Vasorelaxation to the HNO donor isopropylamine NONOate in resistance arteries does not require perivascular CGRP

HNO donors offer considerable therapeutic potential for the treatment of hypertension-related cardiovascular disorders, particularly heart failure, as they combine an inotropic action with peripheral vasodilation. Angeli’s salt (AS) is the only HNO donor whose mechanism has been studied in depth, and recently AS-vasodilation was suggested to be indirect and due to calcitonin gene-related peptide (CGRP) released from perivascular nerves after HNO activates TRPA1 channels. We investigated resistance artery vasorelaxation to the HNO-donor, IPA NONOate (IPA/NO), one of the structures providing a template for therapeutic development. Wire myography in combination with measurements of smooth muscle membrane potential was used to characterize the effect of IPA/NO in mesenteric resistance arteries. Immunohistochemistry was assessed in pressurized arteries. IPA/NO concentration-dependently hyperpolarized and relaxed arteries precontracted with the 1-adrenoreceptor agonist, phenylephrine (PE). These effects were blocked by the soluble guanylyl cyclase inhibitor, ODQ but not the KATP channel inhibitor, glibenclamide. Vasorelaxation persisted in the presence of raised [K+]o, used to block hyperpolarization, capsaicin to deplete perivascular CGRP or HC030031 to block TRPA1 receptors. Without pre-constriction, hyperpolarization to IPA/NO was suppressed by glibenclamide, capsaicin or HC030031. Hyperpolarization but not vasorelaxation to exogenous CGRP was inhibited with glibenclamide. Thus, vascular hyperpolarization is not necessary for vasorelaxation to the HNO donor IPA/NO, even though both effects are cGMP-dependent. The reduced hyperpolarization following depletion of perivascular CGRP or block of TRPA1 receptors indicates some release of CGRP, but this does not contribute to HNO-vasorelaxation. Therefore, HNO-TRPA1-CGRP signalling does not seem important for vasodilation to IPA/NO in resistance arteries