Diminished inotropic response to amrinone in ventricular myocytes from myopathic hamsters is linked to depression of high-gain Ca2+-induced Ca2+ release.
This study investigates whether amrinone (100-1000 microM), 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 degrees C. Normal myocytes exhibited low-gain Ca(2+)-induced Ca(2+) 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 microM amrinone) but had no effect on low-gain CICR. Amrinone decreased L-type Ca(2+) current (I(Ca-L); -5.5 +/- 0.8 to -3.7 +/- 0.5 picoAmp/picoFarad, 300 microM amrinone). In contrast, in CM myocytes, high-gain CICR was virtually absent, and amrinone had no inotropic effect. Amrinone inhibited I(Ca-L) less in CM than normal myocytes. Sarcoplasmic reticulum (SR) Ca(2+) 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 I(Ca-L) because I(Ca-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 Ca(2+) stores because increased stores accompanied the positive inotropic effect in normal myocytes but were absent in CM myocytes.
Xiong
Wei
W
Department of Pharmacology, Sir Charles Tupper Medical Building, Dalhousie University, Halifax, Nova Scotia Canada B3H 4H7.
Ferrier
Gregory R
GR
Howlett
Susan E
SE
D000676:Amrinone / Q000494:pharmacology*; D000818:Animals; D002118:Calcium / Q000037:antagonists & inhibitors* / Q000378:metabolism* / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002316:Cardiotonic Agents / Q000494:pharmacology*; D006224:Cricetinae; D006352:Heart Ventricles / Q000187:drug effects / Q000378:metabolism; D008297:Male; D009135:Muscular Diseases / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism; D018408:Patch-Clamp Techniques
D002121:Calcium Channel Blockers; D002316:Cardiotonic Agents; D000676:Amrinone; D002118:Calcium