Actions by Angiotensin II on Esophageal Contractility in Humans

Casselbrant, Anna; Edebo, Anders; Wennerblom, Johanna; Lönroth, Hans; Helander, Herbert F.; Lundell, Lars; Fändriks, Lars

doi:10.1053/j.gastro.2006.11.010

Cited by 30 publications

(39 citation statements)

References 23 publications

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“…In support of the present data, recent studies have reported pathophysiological and therapeutic significance of RAS and AA pathways in the esophageal achalasia (7,8) and in decreased colonic motility in patients with slow-transit constipation on the basis of lower levels of TXA 2 , PGF 2␣ , and COX-1 in the colon smooth muscle (11). The data that we have presented here in humans have direct implications in the SMC-targeted, novel, and safe therapy of hyper-and hypotonic IAS.…”

Section: Discussionsupporting

confidence: 89%

“…In different systems, these three substances are known to activate RhoA/ ROCK via the G protein-coupled receptors (GPCRs) AT 1 -R, TXA2 receptor (TPR), and PGF 2␣ receptor (FPR), respectively (1,50). Recent studies from different laboratories have demonstrated the role of RAS (8,21,33,48) and AA pathways in the contractility of the human gastrointestinal smooth muscle (5,11,13,24). However, to our knowledge, there have been no published data demonstrating the role of RAS and AA pathway on basal muscular tone in human IAS.…”

mentioning

confidence: 99%

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Nature of extracellular signal that triggers RhoA/ROCK activation for the basal internal anal sphincter tone in humans

Rattan

Singh

Kumar

et al. 2015

American Journal of Physiology-Gastrointestinal and Liver Physi

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The extracellular signal that triggers activation of rho-associated kinase (RhoA/ROCK), the major molecular determinant of basal internal anal sphincter (IAS) smooth muscle tone, is not known. Using human IAS tissues, we identified the presence of the biosynthetic machineries for angiotensin II (ANG II), thromboxane A2 (TXA2), and prostaglandin F2α (PGF2α). These end products of the renin-angiotensin system (RAS) (ANG II) and arachidonic acid (TXA2 and PGF2α) pathways and their effects in human IAS vs. rectal smooth muscle (RSM) were studied. A multipronged approach utilizing immunocytochemistry, Western blot analyses, and force measurements was implemented. Additionally, in a systematic analysis of the effects of respective inhibitors along different steps of biosynthesis and those of antagonists, their end products were evaluated either individually or in combination. To further describe the molecular mechanism for the IAS tone via these pathways, we monitored RhoA/ROCK activation and its signal transduction cascade. Data showed characteristically higher expression of biosynthetic machineries of RAS and AA pathways in the IAS compared with the RSM. Additionally, specific inhibition of the arachidonic acid (AA) pathway caused ~80% decrease in the IAS tone, whereas that of RAS lead to ~20% decrease. Signal transduction studies revealed that the end products of both AA and RAS pathways cause increase in the IAS tone via activation of RhoA/ROCK. Both AA and RAS (via the release of their end products TXA2, PGF2α, and ANG II, respectively), provide extracellular signals which activate RhoA/ROCK for the maintenance of the basal tone in human IAS.

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Section: Discussionsupporting

confidence: 89%

mentioning

confidence: 99%

Nature of extracellular signal that triggers RhoA/ROCK activation for the basal internal anal sphincter tone in humans

Rattan

Singh

Kumar

et al. 2015

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…In addition, inhibitors of ANG II receptor subtype 1 and ANG II converting enzyme cause a significant fall in the IAS tone. Interestingly, similar data have been obtained in the human lower esophageal sphincter (LES) (3). These data suggest that the RAS pathway may be responsible for ϳ30% of the basal tone in the IAS.…”

supporting

confidence: 75%

Role of phospholipase A₂(group I secreted) in the genesis of basal tone in the internal anal sphincter smooth muscle

Godoy¹,

Rattan²

2007

American Journal of Physiology-Gastrointestinal and Liver Physi

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The role of phospholipase A(2) (PLA(2)) in the genesis of basal tone in the internal anal sphincter (IAS) is not known. We determined the effects of PLA(2) and inhibitors on the basal tone and intraluminal pressures (IASP) in the rat IAS vs. rectal smooth muscles (RSM). In addition, we determined the correlations between the IAS tone, PLA(2) levels, and the actual enzymatic activity. Inhibition of PLA(2) by 4-bromophenacyl bromide (universal inhibitor of PLA(2)) and MJ33 [selective inhibitor of secreted isoform of PLA(2) (sPLA(2))] caused concentration-dependent decrease in the IAS tone and in the IASP. Maximal decreases in the IAS tone and IASP by 4-bromophenacyl bromide and MJ33 were 58.8 +/- 6.9 and 51.5 +/- 6.3%, and 66.7 +/- 5.1 and 79.8 +/- 8.2%, respectively. The sPLA(2) inhibitors were approximately 100 times more potent in decreasing the IASP than the mean blood pressure. Conversely, the selective inhibitors of the cytosolic and calcium-independent PLA(2) arachidonyl trifluoromethyl ketone and bromoenol lactone, respectively, produced no significant effect. The IAS had characteristically higher levels of sPLA(2) activity (26.5 +/- 4.9 micromol.min(-1).ml(-1)) vs. the RSM (3.2 +/- 0.4 micromol.min(-1).ml(-1)), and higher levels of sPLA(2) as shown by Western blot and RT-PCR. Interestingly, administration of sPLA(2) transformed RSM into the tonic smooth muscle like that of the IAS: it developed basal tone and relaxed in response to the electrical field stimulation. From the present data, we conclude that sPLA(2) plays a critical role in the genesis of tone in the IAS. PLA(2) inhibitors may provide potential therapeutic target for treating anorectal motility disorders.

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“…Increases motility (Casselbrant et al, 2007). Inflammation Stomach High expression of AT1 receptor in Helicobacter pylori (Hallersund et al, 2011).…”

Section: Large Intestinementioning

confidence: 99%

A Modern Understanding of the Traditional and Nontraditional Biological Functions of Angiotensin-Converting Enzyme

et al. 2012

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Actions by Angiotensin II on Esophageal Contractility in Humans

Cited by 30 publications

References 23 publications

Nature of extracellular signal that triggers RhoA/ROCK activation for the basal internal anal sphincter tone in humans

Nature of extracellular signal that triggers RhoA/ROCK activation for the basal internal anal sphincter tone in humans

Role of phospholipase A₂(group I secreted) in the genesis of basal tone in the internal anal sphincter smooth muscle

A Modern Understanding of the Traditional and Nontraditional Biological Functions of Angiotensin-Converting Enzyme

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Actions by Angiotensin II on Esophageal Contractility in Humans

Cited by 30 publications

References 23 publications

Nature of extracellular signal that triggers RhoA/ROCK activation for the basal internal anal sphincter tone in humans

Nature of extracellular signal that triggers RhoA/ROCK activation for the basal internal anal sphincter tone in humans

Role of phospholipase A2(group I secreted) in the genesis of basal tone in the internal anal sphincter smooth muscle

A Modern Understanding of the Traditional and Nontraditional Biological Functions of Angiotensin-Converting Enzyme

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Role of phospholipase A₂(group I secreted) in the genesis of basal tone in the internal anal sphincter smooth muscle