inotropic and chronotropic effects of 6-hydroxy-4- methylquinolin-2(1h)-one derivatives in isolated rat atria
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abstract
background: selective phosphodiesterase (pde3) inhibitors improve cardiac contractility and may use in congestive heart failure. however, their proarrhythmic potential is the most important side effect. methods: in this research, we evaluated the potential cardiotonic activity of six new synthesized selective pde3 inhibitors (6-hydroxy-4-methylquinolin-2(1h)-one derivatives) using the spontaneously beating atria model. in each experiment, atrium of reserpine-treated rat was isolated and the contractile and chronotropic effects of a synthesized compound were assessed. the 3-isobutyl-1-methylxanthine, a non-selective pde inhibitor, was used for comparison. results: the results showed that, among new compounds, the best pharmacological profile was obtained with the compound 6-[4-(4-methylpiperazine-1-yl)-4-oxobutoxy]-4-methylquinolin-2(1h)-one, c6, which displayed selectivity for increasing the force of contraction (168 ± 5% change over the control) rather than the frequency rate (138 ± 5% change over the control) at 300 μm. however, c6 at concentrations of 10 and 100 μm produced left and upward shift in the positive inotropic concentration-response curve of isoprenaline. the -log ec50 of isoprenaline was 8.843 ± 0.171 in the absence, 9.448 ± 0.138 and 9.456 ± 0.107 in the presence of 10, 100 μm of c6, respectively (p<0.001, n = 6). also, amrinone, a selective pde3 inhibitor, shifted the isoprenaline concentration-response curve to the left and upward. the concentration of 10 and 100 μm amrinone decreased -log ec50 of isoprenaline to 9.527 ± 0.287 and 9.423 ± 0.243, respectively (p<0.001, n = 6). moreover, the positive chronotropic effect of isoprenaline was not affected by amrinone or c6. conclusion: this study provides functional evidence for the positive inotropic effect of c6. considering the augmentation of isoprenaline positive inotropic concentration-response with c6 and amrinone, we conclude that c6 produces its effect via potentiation of camp-dependent signaling system and possibly by inhibition of pde3 activity.
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full textInotropic and chronotropic effects of 6-hydroxy-4-methylquinolin-2(1H)-one derivatives in isolated rat atria.
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Journal title:
iranian biomedical journalجلد ۱۲، شماره ۲، صفحات ۷۷-۸۴
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