Haloperidol, a dopaminergic antagonist: Somatostatin-like inhibition of glucagon and insulin release from the isolated, perfused canine pancreas

Abstract

Summary. The effect of haloperidol, a dopaminergic antagonist, on insulin and glucagon secretion was investigated using the isolated, perfused canine pancreas. Haloperidol at 4 x 10 .7 to 10 .5 mol/1 caused a dose-dependent inhibition of glucagon release both at low (25 mg/100 ml) and high glucose concentrations (150 mg/100 ml). At the low glucose concentration insulin release was already maximally suppressed. At the high glucose concentration haloperidol (4 × 10 -7 to 10 .5 mol/1) also caused a dosedependent inhibition of insulin release. Haloperidol (10 -5 mol/1) inhibited dramatically pancreatic A and B cell responses to isoproterenol (2 ng/ml), acetylcholine (1 ~tmol/1) and arginine (5mmol/1). The inhibitory effect of haloperidol on both glucagon and insulin release could be eliminated by increasing perfusate calcium concentration from 1.3 to 8.8 mmol/1. These findings suggested that haloperidol blocks glucagon and insulin release in a somatostatin-like manner by affecting a fundamental step of the stimulus-secretion coupling, probably by interfering with calcium handling of the pancreatic A and B cells.Key words: Isolated, perfused canine pancreas, haloperidol, acetylcholine, isoproterenol, arginine, calcium, somatostatin-like inhibition, insulin secretion, glucagon secretion.Falck and Hellman [1,2] have demonstrated that in many species the endocrine pancreatic cells contain monoamines, particularly serotonin and dopamine [3,4]. The physiological significance of these monoamines stored within the islet cells is unknown.* Presented in part at the 13 th Annual Meeting of the European Association for the Study of Diabetes, Geneva, Switzerland, September 1977During investigations on monoaminergic mechanisms in pancreatic islets we employed the dopaminergic antagonist haloperidol, which is purported to be a specific dopamine receptor blocking agent in tissues such as brain [5], exocrine pancreas [6] and renal and mesenteric vessels [7]. Using the isolated, perfused canine pancreas it was noted that this dopaminergic antagonist inhibited release of both glucagon and insulin.The purpose of the present study was to investigate further the effect of haloperidol on insulin and glucagon secretion from the isolated, perfused canine pancreas in order to elucidate the mechanisms by which this substance produces its bihormonal inhibitory actions. Material and MethodsMongrel dogs, fasted overnight, weighing 18-25 kg were used as pancreas donors. The technique for isolation of the canine pancreas and the perfusion system have been described in detail by Iversen [8,9]. In brief, the preparation consisted of the pancreas and the proximal 10 cm of the attached duodenum. A nonrecirculating medium consisting of a Krebs Ringer bicarbonate buffer containing dextran 40 g/1 (MW 75,000), 2 g/1 bovine albumin, glutamate, fumarate and pyruvate, each at a concentration of 5 mmol/l was introduced through the splenic and the coeliac arteries, and the total portal effluent was collected every 1 min. Oxygenation of the Krebs-Ringer bicarbo...

Inhibition of ATP‐sensitive potassium channels by haloperidol

“…For example, sulpiride alters glucose homeostasis in rats (Baptista, 1999), but our studies indicate it has little inhibitory effect on K ATP channels, even at high concentration. Third, studies have shown that haloperidol can either reduce insulin secretion (Hermansen, 1978) or have no effect (ElDenshary et al, 1982), but an increase in secretion (which is expected if the drug blocks K ATP channels) has not been reported. It is possible that haloperidol blocks Ca 2 þ currents in b cells, as it does in other tissues, which leads to a reduction in insulin secretion, glucose intolerance, and diabetes.…”

Dopaminergic Control of Ketogenesis in Fasting

“…Dopamine blockade by metoclopramide may directly influence metabolism or act through changes in secretion of other hormones. Studies using specific agonists and antagonists have suggested actions of dopamine to both increase and decrease insulin and glucagon secretion (Hermansen, 1978;Samols & Stagner, 1979) but circulating peripheral insulin and glucagon levels were unaltered by metoclopramide in our experiments. Metoclopramide has been reported to increase or produce no change in growth hormone secretion in man and the rat (Cohen et al, 1979;Fang et al, 1977) and no metoclopramide-induced change in circulating growth hormone concentrations occurred in the present study.…”

The effect of clozapine on blood glucose metabolism

“…Although the studies about the effect of halopeidol on blood glucose metabolism is less than that of chlorpromazine, there are studies that show haloperidol infusion into the canine pancreas inhibited insulin secretion (Hermansen, 1978;Lechin, 1981). Brambilla et al (1976) suggested that haloperidol reduced peripheral glucose metabolism in a study of 18 schizophrenic patients treated with haloperidol 6 mg i.m.…”

“…Besides chlorpromazine, haloperidol also inhibited the secretion of insulin in the canine pancreas (Hermansen, 1978;Lechin, 1981) and there is a report that sulpiride decreased glucose tolerance in the dog and the human (Lechin et al, 1979). Two case reports show that olanzapine induced hyperglycemia and diabetes (Wirshing et al, 1998), along with a case report that quetiapine also induced diabetes (Maxwell et al, 1990).…”