Gastric myoelectric activity during cisplatin-induced acute and delayed emesis reveals a temporal impairment of slow waves in ferrets: effects not reversed by the GLP-1 receptor antagonist, exendin (9-39)

Abstract

Preclinical studies show that the glucagon-like peptide-1 (GLP-1) receptor antagonist, exendin (9-39), can reduce acute emesis induced by cisplatin. In the present study, we investigate the effect of exendin (9-39) (100 nmol/24 h, i.c.v), on cisplatin (5 mg/kg, i.p.)-induced acute and delayed emesis and changes indicative of 'nausea' in ferrets. Cisplatin induced 37.2 ± 2.3 and 59.0 ± 7.7 retches + vomits during the 0-24 (acute) and 24-72 h (delayed) periods, respectively. Cisplatin also increased (P<0.05) the dominant frequency of gastric myoelectric activity from 9.4 ± 0.1 to 10.4 ± 0.41 cpm and decreased the dominant power (DP) during acute emesis; there was a reduction in the % power of normogastria and an increase in the % power of tachygastria; food and water intake was reduced. DP decreased further during delayed emesis, where normogastria predominated. Advanced multifractal detrended fluctuation analysis revealed that the slow wave signal shape became more simplistic during delayed emesis. Cisplatin did not affect blood pressure (BP), but transiently increased heart rate, and decreased heart rate variability (HRV) during acute emesis; HRV spectral analysis indicated a shift to 'sympathetic dominance'. A hyperthermic response was seen during acute emesis, but hypothermia occurred during delayed emesis and there was also a decrease in HR. Exendin (9-39) did not improve feeding and drinking but reduced cisplatin-induced acute emesis by ~59 % (P<0.05) and antagonised the hypothermic response (P<0.05); systolic, diastolic and mean arterial BP increased during the delayed phase. In conclusion, blocking GLP-1 receptors in the brain reduces cisplatin-induced acute but not delayed emesis. Restoring power and structure to slow waves may represent a novel approach to treat the side effects of chemotherapy.

Keywords: GLP-1 receptors; cisplatin; emesis; ferret; gastric myoelectric activity.

Figure 1. Effect of an i.c.v. infusion of saline (10 μl/h) or exendin (9-39) (100 nmol/24 h) on emesis induced by cisplatin (5 mg/kg, i.p.)

Profiles of emesis are shown in (A) and (B); latency to the first emetic episode (C); number of episodes of emesis during the 0-24 h (acute phase) (D) and 24-72 h (delayed phase) (E) are also shown. Data represents the mean ± SEM of 4-6 animals. Sal = saline, Ex-9 = exendin (9-39). Significant differences between Sal and Ex-9 groups are shown as ^*P<0.05 (unpaired t-test).

Figure 2. Running spectrum analysis (RSA) of gastric myoelectric activity (GMA) in the vehicle-control ferret that received cisplatin (5 mg/kg, i.p.)

(A) RSA of GMA from start of baseline recording 24 h prior to cisplatin administration to 72 h after cisplatin administration; (B) an expanded view of the RSA from 4 h before cisplatin injection to 8 h post-cisplatin injection. DF = dominant frequency, DP = dominant power. This animal exhibited emesis after a latency of 2.52 h; it had 13 episodes of emesis during the first 8 h period (during the 0-24 h and 24-72 h periods, it had 37 and 26 episodes of emesis, respectively). Note the decrease in DP and increase in DF following cisplatin administration (arrowed boxes).

Figure 3. Effect of an i.c.v. infusion of saline (10 μl/h; open circles) or exendin (9-39) (100 nmol/24h; filled circles) on gastric myoelectric activity in animals given cisplatin cisplatin (5 mg/kg, i.p.)

(A) DF, (B) percentage change of DF over 24 h, (C) DP, (D) percentage change of DP over 24 h, (E) bradygastria (%), (F) percentage change of bradygastria over 24 h, (G) normogastria (%), and (H) percentage change of normogastria over 24 h, (I) tachygastria (%), and (J) percentage change of tachygastria over 24 h are shown. Sal = saline, Ex-9 = exendin (9-39), DF = dominant frequency, DP = dominant power. Data represents the mean ± SEM of 4-6 animals. Significant differences relative to baseline recordings of the respective treatment groups are shown as ^#P<0.05 (one-way ANOVA).

Figure 4. Representative traces of gastric myoelectric activity recordings in a ferret that had received cisplatin (5 mg/kg, i.p.)

This animal exhibited emesis after 2.52 h. Filled dots indicate episodes of retching and/or vomiting during 1 h period.

Figure 5. Multifractal detrended fluctuation analysis (MFDFA)

(A) Generalized Hurst exponent h(q) vs. order q, and (B) dimension of subset series f(α) vs. Singularity strength α for gastric myoelectric activity in one ferret during four different time periods: pre-cisplatin(-24-0 h) and post-cisplatin-Sal (0-24 h, 24-48 h, 48-72 h); (C) the width of the multifractal spectrum (Δα) of four different periods (-24-0 h, 0-24 h, 24-48 h, 48-72 h) in Sal and Ex-9 are shown, and data represents the mean ± SEM of 4-6 animals. Sal = saline, Ex-9 = exendin (9-39). Significant differences relative to baseline recordings of the respective treatment groups are shown as ^#P<0.05, ^##P<0.01; no significant differences were found between Sal and Ex-9 groups (one-way ANOVA or two-way ANOVA as appropriate).

Figure 6. Effect of an i.c.v. infusion of saline (10 μl/h; open circles) or exendin (9-39) (100 nmol/24 h; closed circles) on systolic blood pressure (BP), diastolic BP, heart rate (HR), heart rate variability (HRV) and core body temperature when animals received cisplatin (5 mg/kg, i.p.)

(A) Systolic BP, (B) percentage change of systolic BP over 24 h, (C) diastolic BP, (D) percentage change of diastolic BP over 24 h, (E) HR, (F) percentage change of HR over 24 h, (G) HRV, (H) percentage change of HRV over 24 h, (I) core body temperature, (J) percentage change of core body temperature over 24 h are shown. Sal = saline, Ex-9 = exendin (9-39). Data represents the mean ± SEM of 4-6 animals. Significant differences relative to baseline recordings of the respective treatment groups are shown as ^#P<0.05; significant differences between Sal and Ex-9 groups are shown as ^*P<0.05, ^**P<0.01 (one-way ANOVA or two-way ANOVA as appropriate).

Figure 7. Effect of an i.c.v. infusion of saline (10 μl/h; open circles) or exendin (9-39) (100 nmol/24 h; closed circles) on heart rate variability (HRV) when animals received cisplatin (5 mg/kg, i.p.)

(A) Low frequency (LF), (B) percentage change of LF over 24 h, (C) high frequency (HF), (D) percentage change of HF over 24 h, (E) LF/HF, (F) percentage change of LF/HF over 24 h are shown. Sal = saline, Ex-9 = exendin (9-39). Data represents the mean ± SEM of 4-6 animals. Significant differences relative to baseline recordings of the respective treatment groups are shown as ^#P<005 (one-way ANOVA or two-way ANOVA as appropriate).