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 microM to 1 mM) were investigated on fully (Triton-treated) or selectively (saponin-treated) 'skinned' ventricle trabeculae from rat. The Ca-sensitivity was increased by 100 microM and amounted to a mean reduction in the Ca2+ necessary for half-maximal activation (1/Kapp) of 0.174 +/- 0.053 (mean +/- s.e.mean) pCa units. ORG30029 (50 microM) gave a smaller mean shift of 0.05 +/- 0.016 pCa units. A slight shallowing of the relationship between -log[Ca2+] (pCa) and steady-state tension was also generally found (mean Hill exponent reduction 0.37 +/- 0.28 at 100 microM). 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 (Cmax), the first significant effects occurred near 10 microM and continued to increase at 1 mM. 3. A small (3.7 +/- 1.1%) but consistent increase in Cmax was produced by ORG30029 at 100 microM. Much larger increases were produced by the drug at higher concentrations (up to 20-50% at 1 mM). 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 microM ORG30029 was considerable: it amounted to a 150-200% increase at a [Ca2+] producing 20% at Cmax. At this drug concentration virtually all the effect was due to Ca-sensitizing rather than increasing Cmax. 5. In the saponin-treated preparations, at concentrations up to 1 mM, 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 microM, 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.
Institute of Physiology, Glasgow University.
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Miller
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Steele
D000818:Animals; D002110:Caffeine / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism / Q000502:physiology*; D002316:Cardiotonic Agents / Q000494:pharmacology*; D006321:Heart / Q000187:drug effects*; D066298:In Vitro Techniques; D009126:Muscle Relaxation / Q000187:drug effects; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000378:metabolism; D009930:Organic Chemicals; D011092:Polyethylene Glycols / Q000494:pharmacology*; D051381:Rats; D012503:Saponins / Q000494:pharmacology*; D012519:Sarcoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism
D002316:Cardiotonic Agents; D009930:Organic Chemicals; D012503:Saponins; C062763:ORG 30029; D002110:Caffeine; D011092:Polyethylene Glycols; D002118:Calcium