AHEART Mar. 45/3

Park, Kyoung Sik, Tae Kon Kim, and Do Han Kim. Cyclosporin A treatment alters characteristics of Ca21-release channel in cardiac sarcoplasmic reticulum. Am. J. Physiol. 276 (Heart Circ. Physiol. 45): H865–H872, 1999.—Chronic treatment with cyclosporin A (CsA) has been reported (H. S. Banijamali, M. H. ter Keurs, L. C. Paul, and H. E. ter Keurs. Cardiovasc. Res. 27: 1845–1854, 1993; I. Kingma, E. Harmsen, H. E. ter Keurs, H. Benediktsson, and L. C. Paul. Int. J. Cardiol. 31: 15–22, 1991) to induce reversible alterations of contractile properties in rat hearts. To define the molecular mechanisms underlying the physiological alterations, the Ca21-release channel (CRC) and Ca21-ATPase from sarcoplasmic reticulum in rats were examined. Ryanodine binding to whole homogenates of rat hearts shows timeand dosedependent alterations in CRC properties by CsA. On 3 wk of treatment with 15 mg CsA·kg body wt21 ·day21, 1) maximal ryanodine binding (Bmax) decreased, 2) the dissociation constant of ryanodine (Kd) increased, 3) caffeine sensitivity of CRC increased, and 4) ruthenium red sensitivity of CRC decreased. On the other hand, Bmax and Kd of ryanodine binding in rat skeletal muscles were not changed. Ryanodinesensitive oxalate-supported Ca21 uptake in whole homogenates was lower in CsA-treated rat hearts than in control hearts, whereas total Ca21 uptake in the presence of 500 M ryanodine was not changed. Functional experiments with rapamycin and Western blot analysis suggest that the CsAinduced alteration of ryanodine binding is due at least in part to an upregulation of calcineurin. The heart muscle-specific alterations of CRC could be responsible for the previously reported contractile changes of CsA-treated rat hearts.