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CARDIOVASCULAR

Pharmacological Effects of ATI22-107 [2-(2-{2-[2-Chloro-4-(6-oxo-1,4,5,6-tetrahydro-pyridazin-3-yl)-phenoxy]-acetylamino}-ethoxymethyl)-4-(2-chloro-phenyl)-6-methyl-1,4-dihydro-pyridine-3,5-dicarboxylic Acid Dimethyl Ester)], a Novel Dual Pharmacophore, on Myocyte Calcium Cycling and Contractility

Departments of Physiology and Cardiology, Temple University, Philadelphia, Pennsylvania (A.S.J., M.P.Q., G.D.M., S.R.H., K.B.M.); and Department of Cardiovascular Biology, Artesian Therapeutics Inc., Gaithersburg, Maryland (D.P.B.)

Historically, inhibitors of type III phosphodiesterases (PDE-III) have been effective inotropes in mammalian myocardium, but their clinical utility has been limited by adverse events, including arrhythmias that are considered to be due to Ca²⁺ overload. ATI22-107 [2-(2-{2-[2-chloro-4-(6-oxo-1,4,5,6-tetrahydro-pyridazin-3-yl)-phenoxy]-acetylamino}-ethoxymethyl)-4-(2-chlorophenyl)-6-methyl-1,4-dihydro-pyridine-3,5-dicarboxylic acid dimethyl ester)], a novel, dual pharmacophore compound, was designed to simultaneously inhibit the cardiac phosphodiesterase (PDE-III) and produce inotropic effects, whereas inhibiting the L-type calcium channel (LTCC) was designed to minimize increases in diastolic Ca²⁺. We compared the effects of ATI22-107 and enoximone, a pure PDE-III inhibitor, on the Fluo-3 calcium transient in normal feline ventricular myocytes and trabeculae. Enoximone-induced dose-dependent increases in peak [Ca²⁺]_i, diastolic [Ca²⁺]_i, T50, and T75. ATI22-107 demonstrated similar dose-dependent increases in peak [Ca²⁺]_i at 300 nM and 1.0 µM doses, with no further increases at higher doses. Throughout the dosing range, ATI22-107 induced much smaller, if any, increases in diastolic [Ca²⁺]_i, T₂₅, and T₇₅. Current measurement of LTCC via patch-clamp techniques revealed dose-dependent decreases in LTCC current with an increasing dose of ATI22-107, thereby validating the dual functionality of the drug that has been proposed in this study. Studies in isolated trabeculae demonstrated that enoximone-induced a dose-dependent augmentation of the entire force-frequency relation in normal myocardium, whereas augmentation of contractility was only observed at lower stimulation frequencies with ATI22-107. These results demonstrate the effects of the LTCC-antagonizing moiety of ATI22-107 and suggest that the novel simultaneous combination of PDE-III and LTCC inhibition by one molecule may produce a favorable profile of limited inotropy without detrimental effects of increased diastolic [Ca²⁺]_i.

Address correspondence to: Dr. Kenneth B. Margulies, Cardiovascular Research Center, Temple University School of Medicine, 3420 N. Broad Street, Room 805 MRB, Philadelphia, PA 19140. E-mail: margul{at}temple.edu

This article has been cited by other articles:

				A. S. Jung, H. Kubo, R. Wilson, S. R. Houser, and K. B. Margulies Modulation of contractility by myocyte-derived arginase in normal and hypertrophied feline myocardium Am J Physiol Heart Circ Physiol, May 1, 2006; 290(5): H1756 - H1762. [Abstract] [Full Text] [PDF]