High K⁺-Induced Relaxation by Nitric Oxide in Human Gastric Fundus

Abstract

This study was designed to elucidate high K+-induced relaxation in the human gastric fundus. Circular smooth muscle from the human gastric fundus greater curvature showed stretch-dependent high K+ (50 mM)-induced contractions. However, longitudinal smooth muscle produced stretch-dependent high K+-induced relaxation. We investigated several relaxation mechanisms to understand the reason for the discrepancy. Protein kinase inhibitors such as KT 5823 (1 µM) and KT 5720 (1 µM) which block protein kinases (PKG and PKA) had no effect on high K+-induced relaxation. K+ channel blockers except 4-aminopyridine (4-AP), a voltage-dependent K+ channel (KV) blocker, did not affect high K+-induced relaxation. However, N(G)-nitro-L-arginine and 1H-(1,2,4)oxadiazolo (4,3-A)quinoxalin-1-one, an inhibitors of soluble guanylate cyclase (sGC) and 4-AP inhibited relaxation and reversed relaxation to contraction. High K+-induced relaxation of the human gastric fundus was observed only in the longitudinal muscles from the greater curvature. These data suggest that the longitudinal muscle of the human gastric fundus greater curvature produced high K+-induced relaxation that was activated by the nitric oxide/sGC pathway through a KV channel-dependent mechanism.

H2Receptor-Mediated Relaxation of Circular Smooth Muscle in Human Gastric Corpus: the Role of Nitric Oxide (NO)

“…These findings indicate that NO-mediated pathways may be involved in histamine-induced tonic relaxation in the human stomach. Since histamine also produced tonic relaxation via activation of NO pathway, histamine might play an important role for adaptive relaxation in human stomach too [ 10 , 11 , 12 ]. As shown in the Results, histamine produced both contraction and relaxation in the same tissue, as shown in the circular smooth muscle of corpus ( Fig.…”

“…3A and 3B ). In our previous study, in fact, we reported activation of the NO/sGC pathways in high K + -induced relaxation in longitudinal smooth muscle of the human gastric corpus and fundus [ 10 , 11 ]. It has also been reported that interstitial cells of Cajal (ICC) express NO-sensitive sGC and it is the primary target of NO released from nNOS neurons even in human stomach [ 13 , 29 , 30 , 31 , 32 , 33 ].…”

“…The written informed consent was obtained from all patients who donated gastric tissue. Human gastric tissues from greater curvature were obtained from patients who underwent gastrectomy [ 10 , 11 , 12 , 13 ]. Specimens from macroscopically normal tissue of neoplastic area were removed immediately after surgical resection of stomach.…”

“…When it is required to rule out nerve mediated response, tetrodotoxin (TTX, 0.4 µM) only and/or nerve blockers cocktail (NBC) was used. NBC contained TTX (0.4 µM), guanethidine (1 µM), and atropine (ATR, 1 µM) [ 10 , 11 ]. All drugs used in this study were purchased from Sigma.…”

“…We have recently found that high K + stimulation produced relaxation via nitric oxide (NO) and soluble guanylate cyclase (sGC) in the longitudinal smooth muscle of the human gastric corpus and fundus [ 10 , 11 ]. Because the gastric corpus and fundus is a specific region for acid secretion and receptive relaxation, such as gastric accommodation after meal ingestion, NO-mediated regulatory mechanisms on GI motility and secretion would seem to be important.…”