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(Circulation. 1995;92:2504-2510.)
© 1995 American Heart Association, Inc.

Articles

Effect of Ryanodine on Sarcoplasmic Reticulum Ca²⁺ Accumulation in Nonfailing and Failing Human Myocardium

Lynn R. Nimer, MD; Dolores H. Needleman, PhD; Susan L. Hamilton, PhD; Judith Krall, BS; Matthew A. Movsesian, MD

From Research Service, Salt Lake City (Utah) Veterans Affairs Medical Center (M.A.M.); the Departments of Internal Medicine (Cardiology) (L.R.N., J.K., M.A.M.) and Pharmacology (M.A.M.), University of Utah School of Medicine; and the Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, Tex (D.H.N., S.L.H.).

Correspondence to Matthew Movsesian, MD, Cardiology Division, University of Utah Health Sciences Center, 50 N Medical Dr, Salt Lake City, UT 84132. E-mail matthew@cardio.med.utah.edu.

Background The purpose of this study was to determine whether abnormal Ca²⁺ release through ryanodine-sensitive Ca²⁺ channels in the sarcoplasmic reticulum might contribute to the abnormal [Ca²⁺]_i homeostasis that has been described in failing human myocardium.

Methods and Results Occupancy of low-affinity ryanodine binding sites on ryanodine-sensitive Ca²⁺ channels stimulates oxalate-supported, ATP-dependent Ca²⁺ accumulation in sarcoplasmic reticulum–derived microsomes by inhibiting concurrent Ca²⁺ efflux through these channels. We examined the effects of 0.5 mmol/L ryanodine on ⁴⁵Ca²⁺ accumulation in microsomes prepared from nonfailing (n=8) and failing (n=10) human left ventricular myocardium. In the absence of ryanodine, ⁴⁵Ca²⁺ accumulation reached similar levels in microsomes from nonfailing and failing hearts. Incubation with 0.5 mmol/L ryanodine caused a 52.2±6.5% increase in peak ⁴⁵Ca²⁺ accumulation in microsomes from nonfailing hearts and a 24.3±4.1% increase in microsomes from failing hearts. The density of high-affinity ryanodine binding sites and the inhibition of [³H]ryanodine dissociation from these sites by 0.1 mmol/L ryanodine were similar in microsomes from nonfailing and failing hearts.

Conclusions These results, which demonstrate a diminished stimulation of Ca²⁺ accumulation by ryanodine in sarcoplasmic reticulum–derived microsomes from failing human myocardium that could be explained by an uncoupling of the occupancy of low-affinity ryanodine binding sites from the reduction in the open probability of these channels or by concurrent Ca²⁺ efflux through a ryanodine-insensitive mechanism, are evidence that increased efflux of Ca²⁺ from the sarcoplasmic reticulum may contribute to the abnormal [Ca²⁺]_i homeostasis described in failing human myocardium.

Key Words: sarcoplasmic reticulum • cardiomyopathy • calcium • calcium channels • heart failure

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