Within the realm of the general hypothesis concerning the role of cGMP on intracellular calcium regulation in biological systems, we have investigated the action of cyclic nucleotides during excitation-contraction coupling in frog sartorius muscle. Our data show that several guanosine nucleotides (GTP, GDP, dibutyryl-cGMP) can increase the isometric twitch tension with a maximum increase of 40% in the muscles treated with cGMP. This increase is completely independent of external Ca2+ concentration. The use of dantrolene sodium (known to inhibit calcium release from sarcoplasmic reticulum) results in a decrease in the twitch tension with a contemporary decrease in the intracellular levels of cGMP; whereas, the addition of cGMP to the muscles treated with dantrolene antagonizes, at least partially, the effect of the drug on tension development. Finally, in chemically skinned muscles, cGMP induces a reversible contracture equal to approximately one-half of that evoked by 10(-4) M Ca2+.