The endothelin peptides: Pharmacology of a novel class of endogenous vasoactive agents
Description
Evidence suggests that an association exists between cardiovascular diseases like hypertension and atherosclerosis and an altered ability of the endothelium to produce vasodilating factors such as prostacyclin and endothelium-derived relaxing factor. Similarly, increased or uncontrolled production of endothelium-derived contractile factors might also contribute to these disease processes. A potent endothelium-derived vasoconstrictor peptide, endothelin, now known as endothelin-1, has recently been discovered and synthesized. It was reported that this peptide is one of the most potent vasoconstrictor agents known. It has now been established that the human genome has three endothelin-related genes and the products of these genes have been designated endothelin-1, endothelin-2, and endothelin-3. This research project was undertaken to provide insight into the pharmacological activities of this novel class of peptides, as well as those of the structurally-related snake venom peptides, the sarafotoxins. At the outset of this project little was known about the cardiovascular responses to the peptides, in vivo, and there were no reports comparing their effects in the cat. Cardiovascular and pulmonary vascular responses to a variety of these novel peptides were investigated in the anesthetized cat. The data presented shows that responses to the endothelin-family of peptides are determined by dose and structure of the peptide, method of administration, and by differences in individual vascular beds. The results of these studies indicated that endothelin-1 is not the most potent vasoconstrictor peptide known and show that vasodilation can be a prominent feature of the response to the peptide. Moreover, these results show that endothelin-1 induces hindquarters vasoconstriction which is not mediated by a variety of known receptors, but is dependent on the influx of extracellular calcium. These data also show that systemic and pulmonary vascular responses to the endothelin peptides in the cat are not mediated by release of cyclooxygenase products, stimulation of beta adrenergic receptors, activation of ATP-regulated potassium channels, and for the most part, on autonomic reflexes. The endothelin peptides also produced bronchoconstriction in the cat and, in contrast to the vascular responses, these effects were mediated, in part, by the formation of thromboxane. In conclusion, the data from these experiments indicate that responses to the endothelin peptides are complex and that endothelin-l could act as an endothelium-derived vasoconstricting and as an endothelium-derived vasodilating hormone