When CGRP is injected into the central nervous system, it produces a variety of effects, including hypertension and suppression of feeding. When injected into the systemic circulation, the peptide causes hypotension and tachycardia. The hypotensive action of CGRP results from the potent vasodilator action of the peptide; indeed, CGRP is the most potent vasodilator yet discovered. It dilates multiple vascular beds, but the coronary circulation is particularly sensitive. The vasodilation is mediated via a nonendothelial mechanism through activation of adenylyl cyclase.
The actions of CGRP are mediated via a single receptor type. This heterodimeric receptor consists of the G protein-coupled calcitonin receptor-like receptor (CLR) combined with the receptor activity-modifying protein RAMP1.
Peptide and nonpeptide antagonists of the CGRP receptor have been developed. CGRP8-37 has been used extensively to investigate the actions of CGRP but displays affinity for other related receptors including those for adrenomedullin (see below). Nonpeptide CGRP receptor antagonists target the interface between CLR and RAMP1 and thereby make them more selective for the CGRP receptor. Examples are olcegepant and telcagepant.
Evidence is accumulating that release of CGRP from trigeminal nerves plays a central role in the pathophysiology of migraine. The peptide is released during migraine attacks, and successful treatment of migraine with a selective serotonin agonist normalizes cranial CGRP levels. Clinical trials showed olcegepant to be effective in treating migraine, but because of its low bioavailability, it has to be administered by intravenous injection. Telcagepant is also effective and is orally active but has exhibited liver toxicity in a small number of patients.
Adrenomedullin (AM) was first discovered in human adrenal medullary pheochromocytoma tissue. It is a 52-amino-acid peptide 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 concentrations 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 the AM receptor. 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.