Isoprenaline (ISP) in the rat (500 mg/kg s.c.) was shown to be able to enhance the creatin phosphokinase activity (CPK) in serum from 135 U/l in the control animals to about 600 U/l in 5 h, i.e. at the peak. When the rats were pretreated with N-methyl-N-(beta-hydroxyethyl)guanidine O-phosphate (creatinol O-phosphate, COP), the CPK enhancement was reduced to an extent related to the doses of COP (250, 500 and 1000 mg/kg i.p.). COP protection was about 16% with the lower dose but increased to 50% with the highest dose according to linear regression (COP doses versus CPK levels, p less than 0.01). The protective action against serum CPK enhancement evoked by ISP is common to other classes of drugs, such as beta-blocking agents, calcium antagonists and corticosteroids. In the case of COP and calcium antagonists a common mechanism, which has the effect or reducing myocardial calcium overload due to ISP, may be assumed on the basis of other previous investigations on the ion balance across the heart cell membrane and on the uptake and subcellular distribution of COP in the isolated perfused rat heart.