Effects of (−)-(R)-1-( p-hydroxyphenyl)-2-[(3,4-dimethoxyphenethyl)amino]ethanol (TA-064), a new cardiotonic agent, on circulating parameters of carbohydrate and lipid metabolism in the rat

Abstract

Effects of the new cardiotonic and selective β 1-adrenergic agonist TA-064, (−)-(R)-1-( p-hydroxyphenyl)-2-[(3,4-dimethoxyphenethyl)amino]ethanol, on circulating concnetrations of glucose, lactate, free fatty acids (FFA), glycerol, cyclic AMP and the pancreatic hormones insulin (IRI) and glucagon (IRG) were examined in rats. TA-064, administered orally or intraperitoneally at the dose of 10 mg/kg ( ca. 50 times the therapeutic dose) or higher, caused a slight transient rise followed by a persistent lowering of blood glucose concentrations, but it did not affect blood lactate levels at all. The same treatment with TA-064 elevated the concentrations of blood FFA, glycerol and plasma IRI and IRG. These changes induced by TA-064 were inhibited by pretreatment with propranolol (a non-selective β-adrenergic antagonist) and practolol (a selective β 1-adrenergic antagonist). The non-selective β-adrenergic agonist isoproterenol and the selective β 2-adrenergic agonist terbutaline elevated both blood glucose and lactate when administered intraperitoneally. They also brought about sustained rises in blood glycerol and plasma IRI, but only transiently increased the plasma IRG level. The cardiotonic agent prenalterol, claimed to be a selective β 1-agonist, elevated blood glucose, lactate, and glycerol only slightly, and plasma IRI significantly, but it had no effect on plasma IRG. The cardiotonic agents dobutamine and amrinone also elevated blood glucose. Thus, TA-064 is unique among the β-adrenergic and other cardiotonic agents in that it produces sustained hypoglycemia while it has no lactacidemic effect. Since this hypoglycemic action of TA-064 was always preceded by a rise in plasma IRI and abolished in streptozotocin-diabetic rats, we conclude that increased secretion of pancreatic insulin and the lack of hyperglycemic action are responsible for the hypoglycemia by high doses of TA-064.