inotropic and chronotropic effects of 6-hydroxy-4- methylquinolin-2(1h)-one derivatives in isolated rat atria
نویسندگان
چکیده
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.
منابع مشابه
Inotropic and Chronotropic Effects of 6-Hydroxy-4- Methylquinolin-2(1H)-One Derivatives in Isolated Rat Atria
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 spontan...
متن کاملInotropic and chronotropic effects of 6-hydroxy-4-methylquinolin-2(1H)-one derivatives in isolated rat atria.
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 spontaneo...
متن کاملInotropic and chronotropic effects of new cilostamide derivatives on isolated rat atria
Introduction: 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. Methods: The inhibitory effect of each compound on PDE3 enzyme was dete...
متن کاملInotropic and chronotropic effects of new cilostamide derivatives on isolated rat atria
Introduction: 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. Methods: The inhibitory effect of each compound on PDE3 enzyme was determi...
متن کاملinotropic and chronotropic effects of new cilostamide derivatives on isolated rat atria
introduction: 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. methods: the inhibitory effect of each compound on pde3 enzyme was determi...
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Objective(s): Recently, we showed that some new synthetic compounds structurally related to cilostamide (4-(1,2-dihydro-2-oxoquinolin-6-hydroxy)- N-cyclohexyl-N-methylbutanamide), a selective phosphodiesterase 3 (PDE3) inhibitor, produce inotropic effect comparable to that of IBMX (3-isobutyl-1-methylxanthine), a non-selective PDE inhibitor, but with differential chronotropic effect. In this in...
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عنوان ژورنال:
iranian biomedical journalجلد ۱۲، شماره ۲، صفحات ۷۷-۸۴
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