Published online Feb 15, 2016. doi: 10.4291/wjgp.v7.i1.150
Peer-review started: March 26, 2015
First decision: April 20, 2015
Revised: April 29, 2015
Accepted: September 2, 2015
Article in press: September 7, 2015
Published online: February 15, 2016
Processing time: 337 Days and 9.9 Hours
AIM: To investigate the mechanism for bradykinin (BK) to stimulate intestinal secretomotor neurons and intestinal chloride secretion.
METHODS: Muscle-stripped guinea pig ileal preparations were mounted in Ussing flux chambers for the recording of short-circuit current (Isc). Basal Isc and Isc stimulated by BK when preincubated with the BK receptors antagonist and other chemicals were recorded using the Ussing chamber system. Prostaglandin E2 (PGE2) production in the intestine was determined by enzyme immunologic assay (EIA).
RESULTS: Application of BK or B2 receptor (B2R) agonist significantly increased the baseline Isc compared to the control. B2R antagonist, tetrodotoxin and scopolamine (blockade of muscarinic receptors) significantly suppressed the increase in Isc evoked by BK. The BK-evoked Isc was suppressed by cyclooxygenase (COX)-1 or COX-2 specific inhibitor as well as nonselective COX inhibitors. Preincubation of submucosa/mucosa preparations with BK for 10 min significantly increased PGE2 production and this was abolished by the COX-1 and COX-2 inhibitors. The BK-evoked Isc was suppressed by nonselective EP receptors and EP4 receptor antagonists, but selective EP1 receptor antagonist did not have a significant effect on the BK-evoked Isc. Inhibitors of PLC, PKC, calmodulin or CaMKII failed to suppress BK-induced PGE2 production.
CONCLUSION: The results suggest that BK stimulates neurogenic chloride secretion in the guinea pig ileum by activating B2R, through COX increasing PGE2 production. The post-receptor transduction cascade includes activation of PLC, PKC, CaMK, IP3 and MAPK.
Core tip: Bradykinin (BK) can stimulate intestinal chloride secretion and the firing of intestinal secretomotor neurons in the small intestine, but the mechanism is not well understood. In this study, muscle-stripped guinea pig ileal preparations were mounted in Ussing flux chambers for the recording of short-circuit current (Isc). BK agonist and BK antagonist were added to check the Isc change. Inhibitors of the signal transductors were pre-incubated with the tissue for 10 min before evoking with BK, and the Isc change was recorded. The change of prostaglandin E2 (PGE2) secretion was detected by ELISA after treatment with BK for 3 h. Results suggest that BK stimulates neurogenic chloride secretion in the guinea pig ileum by activating B2 receptors on secretomotor neurons, activating cyclooxygenase-1, and stimulating PGE2 production. The post-receptor transduction cascade includes activation of PLC, PKC, CaMK, IP3, and MAPK.
- Citation: Qu MH, Ji WS, Zhao TK, Fang CY, Mao SM, Gao ZQ. Neurophysiological mechanisms of bradykinin-evoked mucosal chloride secretion in guinea pig small intestine. World J Gastrointest Pathophysiol 2016; 7(1): 150-159
- URL: https://www.wjgnet.com/2150-5330/full/v7/i1/150.htm
- DOI: https://dx.doi.org/10.4291/wjgp.v7.i1.150
Bradykinin (BK) is a nonapeptide that belongs to a group of structurally related 9-11 amino acid peptides (kinins), which are produced by kallikrein-mediated enzymatic cleavage of kininogen at the site of tissue injury and inflammation[1]. BK is formed in plasma and tissues in response to infection, tissue trauma, or inflammatory alterations, such as an increase in vascular permeability, edema formation, and pain. BK is widely distributed in the central and peripheral nervous systems, including the enteric nervous system[2,3]. Two subtypes of BK receptors, namely, BK receptor type 1 (B1R) and BK receptor type 2 (B2R), are identified based on their amino acid sequence and pharmacological properties[4,5]. BK receptors belong to the family of G-protein-coupled receptors with seven transmembrane helices. BK and kallidin are ligands for the constitutively expressed B2R, whereas des-Arg9-BK (in rodents) and des-Arg10-kallidin (in human) are ligands for the inducible B1R[6,7].
Previously, we demonstrated that B2R is expressed on a majority of the ganglion cells in the myenteric and submucosal plexuses in the small intestine of guinea pigs[8-10]. Exposing neurons in the guinea pig small intestinal myenteric or submucosal plexus to BK in vitro evokes slow activation of depolarization of the membrane potential and enhanced excitability characterized by increased firing frequency during intraneuronal injection of depolarizing current pulses in both AH- and S-type neurons and the appearance of anodal break excitation at the offset of hyperpolarizing current pulses in AH neurons[8,9]. The results suggested that BK acts via B2R on myenteric and submucosal neurons to stimulate the formation of prostaglandins. The eletrophysiologic data recorded using “sharp” microelectrodes suggested that BK might act in the enteric nervous system as a paracrine mediator to alter neural control of secretory and motility functions at the organ level.
This work aimed to investigate how the involvement of BK as an excitatory neuromodulator on submucosal secretomotor neurons at the cellular neurophysiological level translates to the physiology of intestinal secretion at the level of the integrated system[11,12].
The animal protocol was designed to minimize pain or discomfort to the animals. The animals were acclimatized to laboratory conditions (23 °C, 12 h/12 h light/dark, 50% humidity, ad libitum access to food and water) for two weeks prior to experimentation. Adult male Hartley-strain guinea pigs (300-350 g) were stunned by a sharp blow to the head and exsanguinated from the cervical vessels according to a protocol approved by Weifang Medical University Laboratory Animal Care and Use Committee. The tissue preparations were essentially conducted as described[13,14]. Briefly, segments of the small intestine were removed, flushed with ice-cold Krebs solution, and opened along the mesenteric border. The “muscle-stripped” preparations were obtained by removing the longitudinal and circular muscle layers together with the myenteric plexus by microdissection. The submucosal plexus remained intact with the mucosa. About 4-6 of the flat-sheet preparations were obtained from the ileum of each animal for mounting in Ussing flux chambers. The Krebs solution was composed of 120, 6, 2.5, 1.2, 1.35, 14.4, and 11.5 mM of NaCl, KCl, CaCl2, MgCl2, NaH2PO4, NaHCO3, and glucose, respectively.
Ussing flux chambers were equipped with a pair of Ag/AgCl electrodes via Krebs-agar bridges connected to Calomel half-cells for the measurement of transmural potential difference (PD). A second pair of electrodes was connected to an automated voltage clamp apparatus, which compensated for the solution resistance between the PD-sensing bridges. The flat-sheet preparations were mounted between halves of Ussing chambers, which had a total cross-sectional area of 0.64 cm2. The tissues were bathed on both sides with 10 mL of Krebs solution and maintained at 37 °C by circulation from a temperature-controlled water bath. The necessary current to change the transepithelial PD by 2.5 mV was used to monitor tissue conductance and calculated according to the Ohm’s law, as a determinant of tissue viability. Short-circuit current (Isc) was monitored by a voltage-clamp apparatus (DVC-1000, World Precision Instruments, Sarasota, FL). The mounted “muscle-stripped” preparations were balanced at 37 °C and bubbled with 95% O2/5% CO2 for 30 min before the preparations were treated with BK. Pharmacological agents were applied by addition to the bathing solution. BK (10 nM) was added to the serosal compartment of the chamber. To test the effect of other pharmacological agents on BK-evoked chloride secretion, pharmacological agents were added 10 min before the preparations were stimulated by BK (10 nM). The changes in Isc were calculated as ΔIsc, and the effects of pharmacological agents were normalized to the cross-sectional area of the preparations. Each inhibitor was pre-incubated with the tissue for 10 min, and the Isc showed no change.
For these studies, all utensils and solutions were sterilized in 75% ethanol or autoclaved. The submucosa/mucosa preparations were prepared by carefully removing the longitudinal and circular muscle layers, as well as the myenteric plexus. The weight of each piece of preparations was recorded. The preparations were incubated in 2 mL of Dulbecco’s modified Eagle’s medium containing 100 U/mL penicillin G, 100 μg/mL streptomycin sulfate, 0.25 μg/mL amphotericin B, and glucose (12 mM) in a humidified 5% CO2 incubator at 37 °C. Preparations were pre-incubated for 30 min at 37 °C in the presence of FR122047, NS398, U73122, BisI, calmodulin inhibitor W7, or KT5720. Subsequently, 100 nM BK was added to each culture well, and a further 10 min or 3 h incubation was performed. The supernatant of each well was collected for prostaglandin E2 (PGE2) enzyme immunologic assay (EIA) (Cayman chemical, Ann Arbor, Michigan 48108 United States). EIA was preformed following the protocol provided by the manufacturer. Three independent experiments were performed, and the data were analyzed with Sigma plot software. Preparations without any treatment were used as controls.
BK acetate, B1R agonist BK fragment 1-8 acetate hydrate, B2R agonist [Hyp3]-BK, B2R antagonist HOE-140, tetrodotoxin (TTX), N-nitro-L-arginine methyl ester (L-NAME), cyclooxygenase (COX)-2 inhibitor NS398, COX-1 inhibitor FR122047, nonspecific COX inhibitors indomethacin and piroxicam, selective IP3 receptor antagonist 2-APB, MAPK inhibitor PD98059, and tyrosine protein kinase inhibitor genistein were purchased from Sigma (St. Louis, MO). KT5720, W7, and nonselective VIP receptor antagonist VIP6-28 (human, bovine, porcine, rat) were obtained from BACHEM Bioscience, Inc., King of Prussia. U73122 (1-[6-[[(17β)-3-methoxyestra-1,3,5(100-trien-17-yl] amino]hexyl]-1H-pyrrole-2,5-dione), bisindolylmaleimide I (2-[1-(3-dimethylaminopropyl)indol-3-yl]-3-(indol-3-yl)maleimide, BisI), and KN-62 were purchased from Tocris (Ellisville, MO). Stock solutions were prepared in Krebs solution or deionized H2O, except for piroxicam, U73122, and KN-62, which were solubilized in DMSO and stored at -20 °C. AH6809, SC-19220, and GW627368X were from Cayman Chemical (Ann Arbor, MI). The volume added to 10 mL of the bath solutions did not exceed 10 μL. Pharmacological agents were applied by addition to the Krebs’ bathing solution.
Data are presented as mean ± SE. Student’s t-test was used for the statistical analysis of significance of differences in the means with P < 0.05 considered significant. The statistical methods of this study were reviewed by Xiangyun Li from the Department of Statistics, Weifang Medical University.
Baseline Isc and tissue conductance for submucosal/mucosal preparations from the guinea pig ileum were similar to those described previously (Fang et al[14], 2006). The addition of BK to the bathing solution on the submucosal side of the preparations evoked a rapid increase in Isc, and BK (10 nM), applied to the submucosal side of the submucosa/mucosa preparations, increased baseline Isc by 54.3 ± 5.4 μA/cm2 (Figure 1). The B1R agonist, BK fragment 1-8 (1 μM), failed to elicit any changes in baseline Isc. The B2R agonist, [Hyp3]-BK (1 μM), increased baseline Isc by 42.1 ± 5.7 μA/cm2. Pre-incubation with the B2R antagonist, HOE-140 (1 μM), for 10 min significantly suppressed BK-evoked increase in Isc from 54.3 ± 5.4 to -1.1 ± 1.1 μA/cm2 (P < 0.01). The results suggest that BK-evoked increase in Isc is mediated through B2R, but not B1R.
Stimulation of Isc by BK (10 nM) was significantly decreased in the presence of 1 μM of TTX from 57.8 ± 7.1 μA/cm2 to 15.6 ± 1.9 μA/cm2 (n = 6; P < 0.01), which suggested that BK-evoked secretion was largely mediated by activation of the submucosal secretomotor neurons (Figure 2). The nonselective muscarinic acetylcholine antagonist, scopolamine; the vasoactive intestinal peptide (VIP) receptor antagonist, VIP6-28; and the nitric-oxide synthase inhibitor, L-NAME; were used as pharmacological tools to test the kind of enteric neurons involved in BK-evoked secretory responses in the small intestine of guinea pigs. Pretreatment with scopolamine (1 μM) significantly suppressed the 10 nM BK-evoked increase of Isc from 54.3 ± 5.4 μA/cm2 to 30.2 ± 9.4 μA/cm2 (n = 6; P < 0.01). In the presence of VIP6-28 (1 μM) or L-NAME (100 μM), BK (10 nM) increased the baseline Isc to 41.5 ± 5.1 μA/cm2 (n = 6; P > 0.05) or 44.6 ± 6.0 μA/cm2 (n = 6; P > 0.05), respectively; neither showed a significant effect on 10 nM BK-evoked increase of Isc.
The specific COX-2 inhibitor NS398 (10 μM), specific COX-1 inhibitor FR122047 (1 μM), and nonspecific COX inhibitors indomethacin (1 μM) and piroxicam (1 μM) were used to test a hypothesis that BK-evoked increase in Isc is mediated by prostaglandins, and the results are shown in Figure 3. Pretreatment with NS398 (10 μM) and FR122047 (1 μM) suppressed the 10 nM BK-evoked increases in Isc from 59.69 ± 8.45 μA/cm2 to 22.8 ± 5.9 μA/cm2 (n = 6; P < 0.01) and 25.3 ± 6.6 μA/cm2 (n = 6; P < 0.01), respectively. The nonspecific COX inhibitors, indomethacin or piroxicam abolished BK-evoked increase in Isc (n = 6; P < 0.01). Suppression of BK-evoked secretory responses by the COX inhibitors suggested that the responses to BK occurred secondary to the release of prostaglandins and their excitatory action on submucosal secretomotor neurons or directly on intestinal epithelial cells.
Involvement of prostaglandins in BK-evoked secretory responses was further supported by the finding that BK (10 nM) stimulated the synthesis and release of PGE2 from the submucosal preparations of the guinea pig ileum when compared with the preparations that were not treated with BK (Figure 4). Both FR122047 (1 μM) and NS398 (10 μM) suppressed BK-evoked PGE2 production after incubation with BK for 10 min and 3 h, respectively (Figure 4).
Furthermore, BK-evoked increase in Isc was significantly decreased by pretreatment with prostaglandin EP receptor antagonists (Figure 5). Pretreatment with EP1, EP2, EP3-III, and DP1 receptor antagonist AH6809 (10 μM) reduced BK-evoked ΔIsc from 69.5 ± 8.3 μA/cm2 to 24.2 ± 5.5 μA/cm2 (n = 6, P < 0.01), and pretreatment with GW627368X (a potent and selective competitive antagonist of the EP4 receptor, 10 μM) suppressed the ΔIsc from 69.5 ± 8.3 μA/cm2 to 21.8 ± 5.1 μA/cm2 (n = 6, P < 0.01) (Figure 5). Meanwhile, pretreatment with SC-19220 (a selective EP1 receptor antagonist, 10 μM) did not significantly affect the ΔIsc evoked by BK (n = 6, P = 0.13). All of the above information suggests that BK-evoked increase in ΔIsc was mediated by the stimulation of PGE2 release.
Our earlier studies on the mechanisms of post-receptor signal transduction using electrophysiological methods suggested that BK caused excitation of submucosal secretomotor neurons by activation of B2R on submucosal neurons, stimulation of a signal transduction pathway involving phospholipase C (PLC), elevation of intraneuronal IP3, and elevation of free cytosolic Ca2+[9]. These findings suggested that stimulation of PLC and intracellular IP3 would also underlie a component of the stimulatory action of BK on ΔIsc at the tissue level. We followed the earlier electrophysiological studies at the cellular level by using the same pharmacological tools to test the hypothesis at the tissue level in Ussing chamber studies.
U73122 was used to inhibit PLC activity. Exposure to 10 μM U73122 for 10 min prior to the application of 10 nM BK resulted in the suppression of BK-evoked responses from 57.3 ± 6.2 μA/cm2 for BK alone to 9.4 ± 4.3 μA/cm2 (n = 6; P < 0.01) (Figure 6). Pre-exposure of the preparations to the vehicle (DMSO) alone had no significant effect on BK-evoked responses (data not shown). The protein kinase C (PKC) inhibitor bisindolymaleimide I (BisI, 10 μM) decreased the BK-evoked responses to 6.77 ± 5.13 μA/cm2 (n = 6-12; P < 0.01).
Results of our previous work on the cellular neurophysiology of secretomotor neurons suggested that stimulation of calmodulin-dependent protein kinase is involved in B2R-mediated excitation of secretomotor neurons[9]. We used W-7, a membrane permeable calmodulin inhibitor, and KN-62, a selective calmodulin-dependent protein kinase inhibitor, as pharmacological tools to test the hypothesis that stimulation of Isc by BK involved post-receptor activation of calmodulin-dependent protein kinase. Pretreatment with W-7 (50 μM) and KN-62 (10 μM) for 10 min reduced the responses to 10 nM BK from 57.3 ± 6.2 μA/cm2 to 3.6 ± 2.5 μA/cm2 and 14.1 ± 4.9 μA/cm2 (n = 6; P < 0.01), respectively (Figure 6). Meanwhile, pretreatment with 2-APB (10 μM), an IP3 inhibitor, reduced the response to 3.2 ± 4.0 μA/cm2 (n = 6; P < 0.01). The MAPK pathway inhibitor PD98059 was used to test the downstream signal cascade of PKC. Pre-incubation with PD98059 (10 μM) for 10 min prior to the BK (10 nM) exposure significantly reduced BK-evoked increase of Isc to 16.7 ± 4.1 μA/cm2 (n = 6; P < 0.01) (Figure 6).
The protein kinase A (PKA) inhibitor, KT5720, was used to address the question of whether the cAMP/PKA signaling pathway is involved in B2R-evoked secretory response. No suppression of BK-evoked increase of Isc occurred in the 6 preparations that were incubated for 10 min in 10 μM KT5720 (Figure 6). The tyrosine protein kinase inhibitor, genistein, was used to verify whether tyrosine protein kinase plays a role in BK-evoked secretory response. The results showed that pretreatment with genistein (10 μM) for 10 min failed to block BK-evoked Isc (Figure 6).
To test whether the similar signal transduction mechanisms are also involved in BK-induced PGE2 production, the submucosa/mucosa preparations were pretreated with the inhibitors of PLC (U73122 ), PKC (BisI), CaM (W7), or PKA (KT5720) for 30 min before exposure to BK (10 nM). These inhibitors did not significantly affect BK-induced PGE2 production (Figure 7).
BK stimulates Cl- secretion by the guinea pig and rabbit ileum[15], rabbit colon[16], rat colon[17], human colon, monolayers of human HCA-7 cells[18,19], and T-84 cells[20]. However, the detailed mechanism of the action of kinins on intestinal secretion is not fully understood, and results are controversial. Diener et al[21] have found evidence for the involvement of enteric cholinergic nerves in BK-stimulated secretory response in the rat descending colon. However, also using descending rat colon, another group[22] did not find significant inhibition of BK-induced secretion in the presence of TTX (1 μM) and atropine (1 μM). Furthermore, Manning et al[23] reported that BK-induced Cl- secretion by the guinea pig ileum was not TTX-sensitive and thought to occur by a direct action in the mucosa. The reasons for these differences are unknown but could be caused by the degree that the submucosal plexus has been stripped away from the mucosa.
By using guinea pig ileum submucosa/mucosa preparations, we found that BK-induced intestinal secretion was mainly mediated by the enteric nervous system. The neurotoxin TTX inhibited responses to BK by 73%, hence suggesting that the enteric nervous system plays a pivotal role. Secretomotor neurons in the submucosal plexus are the final common motor pathways from the integrative networks of the enteric nervous system to the intestinal secretory glands. They transmit the signals for autonomic minute-to-minute regulation of mucosal secretion and liquidity of the intestinal contents in concert with submucosal vasodilation and increased blood flow in support of the stimulated secretion[24-27]. Enhanced mucosal secretion, after elevation of excitability in secretomotor neurons, increases the liquidity of the luminal contents and might lead to neurogenic secretory diarrhea. Our previous studies found the expression of B2R mRNA and protein in submucosal neurons. BK increased excitatory in both AH- and S-type neurons in the submucosal plexus[9,10]. The S-type neurons are primarily secretomotor neurons that receive excitatory synaptic input from their AH-type neighbors[24]. Although both cholinergic and VIPergic secretomotor neurons are excited by BK, only the cholinergic muscarinic receptor antagonist, scopolamine, attenuated the secretory responses to BK. The VIP receptor antagonist, VIP6-28, had no significant effect. BK stimulated Isc in a TTX- and scopolamine-sensitive manner and therefore correlated with the slow excitatory action of BK on cholinergic secretomotor neurons, which we found at the cellular level. However, direct effects on epithelial cells cannot be ruled out, which is evidenced by the inability of TTX to abolish BK-stimulated secretory responses, and BK stimulates ion transport in cultured monolayers of epithelial cells[28]. The presence of B2 receptors on intestinal epithelial cells[29] also suggests a potential direct action of BK on epithelial cells.
BK-stimulated intestinal Cl- secretion depends on the formation of prostaglandins. Inhibition of prostaglandin formation by indomethacin or piroxicam or blocking the prostaglandin receptors suppresses the secretory responses that are evoked by B2R activation in the small intestine of guinea pigs. This observation is in agreement with previous studies in the rat, rabbit, and human intestine[28] where products of the COX pathway were implicated in BK-stimulated ion transport. However, the isoforms of COX that are involved in the process are not clear. COX enzymes have two isoforms, namely, COX-1 and COX-2. COX-1 is constitutively expressed throughout the gastrointestinal tract. COX-2 was initially considered an inducible form that has been highly expressed at sites of inflammation, but subsequently constitutive expression of COX-2 in normal digestive tract has been demonstrated[5,30]. Both COX-1 and COX-2 inhibitors significantly suppressed BK-induced secretory response in the small intestine of guinea pigs, thus suggesting that the constitutive COX-1, as well as constitutive COX-2, is involved in the production of prostaglandins, which is further supported by the observation that BK-stimulated PGE2 production from submucosa/mucosa preparations was greatly suppressed by COX-1 and COX-2 inhibitors. Several cellular elements of the intestine can produce prostaglandins upon activation of B2R. Our studies and those from others[29] suggest that enteric neurons, fibroblasts, and enterocytes are likely the sources.
We found that the same pharmacological agents, which suppress BK-evoked slow excitatory responses in secretomotor neurons by selective inhibition of individual steps in the PLC-IP3-Ca2+-PKC signal transduction pathway, also suppressed the BK-evoked increase in Isc. These inhibitory effects of the events in the PLC-PKC signal transduction cascade on BK-evoked stimulation of Isc are consistent with the inhibition of intracellular post-B2R signaling in the secretomotor neurons. Nevertheless, the agents that suppressed post-B2R signal transduction in secretomotor neurons might act also to suppress the signal transduction in enterocytes. By contrast, the agents that suppressed BK-evoked increase in Isc did not significantly affect BK-induced PGE2 production in the submucosa/mucosa preparations, thereby suggesting that the PLC-IP3-Ca2+-PKC signal transduction pathway is activated after prostaglandins are released.
In conclusion, the data presented here are consistent with the possibility that BK stimulates secretory responses in the intestine via activating B2 receptors in submucosal secretomotor neurons and in epithelial cells, as shown in Figure 8. Activation of B2R causes the release of prostaglandins through both COX-1 and COX-2 dependent pathways. Once released, prostaglandins excite submucosal cholinergic secretomotor neurons and indirectly stimulate Cl- secretion. Prostaglandins may also act directly in epithelial cells to stimulate ion transport. PLC, IP3, Ca2+, PKC, and MAP kinase all play a role in the signal transduction of BK-stimulated secretory responses.
Bradykinin (BK) is widely distributed in the central and peripheral nervous systems, including the enteric nervous system. BK can stimulate intestinal chloride secretion and the firing of intestinal secretomotor neurons in the small intestine, but the mechanism is not well understood.
The present work aimed to investigate how the involvement of BK as an excitatory neuromodulator on submucosal secretomotor neurons at the cellular neurophysiological level translates to the physiology of intestinal secretion at the level of the integrated system.
This study demonstrates that BK stimulates intestinal chloride secretion responses via activating B2 receptors in submucosal secretomotor neurons and in epithelial cells. Activation of B2 receptors causes the release of prostaglandins through both cyclooxygenase (COX)-1 and COX-2 dependent pathways. Once released, prostaglandins excite submucosal cholinergic secretomotor neurons and indirectly stimulate Cl- secretion. Prostaglandins may also act directly in epithelial cells to stimulate ion transport. Phospholipase C (PLC), IP3, Ca2+, protein kinase C (PKC), and MAP kinase (MAPK) all play a role in the signal transduction of BK-stimulated secretory responses.
The authors studied the mechanism of how BK stimulates the intestinal chloride secretion. The results suggest that BK stimulates neurogenic chloride secretion in the guinea pig ileum by activating B2 receptors on secretomotor neurons, activating COX, and stimulating prostaglandin E2 (PGE2) production. The post-receptor transduction cascade includes the activation of PLC, PKC, CaMK, IP3, and MAPK. This study gives a better understanding of the BK-evoked secretion pathway.
In this manuscript, the authors reported the BK-evoked mucosal secretion in the guinea pig small intestine. By using a list of inhibitors, antagonists, and agonists, the authors concluded that BK-evoked chloride secretion depends on the engagement on the B2 receptor, the activation of COX, production of PGE2, and downstream signaling cascade. Understanding the mechanism may provide a valuable insight into the regulation of mucosal secretion and other intestinal functions. The manuscript is well-organized, and conclusions were precisely based on obtained data.
P- Reviewer: Liao GX S- Editor: Yu J L- Editor: A E- Editor: Jiao XK
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