Human lower oesophageal sphincter relaxation is associated with raised cyclic nucleotide content.

Barnette, Mary S.; Barone, Frank C.; Fowler, Philip J.; Grous, Marilyn; Price, William J.; Ormsbee, Herbert S.

doi:10.1136/gut.32.1.4

Cited by 21 publications

(13 citation statements)

References 17 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The inhibitory pathway of the oesophagus involves the synthesis and release of NO by central neurones within the vagal nuclei in the brain stem and peripheral neurones in the myenteric plexus 2 . The effect of NO is mediated by cGMP 11–16 . In this study we investigated the effect of sildenafil, a drug that increases intracellular cGMP, on oesophageal motor function.…”

Section: Discussionmentioning

confidence: 99%

“…In the oesophagus, NO provokes hyperpolarization of the circular smooth muscle, which regulates the progression of peristaltic contractions 3–6 and relaxes the LOS 7–10 . The effect of nitric oxide is mediated by an increase in content of cyclic guanine monophosphate (cGMP), an intracellular messenger that relaxes smooth muscle 11–16 . Cyclic GMP is broken down rapidly by phosphodiesterase‐5.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Effect of sildenafil, a phosphodiesterase‐5 inhibitor, on oesophageal peristalsis and lower oesophageal sphincter function in cats

Zhang

Tack

Janssens

et al. 2001

Neurogastroenterology Motil

View full text Add to dashboard Cite

The propagation of oesophageal peristaltic contractions and lower oesophageal sphincter (LOS) relaxation depends on neural release of nitric oxide (NO) which acts to increase intracellular cGMP. Sildenafil, a phosphodiesterase-5 inhibitor that increases cGMP, reduces basal LOS pressure in patients with achalasia. We investigated the effect of sildenafil on the propagation of oesophageal contractions and LOS relaxation in the cat. Oesophageal manometry was performed in five cats under light sedation. Peristaltic contractions were monitored at 1, 2, 3, 4 and 8 cm proximal to the LOS, at the LOS using a Dent sleeve, and at 3 cm distal to the upper oesophageal sphincter. Swallow-induced oesophageal contractions and LOS relaxation were recorded during 30 min before and 30 min after intravenous administration of sildenafil. Sildenafil reduced the amplitude of oesophageal contractions only in the smooth muscle oesophagus. The latency from swallow to distal oesophageal contractions was significantly delayed. LOS pressure was significantly reduced but the relaxation nadir was not modified by sildenafil. Sildenafil has profound effects on oesophageal motility: it modifies propagation and amplitude of oesophageal contractions and reduces LOS pressure. Slowing down the propagation of contractions in the transitional zone between the striated and smooth muscle can be a useful tool in patients with segmental aperistalsis or intermittent simultaneous contractions, while the effect on the LOS can benefit patients with achalasia.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Effect of sildenafil, a phosphodiesterase‐5 inhibitor, on oesophageal peristalsis and lower oesophageal sphincter function in cats

Zhang

Tack

Janssens

et al. 2001

Neurogastroenterology Motil

View full text Add to dashboard Cite

show abstract

“…The exact cellular mechanisms responsible for NANC neurally mediated LOS relaxation are not fully known, but may involve an apamin‐insensitive 26 potassium channel activated by nitric oxide and/or a nitrosothiol, 27 via an elevation in intracellular cGMP 28 . 29 A range of other neurotransmitters have also been implicated 30 . Similarly to EFS, there was no difference in potassium‐induced LOS relaxation following oesophagitis.…”

Section: Discussionmentioning

confidence: 99%

Oesophagitis‐induced changes in capsaicin‐sensitive tachykininergic pathways in the ferret lower oesophageal sphincter

Smid

Page

O’Donnell

et al. 1998

Neurogastroenterology Motil

View full text Add to dashboard Cite

Prolonged oesophageal acidification may impair lower oesophageal sphincter (LOS) function in reflux disease. The aim of this study was to investigate aspects of altered LOS innervation in a model of oesophagitis. Oesophagitis was induced by acid (HCl, 0.15 M) and pepsin (0.1% w/v) infusions in anaesthetized ferrets. LOS muscle strip responses to the following stimuli were measured in vitro from control and acid/pepsin-treated ferrets: electrical field stimulation (EFS; 1-50 Hz), potassium chloride KCl; 20 mM), substance P, [beta-Ala8]-neurokinin A 4-10, [Sar9, Met (O2)11]-substance P (all 10(-10) to 10(-6) M) and capsaicin (10(-8) to 10(-6) M). LOS relaxation occurred in response to all stimuli except [beta-Ala8]-neurokinin A 4-10, which evoked contraction. In muscle strips from acid/pepsin-treated animals there were no differences in amplitude or sensitivity of relaxation following EFS, KCl or substance P vs controls. However, the inhibitory response to capsaicin was increased four-fold (10(-8) M; P < 0.05) and an increased sensitivity of the inhibitory response to [Sar9, Met (O2)11]-substance P occurred (pD2 = 8.64 +/- 0.12 acid/pepsin-treated vs 7.94 +/- 0.24 control, P < 0.05). We conclude that in acute oesophagitis, increased sensitivity of capsaicin-activated inhibitory pathways occurs in which activation of NK-1 receptors plays an integral role in the ferret LOS.

show abstract

“…The dominant mechanism underlying the smooth muscle relaxing properties of theophylline is thought to be its inhibitory action on the PDEs, the enzymes which degrade the cyclic nucleotides [23,38,39]. Previous data deriving from studies exploring the mechanism of theophylline's relaxing effects in gastrointestinal tissues [20][21][22][23]26,27], in addition to the well documented role of PDE types III, IV and V in regulating the LOS and fundus tone [20,[40][41][42][43], provide reasons to hypothesize that the here observed relaxing effect of theophylline on the rabbit gastrointestinal tract is mediated mainly through inhibition of PDEs. Thus, the drug's concentrations required to relax the tissues should be adequate to act on the enzymes.…”

Section: Discussionmentioning

confidence: 99%

The gastrointestinal effects that may follow the administration of theophylline reflect the pharmacodynamic profiles of both the parent drug and its metabolites

Psarra

Batzias

Peeters

et al. 2010

Fundamemntal Clinical Pharma

View full text Add to dashboard Cite

This study investigates the effect of theophylline along the rabbit gastrointestinal tract in comparison with the pharmacodynamic effect produced by the combined application of its three major metabolites. At concentrations up to 10(-3) m, theophylline relaxed, in a declining order from the lower oesophageal sphincter (LOS) to pylorus, all regions of the upper gastrointestinal tract, but only the ascending colon from the intestinal regions studied. At concentrations higher than 10(-3) m, instead of relaxing, theophylline strongly contracted the antrum and pylorus. In all three small intestinal regions, at concentrations up to 10(-3) m, theophylline produced a weak contraction, which at higher concentrations became very strong, and at 10(-2) m was comparable to that produced by a supramaximal dose of acetylcholine. The additive relaxing effect resulting from the combined application of the theophylline's metabolites was, from oesophagus to pylorus, weaker than that produced by theophylline, while on the ascending colon it was comparable to that of the parent drug. In contrast, the additive contractile effect of the metabolites on the three small intestinal regions was four to five times higher the one produced by theophylline. In conclusion, this study shows that the additive effect of the combined application of theophylline's major metabolites on the rabbit gastrointestinal tract plays a major role in the final response of the intestine, and a minor one in the final responses of the gastric regions, while both the parent drug and the metabolites contribute to the final responses of the oesophagus and LOS.

show abstract

Human lower oesophageal sphincter relaxation is associated with raised cyclic nucleotide content.

Cited by 21 publications

References 17 publications

Effect of sildenafil, a phosphodiesterase‐5 inhibitor, on oesophageal peristalsis and lower oesophageal sphincter function in cats

Effect of sildenafil, a phosphodiesterase‐5 inhibitor, on oesophageal peristalsis and lower oesophageal sphincter function in cats

Oesophagitis‐induced changes in capsaicin‐sensitive tachykininergic pathways in the ferret lower oesophageal sphincter

The gastrointestinal effects that may follow the administration of theophylline reflect the pharmacodynamic profiles of both the parent drug and its metabolites

Contact Info

Product

Resources

About