Dopamine Receptor Blocking Activity of Sulpiride in the Canine Exocrine Pancreas

Abstract

Abstract-The inhibitory effect of sulpiride on dopamine receptors was investigated in the exocrine pancreas of dogs anesthetized with pentobarbital and with the stomach ligated at the pylorus. All test substances were given intravenously. Dopamine, acetylcholine, histamine and secretin produced a dose-related increase in pancreatic juice secretion, though the dose-effect curves of these secretagogues differed in shape. Epinephrine, norepinephrine, isoproterenol, methamphetamine and serotonin had no secretagogue effects. The effects of acetylcholine and histamine were inhibited by atropine and cimetidine, respectively. The effect of dopamine was blocked by halo peridol, but not by atropine, cimetidine, phentolamine and propranolol. These results suggest that dopamine acts on specific dopamine receptors related to the exocrine pancreatic secretion.Haloperidol had no effect on the effects of acetylcholine and histamine, but did inhibit the secretin-induced secretion, though the inhibitory effect was to a lesser extent than on the dopamine response. Sulpiride and chlorpromazine also suppressed dose-dependently the dopamine-induced secretion. The inhibitory activity of sulpiride was almost the same as that of haloperidol, and 12 times more potent than that of chlorpromazine.Sulpiride was found to be a potent dopamine antagonist in the canine exocrine pancreas.In a previous report we showed that sulpiride`, an antipsychotic drug, has essentially a potent inhibition on dopamine receptors in the central nervous system. This drug, when given intraventricularly to rats, was equally or more effective than haloperidol in inducing catalepsy and in inhibiting apomorphine and methamphetamine-induced circling behavior (1). The present paper deals with antagonism of sulpiride to dopamine in the exocrine pancreas of dogs.Hashimoto and collaborators demonstrated that exogenous dopamine increases the secretion of pancreatic juice, of which the components are similar to those induced by exogenous secretin (2), and that there are specific dopamine receptors related to the exocrine pancreatic secretion in dogs (3-6). Thus, the dopamine receptor response can be easily quantified by measuring the increases in volume of the pancreatic juice. This system is a convenient tool for studies on the interaction between dopamine and test substances.We attempted to evaluate the antidoparnine activity of sulpiride, chlorpromazine and haloperidol given to anesthetized dogs before an i.v. administration of dopamine in order to evoke increased pancreatic secretion. We also examined the specificity of the pancreatic dopamine receptor response to dopamine injected systemically, as the dopamine receptor

Cimetidine increases the pancreatic response to histamine

“…The stimulatory effect of histamine on pancreatic secretion is well established in several species [5,[31][32][33]. This study is in partial agreement with a previous report showing that the stimulatory effect of histamine is mediated by H1 receptors [1].…”

Role of histamine receptors in rabbit pancreatic exocrine secretion stimulated by cholecystokinin and secretin

“…Exogenous application of histamine seems to have stimulatory effects on pancreatic secretion in dog (Tankel, Lester, Richman & Hollander, 1957;Lorenz et al 1968;Satoh, Satoh & Honda, 1980), pig (Hickson, 1970) and in vitro rabbit pancreas (Liebow & Franklin, 1982). It has also been demonstrated that histamine increases dog pancreatic secretion by activation of H2 receptors on pancreatic cells (Iwatsuki, Ikeda & Chiba, 1981).…”

The physiological role of histamine in the exocrine pancreas

“…In both the anaesthetized dog [32] and isolated dog pancreas [31], cimetidine and metiamide can completely inhibit the secretory action of histamine. In another study employing conscious dogs, cimetidine has been shown to decrease postprandial juice flow and bicarbonate output but increase amylase and protein output [65].…”

“…It is similar in efficacy as secretin but slightly more potent than comparable stimulant as vasoactive intestinal polypeptide (VIP) [29,30]. Histamine can stimulate pancreatic juice secretion in the isolated dog pancreas [31], the anaesthetized dog [32,33], rabbit and guinea-pig [23,[34][35][36] but it is less effective as a secretagogue in the anaesthetized rat [37] and conscious dog [38]. In the in vitro pancreatic lobules of rabbit [28], segments of guinea pig [39,40] and rat [41] histamine can evoke marked increases in amylase secretion.…”