What is the effect of cisapride on manometric pressure and propulsive force in the smooth muscle portion of the esophagus ?
C.O.H. Russel, N. Bright (Melbourne)
Cisapride is a new gastrointestinal prokinetic agent that is thought to work by increasing the release of acetylcholine in the myenteric plexuses of the gut[l, 2]. An effect on lower esophageal sphincter pressure and motility as measured by manometry has been demonstrated [3-8],
Manometric pressure tracings measure the intraluminal pressure developed in response to peristalsis. Normal function occurs within a wide range of values of pressure. It therefore seems that absolute values of amplitude duration and velocity of the manometric pressure (MP) wave do not predict esophageal function [9]. Another method of assessing esophageal function is to measure propulsive force
(PF) [10-12]. We have developed a method of measuring PF and assessed the effect of cisapride on this force.
Methods
This study was performed using a solid capsule 9 mm in diameter by 14 mm long containing a linear strain gauge formed of a silastic loop filled with saline. A manometric port at the upper border of the capsule allowed simultaneous measurement of manometric pressure (figure 1). This assembly was connected by manometric tubing and electrical wires to alternating current impedance monitor and three Hewlett Packard pressure transducers. An alternating current generated by the impedance monitor, which has a maximum output of 65 microamps at 6 000 Hz and 1 volt, was passed through the saline filled silastic loop. The gauge was calibrated in a warming oven at 37°C by suspending known weights from the vertically supported gauge and recording the output of the impedance monitor at a series of suitably chosen gain settings. A series of calibration curves for weight ranges from 0-15 mg to 0-200 mg were constructed (figure 2).
Figure 1. Diagram of linear strain gauge transducer (see text for functional description).
Manometric recordings were taken at the level of the capsule and at 4 and 8 cm above the capsule using a standard low compliance perfused catheter system which is an integral part of the catheter assembly. All force and pressure recordings were recorded and stored, for later analysis, on a Macintosh SE, computer via a Maclab digital analogue converter and on heat sensitive paper using a Hewlett Packard chart recorder.
Figure 2. Calibration curve for linear strain gauge transducer over a range of 0 --> 100 gms.
Ten normal, asymptomatic volunteers aged 23 to 38 (4 female and 6 male) were studied. Each subject swallowed the capsule assembly into the stomach, where it was allowed to equilibrate for at least ten minutes before being pulled back through the lower esophageal sphincter, identified using a standard pull-through technique. The capsule was then positioned 5 cm above the sphincter and allowed to stabilise for a further ten minutes. The response to 5 X dry swallows, 5 X 5 ml swallows and 5 X 10 ml swallows was measured. The capsule was then positioned at 10 and
Figure 3. Typical recording as seen on computer screen. The upper tracing is manometry pressure as recorded from the capsule and the lower channel is propulsive force.
15 cm above the sphincter and the response to the same swallows recorded. At the end of these recordings, the gauge was again swallowed into the stomach and repositioned 5 cm above the lower esophageal sphincter. A dose of 10 mg of cisapride was administered in 50 ml of 5 p. cent dextrose over 15 minutes and the response to all three bolus types was again recorded at 5, 10 and 15 cm above the sphincter.
The recordings (figure 3) were analysed using the Maclab programme. The peak manometric pressure, as measured at the level of the capsule, and the peak propulsive force were ascertained. The duration of the pressure and force waves from the start of the sharp upstroke to the end of the sharp downstroke and the area under the pressure wave and the force wave (the impulse) were also calculated.
The data from before and after the administration of cisapride were then compared, using a four way analysis of variance and paired t-tests to determine the significance of the observed differences.
This study was approved by the Research Ethics and Advisory Committee of the Monash Medical Centre and all volunteers gave informed consent prior to entering the study.
Results
Using a four way analysis of variance, we found that for all measurements and all sites, the only significant variables were the site of measurement and the administration of cisapride. Bolus size affected peak values of both manometric pressure and propulsive force but this was independent of the effect of cisapride or measurement site.
Manometric pressure
Cisapride caused an increase in the manometric pressure at all levels in the esophagus and in response to all bolus types (p = 0.0026). This increase was of the order of 31 p. cent (mean 67.7 to 88.6 mmHg) at the lower measurement site, 17 p. cent (mean 76.6 to 89.7 mmHg) at the mid site and 23 p. cent (mean 53.0 to 65.6) at the upper site (figure 4).
Propulsive force
There was a general increase in the propulsive force in response to cisapride (p = 0.021) but this was most marked in the mid esophageal site (10 cm above the lower esophageal sphincter) where the increase was 46.2 p. cent (mean 30.5 to 44.6 gm) compared with an increase of 6.5 p. cent (mean 41.2 to 44.0 gm) at 5 cm and 7.0 p. cent (mean 27.3 to 29.2gm) at 15cm above the lower esophageal sphincter. The effect of measurement site and bolus size were both more important than the effect of cisapride (figure 5).
Duration of the manometric pressure wave
Pressure duration was increased (p = 0.0001) in response to the administration of
Figure 4. The area under the manometric pressure wave before and after cisapride at the 3 different measurement sites (5, 10 and 15 cm above LES) (The error bars are standard errors).
Figure 5. The area under the propulsive force wave before and after cisapride at the 3 different measurement sites (The error bars are standard errors).
cisapride. Again, this effect was most marked in the lower esophagus where the increase was 52.9 p. cent (mean 3.9 to 5.9 sec) compared with 24.9 p. cent (mean 3.6 to 4.4 sec) at the mid and 3.0 p. cent (mean 3.2 to 3.3 sec) at the upper sites.
Duration of the propulsive force wave
There was a similar increase in the duration of the force wave (p = 0.0004). This was again most marked in the distal esophagus (84.5 % — mean 3.5 to 6.6 sec) compared with the mid (27.5 % — mean 3.2 to 4.0 sec) and upper sites (22.8 %
- mean 2.5 to 3.0 sec). This effect of the drug on force duration was of secondary importance to the effect of site on the duration of the wave.
Area under the manometric pressure wave
The area under the manometric pressure wave was markedly increased by the administration of cisapride (p = 0.0001). Again, this effect was most marked in the lower esophagus, with the increase at 5 cm above the sphincter being 122.3 p. cent (mean 143.5 to 319.1 mmHg sec) while the increase at 10 cm was 44.1 p. cent (mean 151.9 to 218.9 mmHg sec) and 15 cm was 14.2 p. cent (mean 101.3 to 115.6 mmHg sec). The measurement site had a significant effect (p = 0.0001) on the magnitude of the increase in the area under the pressure curve and was as important as the effect of cisapride.
Area under the force wave (the impulse)
The area under the force wave was increased (p = 0.0059) by the administration of cisapride but again the measurement site had a larger effect than the drug. The magnitude of the increases was 78.7 p. cent (mean 85.6 to 153.0gm sec) at 5 cm, 71.0 p. cent (mean 62.6 to 107.1 gm sec) at 10cm and 19.3 p. cent (mean 41.3 to 49.4 gm sec) at 15 cm .
Discussion
We have shown that in normal, asymptomatic subjects, cisapride causes an increase in the manometric pressure at all levels in the esophagus. It prolongs the manometric pressure wave and increases the area under the pressure wave (the product of the pressure and the duration). These effects are most marked in the lower esophagus.
Similarly, the propulsive force, the duration of the force wave and the area under the force wave (the impulse) are all increased by the administration of intravenous cisapride. These effects are less marked than the effects on the manometric pressure but again are more evident in the distal than in the proximal esophagus.
The fact that the effects of cisapride were more marked in the lower and mid than in the proximal esophagus probably reflects the higher density of the myenteric plexuses in these areas compared with the upper esophagus.
Our study, in common with others [7, 8, 13, 20], has shown that the motility of the esophagus can be enhanced by the prokinetic agent, cisapride. These findings, if they can be duplicated in patients with known motility disorders, such as scleroderma, may open the way for new therapeutic regimes for the treatment of dysphagia. Similarly, the increase in the propulsive force and impulse generated after the administration of cisapride may, in conjunction with the proven rise in the lower esophageal sphincter pressure and increase in gastric emptying, help to explain the efficacy of cisapride in the treatment of gastroesophageal reflux disease.
Conclusion
Cisapride, as gastrointestinal prokinetic agent that increases the output of acetylcholine in the myenteric plexuses of the gut, has been shown to increase all parameters of esophageal motility including the propulsive force and the impulse (area under the propulsive force curve) in normal subjects. Further studies must now be performed to determine whether these effects occur in people with impaired esophageal motility.
References