Phenylpyrazolone derivatives inhibit gastric emptying in rats by a capsaicin-sensitive afferent pathway

Abstract

Dipyrone (Dp), 4-aminoantipyrine (AA) and antipyrine (At) administered iv and Dp administered icv delay gastric emptying (GE) in rats. The participation of capsaicin (Cps)-sensitive afferent fibers in this phenomenon was evaluated. Male Wistar rats were pretreated sc with Cps (50 mg/kg) or vehicle between the first and second day of life and both groups were submitted to the eye-wiping test. GE was determined in these animals at the age of 8/9 weeks (weight: 200-300 g). Ten minutes before the study, the animals of both groups were treated iv with Dp, AA or At (240 μmol/kg), or saline; or treated icv with Dp (4 μmol/animal) or saline. GE was determined 10 min after treatment by measuring % gastric retention (GR) of saline labeled with phenol red 10 min after orogastric administration. Percent GR (mean ± SEM, N = 8) in animals pretreated with Cps and treated with Dp, AA or At (35.8 ± 3.2, 35.4 ± 2.2, and 35.6 ± 2%, respectively) did not differ from the GR of saline-treated animals pretreated with vehicle (36.8 ± 2.8%) and was significantly lower than in animals pretreated with vehicle and treated with the drugs (52.1 ± 2.8, 66.2 ± 4, and 55.8 ± 3%, respectively). The effect of icv administration of Dp (N = 6) was not modified by pretreatment with Cps (63.3 ± 5.7%) compared to Dp-treated animals pretreated with vehicle (62.3 ± 2.4%). The results suggest the participation of capsaicin-sensitive afferent fibers in the delayed GE induced by iv administration of Dp, AA and At, but not of icv Dp

Evidence for the involvement of peripheral β-adrenoceptors in delayed liquid gastric emptying induced by dipyrone, 4-aminoantipyrine, and antipyrine in rats

“…As done in previous studies (1-5), all groups were treated iv with 240 µmol/kg Dp, AA, or At or with 1 mL/kg sterile saline solution (S) vehicle control, and GE was determined 10 min after treatment.…”

“…GE was assessed indirectly in awake animals by determining the percentage of gastric retention (%GR) of a saline test meal labeled with 60 µg/mL phenol red 10 min after administration by gavage in a volume of 2 mL/100 g rat weight according to a technique standardized in our laboratory (17), with some modifications (5). …”

“…The mechanisms involved in delayed gastric emptying (GE) of liquid in rats induced by the phenylprazolone derivatives dipyrone (Dp), 4-aminoantipyrine (AA), and antipyrine (At) are unknown, although there is evidence that 1) these drugs increase gastric compliance and 2) the vagus nerve, the central nervous system (CNS), and afferent capsaicin-sensitive pathways participate in the phenomenon (1-5). …”

Neurogastroenterology and motility around the world

“…Regarding the physiological aspects of the neural control of gastrointestinal motility, studies using animal models have been carried out at the State University of Campinas in Southeastern Brazil, where mechanisms affecting gastric emptying in the rat have been the object of study of a very active research group for many years 22 . The behavior of the gastric fundus smooth muscle in mice with disruption of the B1 receptor gene was described at the Federal University of São Paulo 23 …”

Dipyrone in association with atropine inhibits the effect on gastric emptying induced by hypoglycemia in rats

“…It is considered to be a pro-drug that probably acts through its major metabolites, i.e., 4-methyl-amino-antipyrine (MAA) and 4-amino-antipyrine (AA) ( 18 – 20 ). When administered intravenously ( iv ) to rats, dipyrone delayed GE of a liquid meal (saline) ( 21 , 22 ), an effect that was abolished by electrolytic lesion of the paraventricular nucleus of the hypothalamus and subdiaphragmatic vagotomy ( 21 ) and that depended on capsaicin-sensitive afferent fibers ( 23 ). Acute iv blockade of the release of norepinephrine from peripheral sympathetic nerves with guanethidine or iv pretreatment with propranolol (a non-selective β-adrenergic antagonist) abolished the effect of dipyrone on GE, suggesting the involvement of the sympathetic nervous system (SNS), and activation of β 1 - and/or β 2 -adrenergic receptors during the phenomenon ( 24 ).…”