4.3 Article

Pharmacological evidence that GABA-induced relaxation of rat proximal duodenum longitudinal muscle depends on NKCC cotransporter activity and Ca2+ influx

出版社

CANADIAN SCIENCE PUBLISHING
DOI: 10.1139/cjpp-2021-0639

关键词

GABA; NKCC cotransporters; NANC neurons; rat duodenum; nitric oxide and Ca2+

资金

  1. Conselho Nacional de Desenvolvimento Cientifico e Tecnologico (CNPq) [480918/2008-2]
  2. FAPESP [97/14208-8]

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This study found that activation of GABA(A) receptors induces nonadrenergic, noncholinergic (NANC) neuronal relaxations in the rat duodenum. These relaxations depend on the activity of Na+ K+ Cl- cotransporters and the activation of calcium channels. It is suggested that neuronal depolarization, caused by Cl- efflux through GABA(A) receptors, leads to calcium influx and nitric oxide release.
gamma-Aminobutyric acid (GABA) is the main inhibitory neurotransmitter in adult central nervous system (CNS) synapses, but it excites immature CNS neurons as well as neurons in the myenteric plexus. The present work aimed to determine whether GABA-induced nonadrenergic, noncholinergic (NANC) neuronal-mediated relaxation of the rat duodenum is dependent on the activity of Na+ K+ Cl- cotransporters (NKCC) and requires calcium influx. In the presence of guanethidine (3 mu mol/L), atropine (3 mu mol/L), and indomethacin (1 mu mol/L), relaxations induced by GABA (100 mu mol/L), KCl (5-10 mmol/L) and electrical field stimulation (1-8 Hz, 2 ms, 60 V), but not those induced by bradykinin (10-100 nmol/L) were abolished by lidocaine (300 mu mol/L). However, only GABA-induced relaxations were reduced in a concentration-dependent manner by the NKCC1/2 inhibitors bumetanide (0.1-1 mu mol/L) and furosemide (1-10 mu mol/L). GABA-induced NANC neuronal relaxationwas abolished by bicuculline (30 mu mol/L) and inhibited by N-nitroarginine methyl ester (l-NAME, 300 mu mol/L). The omega-conotoxin GVIA (1 mu mol/L), which acts exclusively on neuronal Ca(V)2 channels, but not on smooth muscle voltage-gated Ca2+ Ca(V)1 channels, and nonselective blockers of these channels (verapamil 100 nmol/L and ruthenium red 10 mu mol/L), reduced GABA-induced relaxations. These results showed that the activation of GABA(A) receptors induces NANC nitrergic neuronal relaxations in the rat duodenum, which depend on NKCC activity and Ca(V)2 channel activation, suggesting that this phenomenon results from neuronal depolarization promoted by Cl- efflux through GABA(A) receptors, with subsequent Ca2+ influx and nitric oxide release.

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