Glyceryl nonivamide: A capsaicin derivative with cardiac calcitonin gene-related peptide releasing, K⁺ channel opening and vasorelaxant properties

In this study, the aorta vasorelaxant, coronary calcitonin gene-related peptide (CGRP) releasing, and atrial contractility effects of glyceryl nonivamide (GLNVA) were investigated in guinea pigs. In the isolated thoracic aorta, although GLNVA (0.01-50 μM) concentration dependently induced endothelium-independent relaxations and relaxed phenylephrine-(1.0 μM) induced contractions, it failed to relax 80 mM KCl-induced contractions. The GLNVA (1.0 μM) relaxation response in the aorta was significantly inhibited by tetraethylammonium (2.5-10 mM) or ouabain (5.0 μM) and was attenuated by increased extracellular potassium gradient (10-30 mM). Glibenclamide (0.01- 10 μM) dose dependently antagonized the GLNVA relaxant effect. In the isolated perfused guinea pig heart, GLNVA (0.1-10 μM) increased CGRP-like immunoreactivity outflow from coronary circulation in a concentration- dependent manner. In the isolated right and left guinea pig atria, GLNVA (0.01-10 μM) produced concentration-dependent positive inotropic and chronotropic effects, but these effects were inhibited by pretreatments with ruthenium red (1.0 μM), capsazepine (10 μM), human calcitonin-gene-related peptide (CGRP_8-37) (1.0 μM) and sensory neuron denervation, respectively. Based on these findings, we suggest that CGRP may be released by GLNVA from cardiovascular sensory neuron, and it then activates CGRP receptors on the coronary artery and atrium. The GLNVA-induced vasorelaxant effect in the vascular smooth muscle of the aorta is due to CGRP release associated K⁺ channel opening, and this effect eliminates capsaicin-derived excitability-associated K⁺ channel blocking activities.