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CARDIOVASCULAR

Diminished Inotropic Response to Amrinone in Ventricular Myocytes from Myopathic Hamsters Is Linked to Depression of High-Gain Ca²⁺-Induced Ca²⁺ Release

Department of Pharmacology, Dalhousie University, Halifax, Nova Scotia, Canada

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 (I_Ca-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 I_Ca-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 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 Ca²⁺ stores because increased stores accompanied the positive inotropic effect in normal myocytes but were absent in CM myocytes.

Address correspondence to: Dr. Susan E. Howlett, Department of Pharmacology, Sir Charles Tupper Medical Building, Dalhousie University, Halifax, NS, Canada B3H 4H7. E-mail: Susan.Howlett{at}dal.ca