Migraine and beyond: cardiovascular therapeutic potential for CGRP modulators

CGRP is a potent vasodilator that has been shown to have a physiological and/or pathological role in neurogenic inflammation, headaches including migraine, thermal injury, circulatory shock, pregnancy and menopause, hypertension and heart failure and is known to be cardioprotective. CGRP is also a positive inotrope and increases heart rate. Clinical trials have shown beneficial effects of the vasodilatory action of CGRP in hypertension, angina, heart failure, Raynaud's disease and venous stasis ulcers. However, the clinical potential of CGRP is limited as it has to be given by infusion and is quickly broken down. Oral long acting CGRP-mimetics may have potential in disorders in which CGRP has been shown to be beneficial. CGRP-mimetics include capsaicin/vanilloid receptor agonists and gene transfer of an adenoviral vector that encodes prepro-CGRP. CGRP inhibitors have therapeutic potential in conditions in which excessive CGRP-mediated vasodilatation is present; neurogenic inflammation, migraine and other headaches, thermal injury, circulatory shock and flushing in menopause. CGRP inhibitors include capsaicin, antagonists at capsaicin/vanilloid receptors, civamide, CGRP receptor antagonists and 5-HT1D-receptor agonists. Drugs that are 5-HT1D-receptor agonists, the 'triptans' are already commonly used in migraine and the first small molecule CGRP antagonist, BIBN4096BS, is under clinical investigation for the treatment of migraine.