作者: Ni Bhraonain, Emer P ; Gould, Thomas W. ; Hannigan, Karen I. ; Hannigan, Karen I ; Keef, Kathleen D. ; Gould, Thomas W ; Cobine, Caroline A. ; Cobine, Caroline A ; Ni Bhraonain, Emer P. ; Keef, Kathleen D

Two intramuscular interstitial cells of Cajal (ICC-IM) subtypes exist within the internal anal sphincter (IAS). This study provides the first evidence for direct coupling between nitrergic motor neurons and both ICC-IM subtypes as well as indirect coupling between purinergic inputs and Type II ICC-IM. The spatiotemporal properties of whole cell Ca2+ transients in Type II ICC-IM mimic those of smooth muscle cells (SMCs), suggesting that ICC-IM modulate the activity of SMCs via their joint participation in a SIP syncytium (SMCs, ICC, and PDGFRα+ cells).

2023-11-01·Pflugers Archiv : European journal of physiology

Neural targets of the enteric dopaminergic system in regulating motility of rat proximal colon.

Article

作者: Hashitani, Hikaru ; Nakamori, Hiroyuki

In isolated segments of the rat proximal colon, the dopamine reuptake inhibitor GBR 12909 (GBR) causes a dilatation, while the D₁-like receptor antagonist SCH 23390 (SCH) induces a tonic constriction, suggesting that neurally released dopamine tonically stimulates enteric inhibitory efferent neurons. Here, the targets of the enteric dopaminergic neurons were investigated. Cannulated segments of rat proximal colon were bathed in physiological salt solution and luminally perfused with 0.9% saline, while all drugs were applied to the bath. Spatio-temporal maps of colonic motility were constructed from video recordings of peristaltic contractions, and the maximum diameter was measured as an index of colonic contractility. GBR (1 μM)-induced dilatations of colonic segments were prevented by SCH (5 μM), L-nitro arginine (L-NA; 100 μM), a nitric oxide synthase inhibitor, or tetrodotoxin (0.6 μM). In contrast, constrictions induced by a higher concentration of SCH (20 μM) were unaffected by either L-NA or tetrodotoxin. The vasoactive intestinal peptide (VIP) receptor antagonist VIP_10-28 (3 μM) or P2Y₁ receptor antagonist MRS 2500 (1 μM) had no effect on either the GBR-induced dilatation or the SCH-induced constriction. In colonic segments that had been pretreated with 6-hydroxydopamine (100 μM, 3 h) to deplete enteric dopamine, GBR failed to increase the colonic diameter, while SCH was still capable of constricting colonic segments. Enteric dopaminergic neurons appear to project to nitrergic neurons to dilate the proximal colon by activating neuronal D₁-like receptors. In addition, constitutively activated D₁-like receptors expressed in cells yet to be determined may provide a tonic inhibition on colonic constrictions.

2014-03-15·The Journal of Physiology2区 · 医学

Purinergic inhibitory regulation of murine detrusor muscles mediated by PDGFRα⁺ interstitial cells

2区 · 医学

Article

作者: Koh, Sang Don ; Koh, Byoung H. ; Sanders, Kenton M. ; Peri, Lauren E. ; Lee, Haeyeong

Key points

Platelet‐derived growth factor receptor‐α‐positive (PDGFRα+) interstitial cells in detrusor muscles may participate in post‐junctional responses to neurotransmitters.

PDGFRα+ interstitial cells express purinergic receptors (P2Y) and small conductance Ca2+‐activated K+ channels (mainly SK3). ATP elicited large amplitude outward currents and hyperpolarization in PDGFRα+ cells. SK channel blockers and a P2Y1 receptor antagonist blocked responses to ATP.

ATP elicited only minor responses in PDGFRα+ cells of P2ry1−/− mice. ATP elicited transient inward currents in smooth muscle cells and purinergic receptor (P2X) agonists had no effect on PDGFRα+ cells.

A specific P2Y1 receptor blocker decreased electrical field stimulation‐induced relaxation.

Our findings provide an explanation for the purinergic relaxation of detrusor muscles and describe a novel mechanism for inhibitory regulation of bladder muscles that may control detrusor excitability during the filling phase.

AbstractPurines induce transient contraction and prolonged relaxation of detrusor muscles. Transient contraction could be due to activation of inward currents in smooth muscle cells, but the mechanism of purinergic relaxation has not been determined. We recently reported a new class of interstitial cells in detrusor muscles and showed that these cells could be identified with antibodies against platelet‐derived growth factor receptor‐α (PDGFRα+ cells). The current density of small conductance Ca2+‐activated K+ (SK) channels in these cells is far higher (∼100 times) than in smooth muscle cells. Thus, we examined purinergic receptor (P2Y) mediated SK channel activation as a mechanism for purinergic relaxation. P2Y receptors (mainly P2ry1 gene) were highly expressed in PDGFRα+ cells. Under voltage clamp conditions, ATP activated large outward currents in PDGFRα+ cells that were inhibited by blockers of SK channels. ATP also induced significant hyperpolarization under current clamp conditions. A P2Y1 agonist, MRS2365, mimicked the effects of ATP, and a P2Y1 antagonist, MRS2500, inhibited ATP‐activated SK currents. Responses to ATP were largely abolished in PDGFRα+ cells of P2ry1−/− mice, and no response was elicited by MRS2365 in these cells. A P2X receptor agonist had no effect on PDGFRα+ cells but, like ATP, activated transient inward currents in smooth muscle cells (SMCs). A P2Y1 antagonist decreased nerve‐evoked relaxation. These data suggest that purines activate SK currents via mainly P2Y1 receptors in PDGFRα+ cells. Our findings provide an explanation for purinergic relaxation in detrusor muscles and show that there are no discrete inhibitory nerve fibres. A dual receptive field for purines provides the basis for inhibitory neural regulation of excitability.

100 项与 MRS 2500 相关的药物交易

登录后查看更多信息