Abstract
Recent data show that UD-CG 212 in nanomolar concentrations increases myofibrillar Ca++ responsiveness of chemically skinned cardiac preparations in the presence of elevated inorganic phosphate. We studied the effects of UD-CG 212 on cell shortening of intact myocytes and in addition measured the intracellular calcium transients with the aid of INDO-1 fluorescence in the presence of 5 mM inorganic phosphate.
The validity of our experimental system was first tested with the calcium channel opener Bay k 8644. Bay k 8644 at 10−8 M did not significantly influence myocyte shortening ( + 13.9 ± 4.6%, n = 9) but at 10−7 M and 10−6 M significantly increased contraction by 40.1 +- 13.6%and52.5 ± 17.0% respectively. Bay k 8644 at 10−8 M increased the INDO-1 fluorescence ratio by 17.3 ± 4.7% (P < 0.01; n = 9), and at 10−7 M by 21.5 + 4.3% (P < 0.01; n = 9), whereas 10−6 M Bay k 8644 had no significant effect on peak INDO-1 ratio. However, 10−7and 10−6 M Bay k 8644 accelerated and broadened the calcium transients.
Cell shortening of guinea pig ventricular myocytes electrically stimulated at 1 Hz was significantly increased by UD-CG 212 (10−9-10−7 M) and isoprena line(3 × 10−8 M). An increase of 37.0 ± 14.0% (P < 0.05; n = 9) was observed at 10−9 M UD-CG 212, 90.5±18.2% (P<0.05; n=9) at 10−8 M UD-CG 212, 164.0 ± 34.9% (P < 0.05; n = 9) at 10−7 M UD-CG 212, and 258.2 ± 67.4% (P < 0.05; n = 9) at 3 × 10-8 M isoprenaline. Peak INDO-1 fluorescence ratios were not significantly (P > 0.05) influenced after addition of 10−9 M and 10−8 M UD-CG 212, but significantly increased by 19.4 ± 4.9%(P < 0.05; n = 9) at 10−7 MUD-CG 212 and by 81.1 ± 11.1% (P < 0.05; n = 9) at 3 x 10−8 M isoprenaline.
In conclusion, UD-CG 212 (10−9 - 10−7 M) Concentration-dependently increased myocyte shortening in the presence of 5 mM inorganic phosphate. Low concentrations of 10−9 and 10−8 M UD-CG 212 increased myocyte contractility without altering the peak INDO-1 fluorescence ratio whereas 10−7 M UD-CG 212 and 3 × 10−8 M isoprenaline increased cell shortening as well as peak INDO-1 fluorescence ratio. These data suggest that low concentrations of UD-CG 212 increase myocyte contractility by enhancing myofibrillar calcium responsiveness whereas higher concentrations elevate intracellular calcium probably via increased intracellular CAMP brought about by phosphodiesterase inhibition.
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van Meel, J.C.A., Redemann, N., Diederen, W. et al. Low concentrations of UD-CG 212 enhance myocyte contractility by an increase in calcium responsiveness in the presence of inorganic phosphate. Naunyn-Schmiedeberg's Arch Pharmacol 351, 644–650 (1995). https://doi.org/10.1007/BF00170165
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DOI: https://doi.org/10.1007/BF00170165