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 Ca²⁺-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 Ca²⁺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 Ca²⁺₀-depletion plus a rise in [Ca²⁺]_i; and (iii) current theories concerning the mechanisms underlying the genesis of the Ca²⁺-paradox are incorrect or incomplete.