Action Of Cisapride Research Articles

Inhibition of L-type Ca(2+) current in Guinea pig ventricular myocytes by cisapride.

The effect of cisapride on L-type Ca(2+) current (I(Ca,L)) was studied in guinea pig ventricular myocytes using a whole-cell voltage-clamp technique and a conventional action potential recording method. Myocytes were held at -40 mV, and internally dialyzed and externally perfused with Na(+)- and K(+)-free solutions; cisapride elicited a concentration-dependent block of peak I(Ca,L), with a half-maximum inhibition concentration (IC(50)) of 46.9 microM. There was no shift in the reversal potential, nor any change in the shape of the current-voltage relationship of I(Ca,L) in the presence of cisapride. Inhibition of cisapride was not associated with its binding to serotonin or to alpha-adrenergic receptors because ketanserin, SB203186, and prazosin had no effect on the inhibitory action of cisapride on I(Ca,L). Cisapride elicited a tonic block and a use-dependent block of I(Ca,L). These blocking effects were voltage dependent as the degree of inhibition at -40 mV was greater than that at -70 mV. Cisapride shifted the steady-state inactivation curve of I(Ca,L) in the negative direction, but had no effect on the steady-state activation curve. Cisapride also delayed the kinetics of recovery of I(Ca,L) from inactivation. At a slow stimulation frequency (0.1 Hz), the action potential duration in guinea pig papillary muscles showed biphasic effects; it was prolonged by lower concentrations of cisapride, but shortened by higher concentrations. These findings suggest that cisapride preferentially binds to the inactivated state of L-type Ca(2+) channels. The inhibitory effect of cisapride on I(Ca,L) might play an important role in its cardiotoxicity under pathophysiological conditions, such as myocardial ischemia.

Electrocardiographic and hemodynamic effects of cisapride alone and combined with erythromycin in anesthetized dogs

The cardiovascular effects of cisapride administered intravenously at escalating doses with and without pretreatment with erythromycin were evaluated in morphine/chloralose anesthetized dogs. Dogs were instrumented to permit simultaneous recording of ECGs, left ventricular (LVP) and aortic (AoP) pressures, as well as programmed electrical stimulation (PES). Escalating intravenous doses of cisapride from 2 to 8 mg/kg (four times the recommended therapeutic dose) increased the heart rate (HR) and prolonged the corrected QT interval (QTc) (p < 0.05) compared to controls. Pretreatment with erythromycin failed to enhance the effect of cisapride on either HR or QTc. Cisapride with or without erythromycin pretreatment had no effect on AoP, but depressed indices of left ventricular contractility (dP/dt(max) decreased while PEP/ET increased) compared to controls. No dogs developed spontaneous arrhythmias, and arrhythmias were not inducible by PES. Cisapride with or without erythromycin pretreatment altered the orientation of the T-wave vector (p < 0.05) compared to controls, indicating a primary effect of cisapride on ventricular repolarization. The QTc and T wave changes observed were consistent with the known action of cisapride on canine I(Kr) channels.

Effect of cisapride on gallbladder emptying and plasma CCK in normal and vagotomized human subjects

Previous studies have provided conflicting results of cisapride on gallbladder emptying in response to a meal. We studied six volunteers and six patients after a truncal vagotomy in a double-blind, placebo-controlled, prospectively randomized study using 10 mg cisapride four times a day for three days. Gallbladder volume was quantitated using ultrasonography, and plasma CCK levels were measured with a sensitive and specific radioimmunoassay using the DINO antibody before and for 90 min after a fatty, mixed meal. Plasma effect was observed on the gallbladder either in normal subjects or vagotomized patients. Paradoxically, residual volume (RV) was increased in the vagotomized patients after treatment with cisapride: RV cisapride 7.1 (4.1-15.9) ml, RV placebo 5.1 (3.8-14) ml, P < 0.05. Further work is required to clarify the mechanisms of action of cisapride on the gallbladder and the sphincter of Oddi. The use of cisapride during litholytic therapy may impair gallbladder emptying and delay stone clearance.

The hypotensive effect of cisapride in rat

1. Cisapride is a prokinetic agent believed to facilitate acetylcholine release from the myenteric plexus of the gut. The aim of the present study was to investigate the effect of cisapride on blood pressure and the effects of muscarinic receptor antagonists on the cisapride-induced blood pressure changes. 2. Cisapride was given i.v. alone or 10 min after muscarinic receptor antagonists. Cisapride given i.v. produced a significant decrease in blood pressure in a dose-related manner. Atropine, AF-DX 116 and 4-DAMP given 10 min before cisapride injection, partially inhibited the hypotensive response to cisapride. In pithed rat, the effect of cisapride on blood pressure remained unaltered. 3. This study indicates that the action of cisapride is not through central mechanisms and part of cisapride's effect is through the cholinergic system.

Action of cisapride on rat colonic secretion

The stimulating effect of cisapride on the motility of the digestive tract is well known. However, there are only a few studies on the influence of this drug on the absorptive or secretory activity of the colonic mucosa. In the present study, the ability of cisapride to alter the mural transport of water and electrolytes in the colon and its effects on mucus secretion and albumin permeation were studied. The effects of cisapride on the rat colon in vivo were studied under different conditions, by means of an instillation of sodium acetate solution at pH 6.9, which induced absorption of water and electrolytes, and in two models of colonic secretion, one employing the instillation of an acetic acid solution at pH 2.9 and the other, an intravenous infusion of 5-hydroxytryptamine (serotonin) 45 micrograms.kg-1.min-1 together with intracolonic instillation of sodium acetate. Cisapride (i.v.), at a dose of 0.32 mg.kg-1, in rats whose colon was instilled with sodium acetate (pH 6.9) induced an increase in sodium absorption and a reduction in water absorption. Cisapride (i.v.), at doses of 0.32, 0.64 and 1.0 mg.kg-1, inhibited the secretion of water, Na+, Cl-, and mucus and the permeation of albumin induced by acetic acid instillation or by serotonin infusion. It is concluded that the effect of cisapride on the colonic mucosa varies in accordance with the functional mucosal conditions and that this action may be of clinical importance.

The effect and mechanism of the prokinetic action of cisapride on gastrointestinal smooth muscle

Cisapride is a new prokinetic agent which can facilitate or restore motility throughout the entire gastrointestinal tract. Although facilitation of acetylcholine release has been suggested, the mechanism of action of cisapride is not clear. To investigate the effect and mechanism of action of cisapride, we used isolated muscle strips (with mucosa and submucosa removed) of guinea pig antrum, ileum and colon to study: (1) the dose response to cisapride, (2) the effect of antagonists (atropine and tetrodotoxin) on the stimulatory effect of cisapride. Besides these studies, we also used 3H-acetylcholine release method to investigate the acetylcholine release effect of cisapride. Cisapride elicited a dose-related enhancement of baseline activity (motility index) on the antrum and contraction on the ileum and colon at the dose of 4, 40 and 400 nM. At higher doses (4 microM) cisapride caused inhibition. This bell-shaped dose response curve suggested that cisapride might be autoinhibitory or that the receptors of cisapride might consist of high affinity stimulatory and low affinity inhibitory sites. The stimulatory responses elicited by cisapride (400 nM) were not significantly inhibited by atropine and tetrodotoxin in the antrum, ileum and colon. This suggested that cisapride might act directly on the smooth muscle. Cisapride (400 nM) evoked a rather small increase of 3H-acetylcholine release on the antrum, ileum and colon. Because the percentage of increase was small and we had demonstrated that the stimulatory effects of cisapride were not blocked by atropine and tetrodotoxin, the acetylcholine release effect of cisapride was considered unimportant.

Is the action of cisapride on the guinea-pig ileum mediated via 5-HT 4 receptors?

It has been suggested that benzamides, like cisapride, exert their effects on the guinea-pig ileum via activation of a 5-HT receptor (5-HT 4 receptor?) mechanism. The aim of this study was to determine whether an how the 5-HT 4 receptor (previously described in mouse colliculi neurones) is involved in the cisapride-induced effect. The effects induced by cisapride were compared with those of 5-hydroxytryptamine (5-HT) and 5-methoxytryptamine (5-MeOT) either alone or in the presence of a 5-HT 4 antagonist (micromolar concentration of ICS 205–930) or a benzamide antagonist (R 50 595). As a model we used the electrically stimulated longitudinal muscle myenteric plexus preparation from the guinea-pig ileum. Cisapride (3.10 −7 M), 5-HT and a 5-HT 4 receptor agonist 5-MeOT (3.10 −10−10 −6 M) induced similar effects, i.e. enhancement of the twitch responses. After rinsing the organ baths, a second addition of the agonists resulted in a similar response. The studied agonists showed mutual desensitization. Cisapride desensitized the response induced by 5-HT or 5-MeOT, and 5-MeOT or 5-HT desensitized the effect induced by cisapride. In preparations preincubated with a 5-HT 4 receptor antagonist, ICS 205-930- (3.10 −6 M) or R 50 595 (3.10 −7 M), a benzamide with a specific antagonistic action on the effect induced by 5-HT and benzamides on the guinea-pig ileum, the effects induced by cisapride, 5-HT and 5-MeOT were abolished. These results indicate that cisapride indeed exerts its effect via an agonistic action on a serotonin receptor, probably the previously described 5-HT 4 receptor.

Cisapride Effects on Canine Lower Esophageal Sphincter under Various Pharmacological Pretreatments

Cisapride (Ci) stimulates lower esophageal sphincter pressure (LESP). This study aims to test whether the effect of Ci on LES in vivo is still present if LES is relaxed by atropine (Atr) and nifedipine (Nife) prior to the administration of Ci. LESP was continuously recorded by manometry in 6 mongrel dogs with esophageal fistulae. Ci was given as an intravenous bolus following either Atr (40 micrograms/kg i.v.) or Nife (20 mg subl.) at the time of maximal LESP decrease (5/15 min later). Basal LES values ranged between 24.5 +/- 2.5 mm Hg (Atr group) and 23.8 +/- 3.9 mm Hg (Nife group). Following Atr, LESP decreased to a minimal value of 7.0 +/- 0.5 mm Hg; after Nife LESP decreased to a minimal value of 12.3 +/- 2.0 mm Hg. Additional administration of Ci was not able to reincrease LESP. We conclude that the action of Ci on LES cannot take place if (1) muscarinergic receptors are blocked by Atr and (2) the Ca2+ activation system is blocked by Nife. Our results suggest that the action of cisapride on LES, as its action on gastrointestinal smooth muscle cells, is mediated by postsynaptic enhancement of acetylcholine release.

The action of cisapride on the chronic constipation of paraplegia.

Paraplegic patients have intractable constipation associated with prolonged colonic transit time. The agent Cisapride significantly reduced the colonic transit time from 7.7 days to 5.1 days. It also improved the intraluminal tone in the rectum, resulting in a significant reduction in maximal rectal capacity from 305.8 ml to 224.3 ml. There was a reduction in residual urine volume from 51.5 ml to 27.7 ml. The increased number of stools containing transit markers showed that intraluminal mixing was increased by cisapride. Faecal water remained unchanged. A side effect was retention of urine in one subject after sudden withdrawal of the drug but this was avoided by its gradual reduction over 2 days.