Iranian Biomedical Journal, ( ISI ), Volume (12), No (2), Year (2008-2) , Pages (77-84)

Title : ( Inotropic and chronotropic effects of 6-hydroxy-4-methylquinolin-2(1H)-one derivatives in isolated rat atria )

Authors: Seyed Mohammad-Taghi Mansouri , Reza Shafiee-Nick , Heydar Parsaee , Seyed Mohammad Seyedi , Mohammad-Reza Saberi , Hamid Sadeghian ,

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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 concentrationresponse 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.

Keywords

, Phosphodiesterase inhibitor, 4-methylquinolinone derivatives, Inotropic activity, Rat atria, Isoprenaline
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@article{paperid:1008977,
author = {Seyed Mohammad-Taghi Mansouri and Reza Shafiee-Nick and Heydar Parsaee and Seyedi, Seyed Mohammad and Mohammad-Reza Saberi and Sadeghian, Hamid},
title = {Inotropic and chronotropic effects of 6-hydroxy-4-methylquinolin-2(1H)-one derivatives in isolated rat atria},
journal = {Iranian Biomedical Journal},
year = {2008},
volume = {12},
number = {2},
month = {February},
issn = {1028-852x},
pages = {77--84},
numpages = {7},
keywords = {Phosphodiesterase inhibitor; 4-methylquinolinone derivatives; Inotropic activity; Rat atria; Isoprenaline},
}

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%0 Journal Article
%T Inotropic and chronotropic effects of 6-hydroxy-4-methylquinolin-2(1H)-one derivatives in isolated rat atria
%A Seyed Mohammad-Taghi Mansouri
%A Reza Shafiee-Nick
%A Heydar Parsaee
%A Seyedi, Seyed Mohammad
%A Mohammad-Reza Saberi
%A Sadeghian, Hamid
%J Iranian Biomedical Journal
%@ 1028-852x
%D 2008

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