Inotropic and chronotropic effects of new cilostamide derivatives on isolated rat atria

It was shown in a previous study, that MCPIP, a cilostamide derivative, increased atrial contraction force without changing contraction rate. To improve this property, two new derivatives of cilostamide were synthesized and their effects on PDE3 activity and isolated rat atria contraction were investigated. The inhibitory effect of each compound on PDE3 enzyme was determined. Reserpine-treated rat atria were separated and suspended in an organ bath containing Krebs-Henseleit buffer. The effects of each compound alone or in combination with isoprenaline were assessed. Mc2 and mbc2 inhibited PDE3 activity with a potency lower than cilostamide, while they increased the contraction force with a higher efficacy (percentage higher than base line, cilostamide=19±3%, P<0.05, mc2= 43±7% and mbc2=34±5%, P<0.001). The effect of isoprenaline was potentiated by cilostamide and new compounds with different efficacies (mc2>mbc2>cilostamide). Atrial contraction rate was increased in the presence of cilostamide or isoprenaline, but was not changed with synthetic compounds. Furthermore, the effect of isoprenaline on the contraction rate was inhibited by synthetic compounds (percentage higher than base line, isoprenaline=68±9%, +mc2=6±5% and +mbc2=36±6%) and was not changed in the presence of cilostamide. The synthetic compounds induced an increase in the atrial contraction force that was higher than cilostamide and was not correlated to their PDE3 inhibition. These compounds potentiated the effect of isoprenaline on the contraction force which excludes the possibility of their inhibitory effect on the receptor. In addition to PDE3 inhibition, other mechanisms are involved in producing the effects of these compounds, which are not clear and needs further investigation.