Novel cilostamide analogs, phosphodiesterase 3 inhibitors, produce positive inotropic but differential lusitropic and chronotropic effects on isolated rat atria

Document Type: Original Article

Authors

1 Pharmacological Research Center of Medicinal Plants, Mashhad University of Medical Sciences, Mashhad, Iran

2 Department of Pharmacology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran

3 Department of Laboratory Sciences, School of Paramedical Sciences, Mashhad University of Medical Sciences, Mashhad, Iran

Abstract

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 investigation, we compared the pharmacological effects of these compounds as potential cardiotonic agents using the spontaneously beating atria model.
Materials and Methods: In each experiment, rats were treated with reserpine.  The atrium was isolated and mounted in an organ bath. We assessed chronotropic and inotropic effects using cumulativelogconcentration-response curves of isoprenaline alone or in combination of each test-compound.
Results: Majority of test compounds augment atria contraction force (ACF) significantly but with different potencies on atrium contraction rate. Cilostamide, MCPIP ([4-(4-methyl piperazin-1-yl)-4-oxobutoxy)-4-methylquinolin-2(1H)-one]), methyl carbostyril compounds- (mc1), mc2 and mc5 increased the isoprenaline effect on ACF synergistically. But, mc6 failed to potentiate the effect of isoprenalin; mc3 and mc4 did not increase ACF, which may be because of their higher hydrophilic nature. It was interesting that mc2, alone or in combination with isoprenaline, produced the highest inotropic effect while it did not affect the basal contraction rate and almost blocked the isoprenaline chronotropic effect.
Conclusion: Combination of mc2 with isoprenaline had synergistic effect on inotropic effect, but this combination reduced isoprenaline chronotropic effect; therefore, these effects cannot be related to reducing B-adrenergic receptors activity. These compounds showed different effects; probably all of them were not mediated via PDE3 inhibition and other mechanisms are involving.

Keywords


1. Fischemister R, Castro L, Abi-Gerges A, Rochais F, Jurevicius J. Compartmentation of cyclic nucleotide signaling in the heart: the role of cyclic nucleotide phosphodiesterases. Circ Res 2006; 99:816-828.

2. Maurice DH, Palmer D, Tilley D, Raymond DR and Jimmo SL. Cyclic nucleotide phosphodiesterase activity, expression and targeting in cells of the cardiovascular system. Mol Pharmacol 2003; 64:533-536.

3. Lin C, Xin ZC, Lin G and Lue TF. Phosphodiesterases as therapeutic targets. Urol 2003; 61:685-691.

4. Keravis T, Lugnier C. Cyclic nucleotide phosphodiesterase (PDE) isozymes as targets of the intracellular signalling network: benefits of PDE inhibitors in various diseases and perspectives for future therapeutic developments. Br J Pharmacol 2012; 165: 1288–1305.

5. Knight WE, Yan C. Cardiac cyclic nucleotide phosphodiesterases: function, regulation, and therapeutic prospects. Horm Metab Res 2012; 44: 766-75.

6. Zausig YA, Stowe DF, Zink W, Martin E. A comparison of three phosphodiesterase type3 inhibitors on mechanical and metabolic function in guinea pig isolated hearts. Anesth Analog 2006; 102:1646-52.

7. Yano M, Kohno M, Ohkusa T, Mochizuki M, Yamada J, Yukihisaoka T, Tanigava T, Matsuzaki M. Effect of milrinone on left ventricular relaxation and Ca2+ uptake function of cardiac sarcoplasmic reticulum. Am J Physiol Heart Circ Physiol 2000; 279:1898-1905.

8. Sudo T, Tachibana K, Toga K, Tochizawa S, Inoue Y, Kimura Yukio, Hidaka H. Potent effects of novel anti-platelet aggregatory cilostamide analogues on recombinant cyclic nucleotide phosphodiesterase isozyme activity. Biochem Pharmacol 2000; 59:347-356.

9. Mansouri MT, Shafiee-Nick R, Parsaee H, Seyedi M, Saberi MR, Sadeghian H. Inotropic and chronotropic effects of 6-hydroxy-4-methylquinolinone-2 (1H)-one derivatives in isolated rat atria. Iran Biomed J2007; 12:77-84.

10. Sadeghian H, Seyedi M, Saberi MR, Shafiee –Nik R, Hosseini A, Mansouri M, Parsaee H. Design, synthesis and pharmacological evaluation of 6-hydroxy-4-methylquinolin-2 (1H)-one derivatives as inotropic agents. J Enzyme Inhibit Med Chem 2008; 24:918-929.

11. Marín J, Hernández J. Diazepam potentiates the effects of endogenous catecholamines on contractility and cyclic AMP levels in rat ventricular myocardium. Naunyn Schmiedebergs Arch Pharmacol 2002; 365:260-8.

12. Fossa P, Menozzi G, Dorigo P, Floreanib M, Mosti L. Synthesis and pharmacological characterization of functionalized 2-pyridones structurally related to the cardiotonic agent milrinone. Bioorg Med Chem 2003; 11:4749-4759.

13. Bassani RA, Bassani WM. Reduced isolated responsiveness to adrenaline rat atria exposed to hyperosmotic solutions. Gen Pharmacol 1991; 22:151-157.

14. Vandecasteele G, Rochais F, Abi-Gerges A, Fischmeister R. Functional localization of cAMP signalling in cardiac myocytes. Biochem Soc Trans 2006; 34:484-8.

15. Lissandron V, Zaccolo M. Compartmentalized cAMP/PKA signaling regulates cardiac excitation-contraction coupling. J Muscle Res Cell Motil 2006; 27:399-403.

16. Iijima T, Taira N. Membrane current changes responsible for the positive inotropic effect of OPC 8212, a new positive inotropic agent, in single ventricular cells of the guinea pig heart. J Pharmacol Exp Ther 1987; 240: 657-662.

17. Momose Y, Sasayama S. Effect of OPC-8490 on the membrane potentials and membrane currents of single guinea-pig myocytes. Cardiovasc Drugs Ther 1990; 4:713-718.

18. Mori T, Yamashita S, Hosokawa T, Yabuuchi Y. Cardiovascular effects of OPC-8490, a new positive inotropic agent with vasodilator action. Jpn J Pharmacol 1988; 46:130.

19. Joung B, Ogawa M, Lin SF, Chen P. The calcium and voltage clocks in sinoatrial node automaticity. K C J 2009; 39:217-222.

20. Korzick DH. Regulation of cardiac excitation-contraction coupling: a cellular update. Advance Physiol Edu 2003; 27:192-200.

21. Galindo-Tovar A, Vargas ML, Kaumann AJ. Phosphodiesterases PDE3 and PDE4 jointly control the inotropic effects but not chronotropic effects of ()-CGP12177 despite PDE4-evoked sinoatrial bradycardia in rat atrium. Naunyn-Schmied Arch Pharmacol 2009; 379:379–384.

22. Kaumann AJ, Galindo-Tovar A, Escudero E, Vargas ML. Phosphodiesterases do not limit β1-adrenoceptor-mediated sinoatrial tachycardia: evidence with PDE3 and PDE4 in rabbits and PDE15 in rats. Naunyn-Schmied Arch Pharmacol 2009; 380:421–430

23. Juan-Fita MJ, Vargas ML, Henandez J. Comparative actions of diazepam and other phosphodiesterase
inhibitors on the effects of noradrenaline in rat myocardium. Pharmacol Toxicol 2003; 93:23-28.

24. Murthy KS, Zhou H, Makhlouf GM. PKA-dependent activation of PDE3A and PDE4 and inhibition of Adenylyl cyclase V/VI in smooth muscle. Am J Physiol Cell 2001; 282:508-517.

25. Vinogradova TM, Sirenko S, Lyashkove AE, Younes A, Li Y, Yang D, Lakatta EG. Constitutive phosphodiesterase activity restricts spontaneous beating rate of cardiac pacemaker cells by suppressing local Ca2+ releases. Circ Res 2008; 102:761-769.