[Leu]enkephalin stimulates carbohydrate metabolism in isolated hepatocytes and kidney tubule fragments by interaction with angiotensin II receptors

Abstract

The possibility that the effects of [Leu]enkephalin in vitro on hepatic carbohydrate metabolism are mediated by interaction with angiotensin II receptors has been examined. Preincubation of hepatocytes with either the angiotensin II receptor antagonist [Sar1,Ile8]angiotensin II or 10 mM-dithiothreitol abolished the ability of both angiotensin II and [Leu]enkephalin to increase phosphorylase a in hepatocytes prepared from fed rats. Dithiothreitol had no effect on the stimulation of phosphorylase in the presence of glucagon or phenylephrine, although it also inhibited the response to vasopressin. [Leu]enkephalin displaced specifically bound 125I-labelled angiotensin II from hepatic plasma membranes over a concentration range of 10(-7)-10(-5) M. This correlated with the dose-response required to stimulate phosphorylase activity in intact hepatocytes and suggests that the effects of the opioid peptides on carbohydrate metabolism in liver are the result of cross-reactivity of the peptides with angiotensin II receptors. Addition of 10(-5) M-[Leu]enkephalin to isolated kidney tubule fragments stimulated gluconeogenesis from 5 mM-pyruvate, the magnitude of stimulation being comparable to that by either angiotensin II or adrenaline. This effect of the opioid peptide was also abolished by pretreatment of the tubules with [Sar1,Ile8]angiotensin II, suggesting that the ability of [Leu]enkephalin to interact with angiotensin II receptors is not restricted to the liver, but may occur in other tissues where both receptors occur together.

The occurrence and receptor specificity of endogenous opioid peptides within the pancreas and liver of the rat. Comparison with brain

“…However, we did find that high Many of the effects of opioid peptides on hepatic carbohydrate metabolism are not inhibited by naloxone, a non-specific opiatereceptor antagonist (Allan et al, 1983;Leach et al, 1985). (Titheradge & Hothi, 1987;Hothi et al, 1989), and may produce their biological actions (such as increased glucose output) by a cross-reaction at these sites (Allan et al, 1983;Leach et al, 1985;Hothi et al, 1989).…”

“…Attempts to measure specific receptors for opiates in liver have suggested that two specific binding sites for /3-endorphin may exist in hepatic plasma membranes, at least one of which was linked to adenylate cyclase (Dave et al, 1985). No describing receptors for other opioid peptides; however, recent work has suggested that the effect of the enkephalins at least may be explained as a result of cross-reactivity of the peptide with angiotensin II receptors (Hothi et al, 1989).…”