Vasostatins and negative inotropy in vertebrate hearts

We review our recent work on the cardiotropic actions of vasostatins (VS) with emphasis on their putative role in cardiac homeostasis. Studies on the isolated and perfused eel (Anguilla anguilla), frog (Rana esculenta) and rat (Langendorff preparation) hearts, as paradigms of fish, amphibian and mammalian hearts, highlight two important cardiotropic features of VS, i.e. their intrinsic negative myocardial inotropy (in terms of reduced haemodynamic parameters of mechanical performance) and their counteracting action against β-adrenergic (i.e. isoproterenol; ISO)-mediated positive inotropism. This uniform cardiotropic behaviour is consistent with an ubiquitous cardiac role of VS in vertebrates. Comparison of VS-mediated negative inotropy in the eel and frog heats illustrates aspects of uniformity and species-specific differences in the mechanism of action of the peptides. In both eel and frog hearts, VS-mediated inotropy is abolished by pre-treatment with Ca++ and K+ channels antagonists. In contrast, while VS-mediated inotropy in the eel requires an endocardial endothelium (EE) and G protein-nitric oxide (NO)-cGMP signalling, it is independent from this mechanism in frog. By using the isolated working frog heart as a bioassay system, the structural characteristics of several sequences of synthetic VS I-derived peptides (e.g. bovine and frog CgA4-16 and CgA47-66, intact and reduced bovine CgA1-40) have been functionally compared and evaluated in terms of their intrinsic inotropy and "anti-adrenergic" action. This analysis supports the phylogenetic conservation of CgA1-76 and the importance of the intact disulfide bridge-loop CgA1-40SS. On the basis of these data, we suggest that VS I and peptides thereoff are novel cardio-inhibitory agents acting as cardiostatins, i.e. principles able to protect the heart by locally counteracting excessive sympathetic stimulation