The ‘calcium sensitising’ effects of ORG30029 in saponin‐ or Triton‐skinned rat cardiac muscle

1 The effects of a range of concentrations of ORG30029 (1 μ m to 1 m m ) were investigated on fully (Triton‐treated) or selectively (saponin‐treated) ‘skinned’ ventricle trabeculae from rat. The Ca‐sensitivity was increased by 100 μ m and amounted to a mean reduction in the Ca 2+ necessary for half‐maximal activation (1/ K app ) of 0.174 ± 0.053 (mean ± s.e.mean) pCa units. ORG30029 (50 μ m ) gave a smaller mean shift of 0.05 ± 0.016 pCa units. A slight shallowing of the relationship between ‐log[Ca 2+ ] (pCa) and steady‐state tension was also generally found (mean Hill exponent reduction 0.37 ± 0.28 at 100 μ m ). 2 The Ca‐sensitizing action altered in a dose‐dependent fashion. Judged by the ability to enhance force from an initial level of activation of 10–20% of maximum Ca‐activated force (C max ), the first significant effects occurred near 10 μ m and continued to increase at 1 m m . 3 A small (3.7 ± 1.1%) but consistent increase in C max was produced by ORG30029 at 100 μ m . Much larger increases were produced by the drug at higher concentrations (up to 20–50% at 1 m m ). 4 The consequence of these changes is that at levels of activation likely to occur in the heart, the absolute increase in force by 100 μ m ORG30029 was considerable: it amounted to a 150–200% increase at a [Ca 2+ ] producing 20% at C max . At this drug concentration virtually all the effect was due to Ca‐sensitizing rather than increasing C Max . 5 In the saponin‐treated preparations, at concentrations up to 1 m m , ORG30029 did not release Ca from the sarcoplasmic reticulum, as indicated by the failure to evoke contracture under conditions where caffeine induced large responses. 6 At 100 μ m , ORG30029 potentiated the transient, caffeine‐induced contracture (saponin‐treated preparation) to an extent consistent with the Ca‐sensitizing effect seen under conditions of steady‐state tension development.