The endothelins (ETs) are the most potent of the known mammalian vasocontrictor peptides, affecting various tissues and cells. Remarkably similar in structure to the peptides-sarafotoxins (SRTXs) present in the venom of the snake Atractaspis engaddensis, the ETs are involved in diverse biological processes such as contraction, neuromodulation and neurotransmission. Recent studies have established that ET-1 seems to play a functional role in vasoconstriction and heart dysfunction. Since circulating ET-1 is increased in these conditions, ETs may havea functionally significant role in these pathophysiological states.
ETs display a diversity of action which may be attributed to the existence of a number of receptor subtypes and the G-protein-mediated activation of different signal transduction pathways. The combined action of these two variables modulates the response.
Our hypothesis is that the formation of different ligand-receptor-G-protein complexes may explain the diversity of ET action, where each complex can activate a different pathway. Thus, the active complex in the cerebellum, which yields a specific mode of signal differs from that in the cortex or the hypothalamus. Differences may also exist between different parts of the same organ. For example, in recent experiments we have demonstrated that ET-1 stimulated the formation of cGMP in rat atrial slices, while the ventricular fraction is unresponsive to such stimulation. Other studies have shown that cAMP formation is inhibited by ET-1 in ventricular myocytes but stimulated by ET-1 in the atria.
In our current research we are seeking to clarify the functional differences between ET activity in the atria and the ventricles by studying: the nature of receptor subtypes associated with the diverse action of ETs in the cardiac vascular system; which G-proteins are coupled to the receptor during the activation; and which signal transduction pathways are involved in ET response in rat atria versus ventricles.
