Endothelins (ETs) are by far the most potent vasoactive peptides identified to date. These peptides exert vasoregula-
tory action by interacting with cell surface receptors on vascular endothelial and smooth muscle cells [1, 3]. Three structurally similar isoforms of ETs have been identified, ET-1, ET-2, and ET-3. These 21-amino-acid peptides are produced by a number of tissues with vascular endothelium being the major source. ET-1 appears to be the predominant isoform that is constitutively expressed in the vascular endothelium. ETs are regulated primarily at the transcrip-tional level and a number of stimulators have been identified that upregulate ET expression. These ET inducers include growth factors, cytokines, and various physiochemical factors . In addition to transcriptional regulation, ET production may be regulated via destabilization of mRNA species.
ET gene products undergo two steps of enzymatic cleavage to generate biologically active ET peptides. These peptides perform vasoregulatory action by interacting with specific cell surface receptors, ETA, ETB, and ETC. Among the ET receptors, only ETA and ETB receptor types are expressed in mammals. These receptors are coupled to phos-pholipase C via G proteins [1, 3]. ETA receptors are localized primarily on vascular smooth muscle cells and are involved in sustained slow-onset vasoconstriction. Activation of ETA receptors results in calcium influx via phos-pholipase C-mediated diacylglycerol (DAG) and inositol trisphosphate (IP3) production. Elevated intracellular calcium and DAG-mediated protein kinase C (PKC) activation lead to myosin light chain kinase (MLCK) phosphorylation and smooth muscle cell contraction. ETB receptors are involved in generation of nitric oxide (NO) by endothelial cells and thus regulate vasodilation. Endothelial-derived NO activates guanylate cyclase in smooth muscle cells and causes vasodilation by decreasing intracellular calcium levels. The net vascular effect would, therefore, depend on
ET concentration, relative density of ET receptor types, and the vascular tissue.
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This ebook provides an introductory explanation of the workings of the human body, with an effort to draw connections between the body systems and explain their interdependencies. A framework for the book is homeostasis and how the body maintains balance within each system. This is intended as a first introduction to physiology for a college-level course.