Abstract
This study investigates whether amrinone (100-1000 μM), a phosphodiesterase-III inhibitor, can alleviate depression of contractions in ventricular myocytes from prefailure cardiomyopathic (CM) hamsters (80-100 days). Cell shortening and ion currents were measured in voltage-clamped cells at 37°C. Normal myocytes exhibited low-gain Ca2+-induced Ca2+ release (CICR) initiated by test steps from -40 mV and high-gain CICR initiated from more negative potentials. In normal myocytes, amrinone selectively increased contractions initiated by high-gain CICR (fractional shortening increased from 3.6 ± 0.5% to 5.3 ± 0.6%, 300 μM amrinone) but had no effect on low-gain CICR. Amrinone decreased L-type Ca2+ current (ICa-L; -5.5 ± 0.8 to -3.7 ± 0.5 picoAmp/picoFarad, 300 μM amrinone). In contrast, in CM myocytes, high-gain CICR was virtually absent, and amrinone had no inotropic effect. Amrinone inhibited ICa-L less in CM than normal myocytes. Sarcoplasmic reticulum (SR) Ca2+ stores, assessed by caffeine, were significantly increased by amrinone in normal but not CM myocytes. Thus, the positive inotropic effect of amrinone in normal hamster myocytes was mediated by selective enhancement of high-gain CICR. This effect was not mediated by stimulation of ICa-L because ICa-L is inhibited by this drug in hamster. High-gain CICR, which is depressed in CM myocytes, cannot be restored by amrinone. However, minimal stimulation of adenylyl cyclase with forskolin restored the positive inotropic effect of amrinone in CM cells. This positive inotropic effect of amrinone may reflect increased SR Ca2+ stores because increased stores accompanied the positive inotropic effect in normal myocytes but were absent in CM myocytes.
Footnotes
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This work was supported in part by grants from the Canadian Institutes of Health Research and the Heart and Stroke Foundation of Nova Scotia. W.X. was a Killam Scholar. This work has been presented in part previously in the following abstracts: Xiong W, Ferrier GR, and Howlett SE (1998) Amrinone potentiates contractions initiated by a voltage sensitive mechanism in ventricular myocytes from normal but not cardiomyopathic hamsters. Biophys J 74:A54; Xiong W, Ferrier GR, and Howlett SE (2000) Depression of the voltage-sensitive release mechanism in cardiomyopathic hamster ventricular myocytes is not reversed by exposure to the phosphodiesterase III inhibitor amrinone. Biophys J 78:372A; and Xiong W, Ferrier GR, and Howlett SE (2001) Reduced inotropic response to amrinone in cardiomyopathic (CM) hamsters is related to defective Ca release by the voltage-sensitive release mechanism (VSRM). Biophys J 80:596A.
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DOI: 10.1124/jpet.103.064873.
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ABBREVIATIONS: CM, cardiomyopathic; EC, excitation-contraction; CICR, Ca2+-induced Ca2+ release; ICa-L, L-type Ca2+ current; SR, sarcoplasmic reticulum; PKA, protein kinase A; PDE-III, phosphodiesterase III.
- Accepted March 30, 2004.
- Received December 23, 2003.
- The American Society for Pharmacology and Experimental Therapeutics
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