AC-201

6‐Nitrodopamine (6‐ND) is a novel endogenous catecholamine that has a potent relaxant action on vascular smooth muscle in vitro.

To evaluate the basal release of 6‐ND and noradrenaline from rabbit‐isolated corpus cavernosum (RbCC) and its relaxing action on this tissue.

Rabbit corpus cavernosa were dissected and suspended in a 5‐mL organ bath containing oxygenated Krebs‐Henseleit's solution. 6‐ND and noradrenaline release was quantified by liquid chromatography coupled to tandem mass spectrometry. The relaxant activity of 6‐ND was assessed in RbCC strips pre‐contracted with endothelin‐1 (10 nM).

Rabbit corpus cavernosum presented basal release of both 6‐ND (2.9 ± 0.8 ng/mL, n = 12) and noradrenaline (1.7 ± 1.3 ng/mL, n = 12). The 6‐ND release was reduced by pre‐treatment with Nω‐nitro‐l‐arginine methyl ester (l‐NAME) (100 µM), whereas that of noradrenaline was unaffected. Tetrodotoxin (TTX, 1 µM) abolished the noradrenaline release but had no effect on 6‐ND release, indicating a non‐neurogenic origin for 6‐ND. 6‐ND and the selective dopamine D2‐agonist L‐741,626 caused concentration‐dependent RbCC relaxations (pEC50 of 11 ± 0.15 and 11.15 ± 0.28, respectively). Pre‐treatment with either l‐NAME or the soluble guanylate cyclase inhibitor 1H‐[1,2,4] oxadiazolo[4,3‐a]quinoxalin‐1‐on (ODQ) (100 µM) caused a rightward shift of the concentration–response curve to 6‐ND, without affecting the L‐741,626 responses. In TTX (100 nM)‐pre‐treated preparations, neither l‐NAME nor ODQ shifted the 6‐ND concentration–response curve. Dopamine, noradrenaline, and adrenaline caused concentration‐dependent RbCC contractions. Pre‐incubation with 6‐ND concentration‐dependently inhibited the dopamine‐induced contractions, without affecting those induced by either noradrenaline or adrenaline.

6‐Nitrodopamine is the most potent endogenous relaxant agent in RbCC ever described and represents a novel mechanism by which NO causes corpus cavernosum smooth muscle relaxation. The finding that 6‐ND acts as a truly selective dopamine D2‐receptor antagonist indicates that the balance of dopamine and 6‐ND release/synthesis may be the main mechanism that modulates corpus cavernosum smooth muscle tonus in vivo.