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The direct vasodilatory effect of VIP and PACAP might be less relevant than the central effect of this compound in migraine pathogenesis.

The sensory neuropeptide calcitonin gene-related peptide (CGRP) plays a role in primary headaches, and CGRP receptor antagonists are effective in migraine treatment. CGRP is a potent vasodilator, raising the possibility that antagonism of its receptor could have cardiovascular effects. We therefore investigated the effects of the antimigraine CGRP receptor antagonist telcagepant on human isolated coronary arteries. Arteries with different internal diameters were studied to assess the potential for differential effects across the coronary vascular bed. The concentration-dependent relaxation responses to human ␣CGRP were greater in distal coronary arteries (i.d. 600 -1000 m; E max ϭ 83 Ϯ 7%) than proximal coronary arteries (i.d. 2-3 mm; E max ϭ 23 Ϯ 9%), coronary arteries from explanted hearts (i.d. 3-5 mm; E max ϭ 11 Ϯ 3%), and coronary arterioles (i.d. 200 -300 m; E max ϭ 15 Ϯ 7%). Telcagepant alone did not induce contraction or relaxation of these coronary blood vessels. Pretreatment with telcagepant (10 nM to 1 M) antagonized ␣CGRP-induced relaxation competitively in distal coronary arteries (pA 2 ϭ 8.43 Ϯ 0.24) and proximal coronary arteries and coronary arterioles (1 M telcagepant, giving pK B ϭ 7.89 Ϯ 0.13 and 7.78 Ϯ 0.16, respectively). ␣CGRP significantly increased cAMP levels in distal, but not proximal, coronary arteries, and this was abolished by pretreatment with telcagepant. Immunohistochemistry revealed the expression and colocalization of the CGRP receptor elements calcitonin-like receptor and receptor activity-modifying protein 1 in the smooth muscle cells in the media layer of human coronary arteries. These findings in vitro support the cardiovascular safety of CGRP receptor antagonists and suggest that telcagepant is unlikely to induce coronary side effects under normal cardiovascular conditions.

There is limited information about age-specific structural and functional properties of human heart valves, while this information is key to the development and evaluation of living valve replacements for pediatric and adolescent patients. Here, we present an extended data set of structure-function properties of cryopreserved human pulmonary and aortic heart valves, providing age-specific information for living valve replacements. Tissue composition, morphology, mechanical properties, and maturation of leaflets from 16 pairs of structurally unaffected aortic and pulmonary valves of human donors (fetal-53 years) were analyzed. Interestingly, no major differences were observed between the aortic and pulmonary valves. Valve annulus and leaflet dimensions increase throughout life. The typical three-layered leaflet structure is present before birth, but becomes more distinct with age. After birth, cell numbers decrease rapidly, while remaining cells obtain a quiescent phenotype and reside in the ventricularis and spongiosa. With age and maturation–but more pronounced in aortic valves–the matrix shows an increasing amount of collagen and collagen cross-links and a reduction in glycosaminoglycans. These matrix changes correlate with increasing leaflet stiffness with age. Our data provide a new and comprehensive overview of the changes of structure-function properties of fetal to adult human semilunar heart valves that can be used to evaluate and optimize future therapies, such as tissue engineering of heart valves. Changing hemodynamic conditions with age can explain initial changes in matrix composition and consequent mechanical properties, but cannot explain the ongoing changes in valve dimensions and matrix composition at older age.