Electrophysiological Effects of Prucalopride, a Novel Enterokinetic Agent, on Isolated Atrial Myocytes from Patients Treated with β-Adrenoceptor Antagonists

Pau, Davide; Workman, Antony J.; Kane, Kathleen A.; Rankin, Andrew C.

doi:10.1124/jpet.104.076869

Cited by 25 publications

(26 citation statements)

References 37 publications

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“…Previous lines of evidence have shown that 5-HT and prucalopride increase the L-type calcium current (I [ca] ) in human isolated atrial myocytes (Pau et al, 2003(Pau et al, , 2005. Accordingly, we have now shown in human atrial trabeculae that 5-HT and 5-MeOT induced contractile responses were attenuated by verapamil (about 40%).…”

Section: Role Of Calcium Channels In the Positive Inotropic Responsesmentioning

confidence: 76%

Inotropic effects of prokinetic agents with 5-HT4 receptor agonist actions on human isolated myocardial trabeculae

Chai¹,

Chan²,

Vries³

et al. 2012

Life Sciences

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Section: Role Of Calcium Channels In the Positive Inotropic Responsesmentioning

confidence: 76%

Inotropic effects of prokinetic agents with 5-HT4 receptor agonist actions on human isolated myocardial trabeculae

Chai¹,

Chan²,

Vries³

et al. 2012

Life Sciences

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“…In human atrial myocytes and only at doses that were markedly supratherapeutic, prucalopride acted as a partial agonist of L-type calcium channels. 35 However, there were no effects on late repolarizations or the refractory period and there was no evidence of any arrhythmic activity. 35 Prucalopride: clinical evidence in chronic idiopathic constipation Based on the aforementioned effects of prucalopride on colonic motility and transit, [30][31][32] it should come as no surprise that a major clinical focus has been on its therapeutic role in constipation.…”

Section: -Ht4 Receptor Agonists In CCmentioning

confidence: 94%

“…35 However, there were no effects on late repolarizations or the refractory period and there was no evidence of any arrhythmic activity. 35 Prucalopride: clinical evidence in chronic idiopathic constipation Based on the aforementioned effects of prucalopride on colonic motility and transit, [30][31][32] it should come as no surprise that a major clinical focus has been on its therapeutic role in constipation. Efficacy, tolerability, safety and impact on quality of life have been demonstrated in a number of large, randomized, placebo-controlled trials 36 which have led to the approval of prucalopride in several countries, with the usual recommended dose being 2 mg per day in patients under 65 years of age and 1 mg per day in patients over 65 years.…”

Section: -Ht4 Receptor Agonists In CCmentioning

confidence: 94%

An update on prucalopride in the treatment of chronic constipation

Aras

Quigley

2017

Therap Adv Gastroenterol

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Chronic constipation (CC) is a highly prevalent and often under-appreciated gastrointestinal disorder associated with significant impairment in quality of life. Symptoms of constipation are typically present for a number of years prior to a patient seeking help. Lifestyle modifications followed by, or coupled with, over-the-counter laxatives represent the initial treatment option; however, relief for many is limited and dissatisfaction rates for these approaches remain high. Over recent years, therefore, considerable effort has been exerted on the development of novel pharmacological approaches. Two major targets have emerged, motility and secretion. Research on the former led to the development of a number of prokinetic agents capable of stimulating colonic motility and, thus, accelerating colonic transit. Of these, earlier prototypes such as cisapride and tegaserod, though effective, were ultimately withdrawn due to cardiovascular adverse events due in part to receptor nonselectivity. Highly selective serotonergic receptor agonists have since emerged which appear to be equally effective in stimulating gut motility but are devoid of cardiac side effects. One such agent is prucalopride, which has now been approved for the management of chronic idiopathic constipation in several countries, but not in the United States. Multiple multicenter, randomized placebo-controlled clinical trials have demonstrated superiority for prucalopride compared to placebo in the short to medium term in relieving the major symptoms of constipation in both men and women across a broad spectrum of ages, ethnicities and geographic locations. To date, prucalopride has enjoyed a favorable safety profile and there have been no signals to suggest arrythmogenicity. Efficacy over longer periods of treatment remains to be confirmed. Evidence for efficacy in other forms of constipation, such as opioidinduced constipation and that related to Parkinson's disease is beginning to emerge; its status in the management of constipation-predominant irritable bowel syndrome or foregut motility disorders, such as gastroparesis, remains to be established.

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“…Interestingly, the incidence of arrhythmias was enhanced in isolated atria from humans treated prior to surgery with β-adrenoceptor blockers [102,103]. The arrhythmias could be explained on a single cell basis via late afterdepolarizations [104,105]. In addition, arrhythmogenesis due to 5-HT might also involve stimulation L-type Ca…”

Section: Chronotropic and Proarrhythmic Effects Of 5-ht In The Heartmentioning

confidence: 95%

Production and Function of Serotonin in Cardiac Cells

Neumann¹,

Hofmann²,

Gergs³

2017

Serotonin - A Chemical Messenger Between All Types of Living Cells

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Serotonin [5-hydroxy-tryptamine (5-HT)] exerts a number of effects in the mammalian heart: increase in heart rate, increase in force of contraction, fibrosis of cardiac valves, coronary constriction, arrhythmias and thrombosis. These effects are, in part, mediated by 5-HT-receptors, in part, directly by 5-HT action on intracellular proteins. In the beginning, 5-HT was thought to be only produced in the gut and then transported into the heart via platelets, because platelets can take up 5-HT in the gut and enter the capillaries and thus the mammalian heart. 5-HT is to a large extent metabolized in the liver and excreted via the urine. Here, we will also overview data that argue for additional pathways, namely production and degradation of 5-HT in the cells of the heart itself.

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Electrophysiological Effects of Prucalopride, a Novel Enterokinetic Agent, on Isolated Atrial Myocytes from Patients Treated with β-Adrenoceptor Antagonists

Abstract: Prucalopride is a selective 5-hydroxytryptamine type 4 (5-HT 4 ) receptor agonist developed for the treatment of gastrointestinal disorders. The endogenous agonist 5-HT acting via 5-HT 4 receptors increases the L-type Ca 2ϩ current

Cited by 25 publications

References 37 publications

Inotropic effects of prokinetic agents with 5-HT4 receptor agonist actions on human isolated myocardial trabeculae

Inotropic effects of prokinetic agents with 5-HT4 receptor agonist actions on human isolated myocardial trabeculae

An update on prucalopride in the treatment of chronic constipation

Production and Function of Serotonin in Cardiac Cells

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