Mechanism of Resistance Artery Vasorelaxation to HNO Release by IPA Nonoate

In contrast to nitric oxide (NO), the reduced congener HNO has a positive inotropic/lusitropic effect alongside a shared ability with NO to evoke peripheral vasodilatation. Thus, HNO-donors offer therapeutic potential to treat heart failure and potentially other cardiovascular disorders (Kemp-Harper et al, 2016). The mechanism of vasodilation to HNO has been suggested to be indirect, and mediated by CGRP released from perivascular nerves following HNO-activation of TRPA1 channels (Eberhardt et al, 2014). We used wire myography and smooth muscle membrane potential measurements to investigate HNO-vasorelaxation to the donor, IPA NONOate (IPA/NO), a structure offering potential for development as a therapeutic agent. IPA/NO concentration-dependently hyperpolarized and relaxed precontracted arteries. These effects were blocked by the soluble guanylyl cyclase inhibitor, ODQ but not the K_ATP channel inhibitor, glibenclamide. Vasorelaxation persisted in the presence of raised [K⁺]_o, 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. Therefore, smooth muscle hyperpolarization is not necessary for IPA/NO vasorelaxation, even though both effects are cGMP-dependent. While a reduction in hyperpolarization after perivascular CGRP depletion or TRPA1 receptor block does indicate a release of CGRP, the amounts were insufficient to contribute to vasorelaxation. We conclude that HNO-TRPA1-CGRP signalling is not important for vasodilation to IPA/NO in resistance-size arteries.