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Abstract; Force of contraction (F,) of isolated human and rat atrial myocardium shows characteristic patterns of mechanical restitution when single test intervals are interposed in regular stimulation. With several pharmacological agents that modify the function of the sarcoplasmic reticulum we have investigated the role of the sarcoplasmic reticulum in mechanical restitution in these two species. Caffeine, thapsigargin and 2,5-di-(terr-butyl)-l ,4-benzohydroquinone (BHQ) were used to reduce Ca'+ uptake, ryanodine to open Ca2+ release channels, and forskolin to stimulate Ca'+ uptake. Under control conditions, F, recovered rapidly with test intervals shorter than steady-state. and was potentiated with longer than steadystate intervals. In human atrial tissue the maximum potentiation factor was 1.2620.03 after a mean test interval of 9.70% 1.55 s (n=43) as compared to 3.07%0.45 after 30 sec. in rat atria (n=48). Caffeine (3 mM) did not significantly affect steady-state F, but abolished post-rest potentiation in human and rat preparations. Forskolin ( I pM) enhanced and accentuated the mechanical restitution curve in particular for short test intervals. In the presence of thapsigargin (10 pM), steady-state F, and mechanical restitution could not be distinguished from time-matched controls exposed to solvent only.indicating that this agent is ineffective in human and rat atrial tissue. In contrast, the putative Ca2+ uptake inhibitor BHQ (100 pM) strongly reduced steady-state F, and decreased potentiation at all intervals in human muscle, but shifted the mechanical restitution curve in parallel to lower values in rat atria. Ryanodine (10 nM) induced post-rest decay in human and depressed both steady-state F, and post-rest potentiation in rat atrial muscle. From these results it is concluded that human and rat atrial muscle differ in the Ca2+ handling by the sarcoplasmic reticulum during mechanical restitution.In heart muscle, Ca2+ entry via L-type Ca2+ channels triggers the release of further Ca2+ from the sarcoplasmic reticulum. The increase in cytosolic C2+concentration activates contractile proteins for force production. During relaxation, Ca*+ is taken up again into the sarcoplasmic reticulum by the ATP-dependent Ca2+ pump and an amount equivalent to the systolic Ca" entry is transported out of the cell mainly via the Na+/Ca'+ exchanger. When regular pacing is disturbed by a single test pulse of variable interval, force of contraction (F,) changes in a characteristic pattern. The relationship between force of an interposed contraction and the preceding test interval is referred to as mechanical restitution. It consists of three phases (Schouten 1990): The initial one is a short and rapid phase of recovery for intervals shorter than steady-state. The second phase during which F, is potentiated with longer than regular intervals is followed by a third phase of force decline (post-rest decay).The adaptive changes in F, during mechanical restitution are considered to represent a physiological correlate of cellular Ca...

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