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The intravenous injection of isoprenaline (10 nmole/kg) into conscious beagle dogs caused significant increases in the blood level of lactate, glucose, FFA, insulin and cyclic AMP. These metabolic alterations induced by isoprenaline were blocked completely by pretreatment of the dog with propranolol (1 mg/kg). Butoxamine (10 mg/kg) antagonized isoprenaline-induced increases in glucose, lactate and insulin, but not the increases in FFA. Practolol (10 mg/kg) diminished the increase in blood FFA very strongly. Salbutamol, which is known to be an agonist of the β2-subtype in its bronchomotor and cardiovascular actions, produced marked increases in the blood concentrations of lactate, glucose and insulin but were without effect on the FFA level. Thus metabolic responses of conscious beagle dogs to β-adreboceptor agonists appeared to depend differentially on two types of β-adrenoceptors: β1-adrenoceptors are largely involved in lipolysis while β2-adrenoceptors are involved in the regulation of blood glucose metabolism and insulin secretion. A new β-adrenoceptor agonist, 5-(1-hydroxy-2-isopropylaminobutyl)-8-hydroxycarbostyril hydrochloride hemihydrate (Procaterol), was classified as a β2- agonist, because it markedly increased plasma concentrations of glucose, lactate and insulin but increased the plasma level of FFA to a lesser degree. The order of potency of β2-agonists was procaterol salbutamol trimetoquinol. Metabolic responses of beagle dogs would be useful for appreciating the selectivity and potency of β-adrenoceptor agonists and antagonists.

Intraperitoneal injection of epinephrine caused a slight but significant increase in cyclic AMP in the liver and skeletal muscle in 5–10 min. Likewise, there was a significant increase in cyclic AMP in the muscle and adipose tissue 5 min after the injection of isoproterenol. However, no change was detected in the cardiac muscle. Pretreatment of rats with theophylline was so effective in enhancing responses of tissue cyclic AMP as to make it possible to detect a 2- to 3-fold increase of cyclic AMP even in the heart. The maximal increases in tissue cyclic AMP induced by 500 μg/kg of isoproterenol or epinephrine were blocked by carteolol, a new beta-adrenergic blocking agent, at doses of 10–100 μg/kg, regardless of whether or not the rats had been treated with theophylline. In contrast, neither the increase of liver cyclic AMP by glucagon nor the increase of adrenal cyclic AMP by adrenocorticotropic hormone (ACTH) was affected by this agent. Blood cyclic AMP rose sharply after isoproterenol, the maximal response attaining 20- to 30-fold of the preinjection level. Based on this tremendous increase of blood cyclic AMP, the dose of isoproterenol and carteolol required for the half-saturation of the beta-adrenergic receptor was calculated as 20–30 and 0.5 μg/kg of body wt respectively. These values are in the same order as the respective values obtained from the response of carbohydrate and lipid metabolites in blood.

Lindane analogs, in which one or two chlorine atoms are replaced by various substituents, exhibit convulsive and lethal effects on Periplaneta americana (L.). Some analogs are as active as lindane. These effects are well related to the neuroexcitatory action which produces after-discharges in the central nervous system. Carbamate insecticides have potent convulsive and lethal effects on P. americana , which are also related to after-discharges produced in nerve cords. Convulsion caused by lindane analogs and carbamates is solely attributable to their neuroexcitatory effects on the nervous system, in spite of the difference in their ultimate modes of action.

The neuroexciting activity of DDT and its analogs to produce repetitive responses on the nerve cord of Periplaneta americana was determined using the extracellular electrode method. The convulsive activity on P. americana and the insecticidal effect on Callosobruchus chinensis were also examined. It was found that the convulsive and insecticidal activities increase almost proportionally with increase in the neuroexciting activity within a set of p,p′-substituted DDT analogs. The intimate connections among these biological effects suggest that symptoms such as convulsion and death caused by DDT analogs are closely related with their neuroexcitory effect and there is a common mode of action in spite of differences in insect species.

Increases in blood concentrations of glucose induced by epinephrine, of lactate induced by epinephrine and isoproterenol, and of glycerol and insulin induced by isoproterenol in rats showed graded responses dependent on the dose of the catecholamines and were blocked also progressively by increasing doses of 5-(3-tert-butylamino-2-hydroxy)propoxy-3,4-dihydrocarbostyril hydrochloride (carteolol), a new beta-adrenergic blocking agent. The ed 50 estimated for these metabolic parameters, other than blood insulin, was 100–200 μg/kg of body wt for epinephrine and 10–20 μg/kg for isoproterenol, while the “corrected id 50” for carteolol, reflecting the dissociation constant of the antagonist-receptor complex, was 1–3 μg/kg. It is concluded that the beta-adrenergic receptors of the same character concerning the affinity to agonists and antagonists mediate the increase of blood levels of these carbohydrate and lipid intermediary metabolites, and that the affinity of carteolol is one order higher than that of isoproterenol, which in turn is ten times higher than that of epinephrine. In contrast, much higher ed 50 for isoproterenol and “corrected id 50” for carteolol were obtained when hyperinsulinemia was used as a measure of beta action, suggesting that the beta-adrenergic receptor mediating pancreatic secretion of insulin is distinct in nature from the receptors involved in the control of carbohydrate and lipid metabolism. Comparison of the potency of carteolol with those of propranolol and pindolol showed that carteolol is the most potent beta-adrenergic blocking agent.