric relaxation of the papillary muscles.