All positive inotropic agents that are available for clinical use exercise their effect predominately via an increase in cell calcium loading. However once the myocardial preparation has reached@ @its peak contractile response a further increase in cell calcium loading is associated initially with a plateau and then with a decline in the inotropic state of the muscle, an increase in diastolic tone, aftercontractions and arrhythmias. This condition which has been defined as """"""""calcium overload"""""""" represents the limiting factor in the clinical use of positive inotropic agents. Thus, it is desirable to develop drugs that increase the contractility of the heart via an enhancement in myofilament responsiveness to calcium rather than by increasing the extent of cell calcium loading. We tested the effect of novel thiadiazinone derivatives (designed by E. Merck, Darmstadt, FRG) that vary in potency (1) to sensitize skinned myocardial Tibers to Ca 2+: EMD 54622 > 53998 > 54650,-and (2) to inhibit phosphodiesterase Ill in cell homogenates (54650 > 53998 > 54622). We determined whether differential Ca 2+-myofilament effects are expressed in intact guinea pig cells, bathed in Hepes buffer (23 degree C) and loaded with the fluorescent Ca 21 probe, indo-1. Our results show that the steepness of relationship among twitches and indo-1 fluorescence transients measured across drug dose varies as 54622 > 53998 > 54650. Thus, differential modifications of the myofilament Ca 2+ response in intact cells can be effected via molecular modifications of thiadiazinone that enhance its potency to sensitize myofilaments to Ca 2+.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Intramural Research (Z01)
Project #
1Z01AG000260-02
Application #
3808887
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
2
Fiscal Year
1990
Total Cost
Indirect Cost
Name
National Institute on Aging
Department
Type
DUNS #
City
State
Country
United States
Zip Code
Lakatta, Edward G; Maltsev, Victor A (2012) Rebuttal: what I(f) the shoe doesn't fit? ""The funny current has a major pacemaking role in the sinus node"". Heart Rhythm 9:459-60
Zahanich, Ihor; Sirenko, Syevda G; Maltseva, Larissa A et al. (2011) Rhythmic beating of stem cell-derived cardiac cells requires dynamic coupling of electrophysiology and Ca cycling. J Mol Cell Cardiol 50:66-76
Chico, Laura K; Behanna, Heather A; Hu, Wenhui et al. (2009) Molecular properties and CYP2D6 substrates: central nervous system therapeutics case study and pattern analysis of a substrate database. Drug Metab Dispos 37:2204-11
Vinogradova, Tatiana M; Lakatta, Edward G (2009) Regulation of basal and reserve cardiac pacemaker function by interactions of cAMP-mediated PKA-dependent Ca2+ cycling with surface membrane channels. J Mol Cell Cardiol 47:456-74
Lyashkov, Alexey E; Vinogradova, Tatiana M; Zahanich, Ihor et al. (2009) Cholinergic receptor signaling modulates spontaneous firing of sinoatrial nodal cells via integrated effects on PKA-dependent Ca(2+) cycling and I(KACh). Am J Physiol Heart Circ Physiol 297:H949-59
Yang, Dongmei; Zhu, Wei-Zhong; Xiao, Bailong et al. (2007) Ca2+/calmodulin kinase II-dependent phosphorylation of ryanodine receptors suppresses Ca2+ sparks and Ca2+ waves in cardiac myocytes. Circ Res 100:399-407