Paracetamol (PAR), also named acetaminophen, has been the most frequently consumed non-prescription drug in the world for several decades. It is the first line of non-steroidal anti-inflammatory drugs (NSAID) used for a large variety of clinical management of pain and fever, from the simple cold and migraines to osteoarthrosis and cancer. Given the easy accessibility and low price, approximately 10%-15% of patients overdose and need to be hospitalized for PAR intoxication, affecting 30 000 patients annually in the USA alone. 1 Hepatotoxicity and renal damage are the most important toxic effects reported from high-dose PAR. 2 However, in the last years, a number of studies have gradually revealed the side effects of this drug on many systems, namely the cardiovascular and respiratory systems. 3-5 Chan et al 6 demonstrated increased risk of vascular disorders like stroke and myocardial infarction after PAR use. This phenomenon has also been
Background
Rat isolated vas deferens releases 6‐nitrodopamine (6‐ND), and the spasmogenic activity of this novel catecholamine is significantly reduced by tricyclic compounds such as amitriptyline, desipramine, and carbamazepine and by antagonists of the α1‐adrenergic receptors such as doxazosin, tamsulosin, and prazosin.
Objectives
To investigate the liberation of 6‐ND by human epididymal vas deferens (HEVDs) and its pharmacological actions.
Methods
The in vitro liberation of 6‐ND, dopamine, noradrenaline, and adrenaline from human vas deferens was evaluated by LC‐MS/MS. The contractile effect of the catecholamines in HEVDs was investigated in vitro. The action of tricyclic antidepressants was evaluated on the spasmogenic activity ellicited by the catecholamines and by the electric‐field stimulation (EFS). The tissue was also incubated with the inhibitor of nitric oxide (NO) synthase L‐NAME and the release of catecholamines and the contractile response to EFS were assessed.
Results
6‐ND is the major catecholamine released from human vas deferens and its synthesis/release is inhibited by NO inhibition. The spasmogenic activity elicited by EFS in the human vas deferens was blocked by tricyclic antidepressants only at concentrations that selectively antagonize 6‐ND induced contractions of the human vas deferens, without affecting the spasmogenic activity induced by dopamine, noradrenaline, and adrenaline in this tissue. Incubation of the vas deferens with L‐NAME reduced both the 6‐ND release and the contractions induced by EFS.
Discussion and conclusion
6‐ND should be considered a major endogenous modulator of human vas deferens contractility and possibly plays a pivotal role in the emission process of ejaculation. It offers a novel and shared mechanism of action for tricyclic antidepressants and α1‐adrenergic receptor antagonists.
6-Nitrodopamine is a novel catecholamine released by vascular tissues, heart, and vas deferens. The aim of this study was to investigate whether 6-nitrodopamine is released from the thoracic aorta and pulmonary artery rings of marmosets (
Callithrix spp.
) and to evaluate the relaxing and anti-contractile actions of this catecholamine. Release of 6-nitrodopamine, dopamine, noradrenaline, and adrenaline was assessed by liquid chromatography with tandem mass spectrometry (LC-MS/MS). The relaxations induced by 6-nitrodopamine and by the selective dopamine D2 receptor antagonist L-741,626 were evaluated on U-46619 (3 nM)-pre-contracted vessels. The effects of 6-nitrodopamine and L-741,626 on the contractions induced by electric-field stimulation (EFS), dopamine, noradrenaline, and adrenaline were also investigated. Both aorta and pulmonary artery rings exhibited endothelium-dependent release of 6-nitrodopamine, which was significantly reduced by the NO synthesis inhibitor L-NAME. Addition of 6-nitrodopamine or L-741,626 caused concentration-dependent relaxations of both vascular tissues, which were almost abolished by endothelium removal, whereas L-NAME and the soluble guanylate cyclase inhibitor ODQ had no effect on 6-nitrodopamine-induced relaxations. Additionally, pre-incubation with 6-nitrodopamine antagonized the dopamine-induced contractions, without affecting the noradrenaline- and adrenaline-induced contractions. Pre-incubation with L-741,626 antagonized the contractions induced by all catecholamines. The EFS-induced contractions were significantly increased by L-NAME, but unaffected by ODQ. Immunohistochemical assays showed no immunostaining of the neural tissue markers S-100 and calretinin in either vascular tissue. The results indicated that 6-nitrodopamine is the major catecholamine released by marmoset vascular tissues, and it acts as a potent and selective antagonist of dopamine D
2
-like receptors. 6-nitrodopamine release may be the major mechanism by which NO causes vasodilatation.
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