Departments of Pharmacology & Therapeutic~ and MedMne, McGill Unilwrsio'. Montreal, Quebec, Canada. l'he nature of the hepatic wadrenoceptor has been described only relatively recen@; originally it was thought to represent a septsate class of'metabolic" adrenoceptor. George Kunos discusses this problem of clas~ fication, and how it has been overcome in this article. The quantitative analysis of drug-receptor interactions in the liver has been complicated by the ability of liver cells to rapidly take up mad metabolize drugs. When using very dilute hepatocyte suspenskms, which minimizes this complication, the glycogenolytic effect of catecholamines in the adult, male rat is found to be mediated by aradrenoceptors, which have pharmacological properties identical to those of arreceptors in o,: her tissues. In-vitro studies of the isolated, solubilized ar receptor of rat liver have/dentified several proteins that contain the ligand binding site. Of these, a protein with a tool. wt of 80 000 is most likely the complete receptor binding subunit, from which lower tool. wt fragments may be generated by proteolysis, arAdrenoceptor responses of the liver are mediated by a calciumsensitive cascade triggerea by a transient rise in cytosolic calcium, which is followed by extrusion of calcium from the cells. T~,, e nature of the link between receptor activation and calcium mobilization from intracellular pools is not quite clear, and in the liver the role of phosphoinositide breakdc~, wn has not yet been definitely settled. It is also unclear whether or not hepatic o~: rreceptors are regulated by guanine nucleotides. A selective reduction in the a t-~ drenoceptor response of the rat liver is associated with a reciprocal increase in [3-reo~'ptor activity in a number of conditions, many of which represent a lower level of cellular differentiation. Such changes can develop rapidly and may be mediated by changes in the activity of membrane phospholipase A 2.

Cyclic AMP, the second messenger of I~. adrenergic responses, was discovered in a study of the effects of adrenaline on hepatic gly~ genolysis. It is therefore ironic that, until recently, hepatic adrenergic receptors could not be easily classified as a or 13. At least part of this difficulty arose because of attempts to analyse the effects of catecholamines in intact animals. Catecholamine-induced hyperglycemia is a complex response involving not only direct effects on the liver, but also effects on insulin and glucagon secretion by the pancreas, glucose uptake and lactate production by muscle, iipolysis in adipose tissue as well as other minor effects. Another confounding factor is that the nature of the adrem.~ e,. ptor involved in liver glycogenolysis appears to vary not only with species, but also with the age, sex and physiological condition of the animal, as discussed below.