A stomach road or “Magenstrasse” for gastric emptying

Pal, Anupam; Brasseur, James G.; Abrahamsson, Bertil

doi:10.1016/j.jbiomech.2006.06.006

Cited by 174 publications

(156 citation statements)

References 17 publications

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“…Analogs of PGI 2 contract gastric smooth muscle via the stimulation of EP 3 receptors (Morrison et al, 2010). Activation of the EP 3 receptor subtype mediates disruption of gastric contractility (Pal et al, 2007;Forrest et al, 2009) and underlies the development of emesis (Kan et al, 2002). Selexipag does not evoke gastric contraction or disrupt gastric function in the rat stomach (Morrison et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

Differential Effects of Selexipag and Prostacyclin Analogs in Rat Pulmonary Artery

Morrison

Studer

Ernst

et al. 2012

J Pharmacol Exp Ther

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{4-[(5,6-Diphenylpyrazin-2-yl)(isopropyl)amino]butoxy}acetic acid (ACT-333679) is the main metabolite of the selective prostacyclin (PGI 2 ) receptor (IP receptor) agonist selexipag. The goal of this study was to determine the influence of IP receptor selectivity on the vasorelaxant efficacy of ACT-333679 and the PGI 2 analog treprostinil in pulmonary artery under conditions associated with pulmonary arterial hypertension (PAH). Selexipag and ACT-333679 evoked full relaxation of pulmonary artery from control and monocrotaline (MCT)-PAH rats, and ACT-333679 relaxed normal pulmonary artery contracted with either endothelin-1 (ET-1) or phenylephrine. In contrast, treprostinil evoked weaker relaxation than ACT-333679 of control pulmonary artery and failed to induce relaxation of pulmonary artery from MCT-PAH rats. Treprostinil did not evoke relaxation of normal pulmonary artery contracted with either ET-1 or phenylephrine. Expression of prostaglandin E 3 (EP 3 ) receptor mRNA was increased in pulmonary artery from MCT-PAH rats.In contraction experiments, the selective EP 3 receptor agonist sulprostone evoked significantly greater contraction of pulmonary artery from MCT-PAH rats compared with control rats. The presence of a threshold concentration of ET-1 significantly augmented the contractile response to sulprostone in normal pulmonary artery. ACT-333679 did not evoke direct contraction of rat pulmonary artery, whereas treprostinil evoked concentration-dependent contraction that was inhibited by the EP 3 receptor antagonist (2E)-3-(3Ј,4Ј-dichlorobiphenyl-2-yl)-N-(2-thienylsulfonyl)acrylamide. Antagonism of EP 3 receptors also revealed a relaxant response to treprostinil in normal pulmonary artery contracted with ET-1. These data demonstrate that the relaxant efficacy of the selective IP receptor agonist selexipag and its metabolite ACT-333679 is not modified under conditions associated with PAH, whereas relaxation to treprostinil may be limited in the presence of mediators of disease.

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Section: Introductionmentioning

confidence: 99%

Differential Effects of Selexipag and Prostacyclin Analogs in Rat Pulmonary Artery

Morrison

Studer

Ernst

et al. 2012

J Pharmacol Exp Ther

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“…Iloprost also induces emesis in the ferret, whereas the selective IP receptor agonist cicaprost has no effect (Kan et al, 2002). Moreover, in the present study, iloprost evoked EP 3 receptor-dependent contraction of rat fundus, which may disturb the regulated and coordinated waves of contraction in the stomach, leading to dysregulation of food mixing and gastric emptying (Pal et al, 2007). It is noteworthy that gastric muscular dysrhythmias are initiated by EP 3 receptor agonists in the mouse (Forrest et al, 2009).…”

Section: Selexipag and Gastric Function 253mentioning

confidence: 51%

“…In contrast, analogs of PGI 2 contract gastric fundus via activation of EP 3 and EP 1 receptors, and beraprost slows gastric function. Contraction of rat fundus may disturb the regulated and coordinated waves of contraction in the stomach, leading to dysregulation of food mixing and gastric emptying (Pal et al, 2007). The pronounced contraction of gastric smooth muscle to analogs of PGI 2 reported here may help explain the abdominal pain and cramping associated with use of these compounds in the clinic.…”

Section: Discussionmentioning

confidence: 79%

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Selexipag: A Selective Prostacyclin Receptor Agonist that Does Not Affect Rat Gastric Function

Morrison¹,

Ernst²,

Hess³

et al. 2010

J Pharmacol Exp Ther

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Selexipag [2-{4-[(5,6-diphenylpyrazin-2-yl)(isopropyl)amino]butoxy}-N-(methylsulfonyl)acetamide] is an orally available prostacyclin (PGI 2 ) receptor (IP receptor) agonist that is chemically distinct from PGI 2 and is in clinical development for the treatment of pulmonary arterial hypertension. Selexipag is highly selective for the human IP receptor in vitro, whereas analogs of PGI 2 can activate prostanoid receptors other than the IP receptor. The goal of this study was to determine the impact of selectivity for the IP receptor on gastric function by measuring 1) contraction of rat gastric fundus ex vivo and 2) the rates of gastric emptying and intestinal transport in response to selexipag in comparison with other PGI 2 analogs. The rat gastric fundus expresses mRNA encoding multiple prostanoid receptors to different levels: prostaglandin E receptor 1 (EP 1 ) Ͼ prostaglandin E receptor 3 (EP 3 ), IP receptor Ͼ prostaglandin D 2 receptor 1, thromboxane receptor. Selexipag and metabolite {4-[(5,6-diphenylpyrazin-2-yl)(isopropyl)amino]butoxy}acetic acid (ACT-333679) did not contract gastric fundus at concentrations up to 10 Ϫ3 M. In contrast, the PGI 2 analogs iloprost and beraprost evoked concentration-dependent contraction of gastric fundus. Contraction to treprostinil was observed at high concentration (10 Ϫ4 M). Contraction to all PGI 2 analogs was mediated via activation of EP 3 receptors, although EP 1 receptors also contributed to the contraction of gastric fundus to iloprost and beraprost. Antagonism of IP receptors did not affect responses. Oral selexipag did not significantly alter gastric function in vivo, as measured by rates of stomach emptying and intestinal transport, whereas beraprost slowed gastrointestinal transport. The high functional selectivity of selexipag and ACT-333679 for the IP receptor precludes a stimulatory action on gastric smooth muscle and may help minimize gastric side effects such as nausea and vomiting.

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“…However, by using computational fluid dynamics modeling, a second process has been proposed. In this case, a contraction in the proximal stomach initiates flow down the center of the gastric bolus, pushing material from the center of the stomach into the antrum and duodenum (12). Yet, it is not clear how important this second model is in the normal healthy stomach, but instances of elevated abdominal pressure (e.g., exertion) could certainly create the conditions needed for this mechanism to operate.…”

Section: General Considerationsmentioning

confidence: 99%

The Design, Operation, and Application of a Dynamic Gastric Model

Wickham¹,

Faulks²,

Mann³

et al. 2012

Dissolution Technol.

112

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The mechanical functioning of the stomach has been well researched (1). The contractions that mix, break up, and propel the gastric bolus in the main body and antrum have been described in detail and have been partially modeled mathematically. Because the antral forces are particularly important in the mixing and break up of food, they have been measured using manometers, pressure transducers, MRI imaging of agar beads of differing strength (2), and other methods (3, 4). The chemical and biochemical environment of the stomach, its acid and digestive enzymes, and their production and activity rates under different conditions have been studied for many years, and reference ranges established mainly for diagnostic purposes. All these areas have been extensively reviewed (5-7).Despite this understanding of gastric function, many in vitro digestion studies use grossly simplified systems that often include food homogenization, nonphysiological mixing and shear, and unrealistic acid and enzyme concentrations that do not change over time as happens in vivo.This paper describes the design and operation of a computer-controlled dynamic gastric model (DGM) that was built to investigate the effects of the biochemical and physical processing of foods and oral pharmaceuticals.Our intention was to draw together the physical and biochemical features of the human stomach with data on gastric residence time and emptying profiles and to design a computer-controlled mechanical stimulation that works in real time with realistic chewed foods or meals and oral pharmaceutical and nutraceutical products.

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A stomach road or “Magenstrasse” for gastric emptying

Cited by 174 publications

References 17 publications

Differential Effects of Selexipag and Prostacyclin Analogs in Rat Pulmonary Artery

Differential Effects of Selexipag and Prostacyclin Analogs in Rat Pulmonary Artery

Selexipag: A Selective Prostacyclin Receptor Agonist that Does Not Affect Rat Gastric Function

The Design, Operation, and Application of a Dynamic Gastric Model

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