Heart rate (HR) is a reflection of cardiac function as well as of the lifespan and energy metabolism among mammals. In comparison with most terrestrial mammals, the extraordinary reduction of cetacean HR rarely has been explored. It has been shown that the decreased HR contributes to an increase of lifespan, and high efficiency of energy utilization which provides many advantages for cetacean adaptation into aquatic habitats. However, the molecular mechanisms leading to the reduced HR in cetaceans remains unresolved until now. Branch models and branch-site models combined with analysis of protein functional differentiation, based on the maximum likelihood method have been used in the present research to test the molecular evolution acting on cetacean exchange proteins directly activated by cAMP (Epac1 and Epac2), two vital molecules in the cAMP signal that controls HR. Our results show an accelerated evolution of Epac1 at the combined branch of Baleen whales and sperm whale (Physeter macrocephalus). Branch-site models have determined remarkable positive selection at the ancestor node of baleen whales with positively selected sites located in the protein catalytic domain. Furthermore, functional modification of Epac1 also has been detected in cetaceans.  In addition, strong positive selection of Epac2 in the bowhead whale (Balaena mysticetus) with a lifespan of up to 200 years has been discovered as was seen for Epac1. These results suggest adaptive evolution of Epac1 and Epac2 in cetaceans, which might not only result in reduced HR, but also may contribute to extended lifespans and high effective energy utilization.