While the stimulating effect of concentrated salts on ryanodine receptor (RyR) is widely accepted in Ca(2+)-induced Ca2+ release (CICR) and [3H]ryanodine binding, the effect of non-ionic solutes on RyR is controversial. We investigated the effects of polyols on [3H]ryanodine binding to alpha- and beta-RyR purified from bullfrog skeletal muscle, and on CICR from sarcoplasmic reticulum (SR) in a skinned frog skeletal muscle fibre. Addition of polyols (glucose, sucrose, sorbitol, glycerol and ethylene glycol) in submolar to molar concentrations to an isotonic salt medium increased dose-dependently Ca(2+)-activated [3H]ryanodine binding to alpha- and beta-RyR of a similar magnitude. The increase is due to the rise in both apparent affinity (1/KD) and maximal numbers of binding sites (Bmax) for ryanodine. In addition to this stimulating effect, glucose sensitized both isoforms to Ca2+ in the Ca(2+)-activated reaction, which is distinct in mechanism(s) from caffeine. These stimulating effects of polyols were not observed unless some NaCl was present, which might explain the discrepancy among reported results. Consistent with these findings, polyols reversibly enhanced the rate of CICR from SR in skinned fibres with an increase in the Ca2+ sensitivity. The enhanced CICR was still sensitive to well-known modulators for CICR (Ca2+, Mg2+, adenine nucleotides and procaine), as with [3H]ryanodine binding. The results of this study reveal that polyols stimulate alpha- and beta-RyR in frog skeletal muscle, bringing about increased CICR activity. The finding that the specific activity of polyols in stimulation of [3H]ryanodine binding was approximately proportional to their molecular weights leads us to discuss the possible modification of protein surface-water molecule interaction as an underlying mechanism.