Clinical perspectives of calcitonin gene related peptide pharmacology

Calcitonin gene related peptide (CGRP), a potent vasoactive and cardiotonic peptide, interacts with specific G-protein-coupled receptors. CGRP is synthesized and released from small, capsaicin-sensitive sensory nerves. This extensive network of sensory nerves, found in virtually all organs, suggest a potential role for CGRP in diverse physiologic and pathophysiologic processes. The potent vasodilation elicited by CGRP in the cerebral, coronary, and peripheral vasculature has led to its therapeutic evaluation in the treatment of cerebral vasospasm following subarachnoid hemorrhage, stable angina, and Raynaud's phenomenon. The potential inotropic action and coronary vasodilation have also led to a potential beneficial effect in congestive heart failure. The enriched localization of CGRP in trigeminal sensory ganglia may indicate a role in the neurogenic inflammation associated with migraine. Thus, CGRP antagonists may represent a novel therapeutic approach to the treatment of migraine. In addition, CGRP and amylin (homologous pancreatic peptide) reduce the tissue--glucose response to insulin. It has been suggested that a CGRP antagonist may therefore improve insulin sensitivity in non-insulin-dependent diabetes, NIDDM. This brief review provides a preliminary exploration of the potential therapeutic opportunities surrounding CGRP and CGRP antagonists. Future advances are dependent on a better understanding of the structure and function of CGRP receptor(s) and the concomitant identification of selective and potent agonists and antagonists useful for addressing therapeutic hypotheses.