Adrenomedullin (AM) was first discovered in human adrenal medullary pheochromocytoma tissue. It is a 52-amino-acid pep-tide with a six-amino-acid ring and a C-terminal amidation sequence. Like CGRP, AM is a member of the calcitonin family of peptides. A related peptide termed adrenomedullin 2, also called intermedin, has been identified in humans and other mammals.
AM is widely distributed in the body. The highest concentra-tions are found in the adrenal glands, hypothalamus, and anterior pituitary, but high levels are also present in the kidneys, lungs, cardiovascular system, and gastrointestinal tract. AM in plasma apparently originates in the heart and vasculature.
In animals, AM dilates resistance vessels in the kidney, brain, lung, hind limbs, and mesentery, resulting in a marked, long-lasting hypotension. The hypotension in turn causes reflex increases in heart rate and cardiac output. These responses also occur during intravenous infusion of the peptide in healthy human subjects. AM also acts on the kidneys to increase sodium excretion and renin release, and it exerts other endocrine effects including inhibition of aldosterone and insulin secretion. It acts on the central nervous system to increase sympathetic outflow.
The diverse actions of AM are mediated by a receptor closely related to the CGRP receptor (see above). CLR co-assembles with RAMP subtypes 2 and 3, thus forming a receptor-coreceptor system. Binding of AM to CLR activates Gs and triggers cAMP formation in vascular smooth muscle cells, and increases nitric oxide production in endothelial cells. Other signaling pathways are also involved.
Circulating AM levels increase during intense exercise. They also increase in a number of pathologic states, including essential hypertension, cardiac and renal failure, and septic shock. The roles of AM in these states remain to be defined, but it is currently thought that the peptide functions as a physiologic antagonist of the actions of vasoconstrictors including ET-1 and ANG II. By virtue of these actions, AM may protect against cardiovascular overload and injury, and AM may be beneficial in the treatment of some cardiovascular diseases.