The presence of k-binding sites in the heart suggests a regulatory role of k-receptor in the cardiac functions. Recent studies have provided evidence that activation of cardiac k-receptor elevates intracellular free calcium ([Ca2+]i) by increasing mobilization of calcium from the intracellular store. The mobilization of intracellular calcium results from an increased production of inositol-1,4,5-trisphosphate (IP3). The increase in [Ca2+]i may manifest in cardiac arrhythmias while the depletion of calcium from the intracellular store may reduce the contractility elicited upon depolarization. The responses of IP3/[Ca2+]i are significantly attenuated after development of tolerance to k-opioids due mainly to the impairment of postreceptor events. The attenuated responses of IP3/[Ca2+]i to k-receptor activation may be responsible for the failure of the k-agonists to induce cardiac arrhythmias and to reduce electrically induced calcium transients in the ventricular myocytes.