Heavy-sarcoplasmic-reticulum vesicles from rabbit skeletal muscle show not only caffeine-induced calcium release in a medium allowing active calcium loading, but also oscillations in calcium concentration under appropriate conditions. The xanthine derivatives 7-isobutyl-1-methylxanthine and theophylline also induce oscillations under the same conditions. Calcium-releasing substances with other chemical structures such as adenosine nucleotides or calmodulin antagonists do not induce this effect. With the help of specific inhibitors such as ruthenium red, neomycin or magnesium it was demonstrated that the oscillation mechanism involves the ryanodine receptor/calcium channel. When ATP was substituted by GTP or ITP no oscillations occurred after caffeine application. The subsequent application of ATP, but not of adenosine 5'-[gamma-thio]triphosphate or adenosine 5'-[beta,gamma-methylene]triphosphate activated the oscillating mechanism, showing ATP to be an essential component of the oscillating system. We investigated the influence of the experimental conditions by altering the caffeine and ATP concentrations, calcium load, pH and ionic strength amongst other parameters. Potassium and anion channels are not involved in calcium oscillations of heavy sarcoplasmic reticulum, nor are the oscillations dependent on membrane potential.