Norepinephrine Has Dual Effects on Human Colonic Contractions Through Distinct Subtypes of Alpha 1 Adrenoceptors

Abstract

Background & aims: Colonic musculature contain smooth muscle cells (SMC), interstitial cells of Cajal (ICC), and platelet-derived growth factor receptor α⁺ cells (PDGFRα⁺ cells), which are electrically coupled and operate together as the SIP syncytium. PDGFRα⁺ cells have enriched expression of small conductance Ca²⁺-activated K⁺ (SK) channels. Purinergic enteric neural input activates SK channels in PDGFRα⁺ cells, hyperpolarizes SMC, and inhibits colonic contractions. Recently we discovered that PDGFRα⁺ cells in mouse colon have enriched expression of α1A adrenoceptors (ARs), which coupled to activation of SK channels and inhibited colonic motility, and α1A ARs were principal targets for sympathetic regulation of colonic motility. Here we investigated whether PDGFRα⁺ cells in human colon express α1A ARs and share the roles as targets for sympathetic regulation of colonic motility.

Methods: Isometric tension recording, intracellular recording, and Ca²⁺ imaging were performed on muscles of the human colon. Responses to α1 ARs agonists or electric field stimulation with AR antagonists and neuroleptic reagents were studied.

Results: Exogenous or endogenous norepinephrine released from nerve fibers inhibited colonic contractions through binding to α1A ARs or enhanced colonic contractions by acting on α1D ARs. Inhibitory responses were blocked by apamin, an antagonist of SK channels. Phenylephrine, α1 AR agonists, or norepinephrine increased intracellular [Ca²⁺] in PDGFRα⁺ cells, but not in ICC, and hyperpolarized SMCs by binding to α1 ARs expressed by PDGFRα⁺ cells.

Conclusions: Human colonic contractions are inhibited by α1A ARs expressed in PDGFRα⁺ cells and activated by α1D ARs expressed in SMC.

Keywords: Colonic Motility; PDGFRα(+) Cells; SIP Syncytium; Sympathetic Nervous System; α1 Adrenoceptor.