Cellular damage in the rat heart caused by caffeine or dinitrophenol.

1. Langendorff-perfusion of rat hearts with either 10 mM caffeine or 1 mM 2,4-dinitrophenol (DNP) caused severe ultrastructural damage to the myofilaments and mitochondria that was similar to that found in a standard Ca(2+)-paradox. 2. This damage occurred in the presence and absence of extracellular Ca2+. 3. Creatine kinase (CK) release (indicative of sarcolemma breakdown) was not recorded unless the caffeine- or DNP-perfusion was preceded by Ca(2+)0-depletion. 4. It is concluded that: (i) the pathways leading to damage to the myofilaments and sarcolemma are independent; (ii) the CK release mechanism requires dual activation of Ca(2+)0-depletion plus a rise in [Ca2+]i; and (iii) current theories concerning the mechanisms underlying the genesis of the Ca(2+)-paradox are incorrect or incomplete.