EFFECT OF SOME NEW -ADRENERGIC BLOCKING AGENTS ON CERTAIN METABOLIC RESPONSES TO CATECHOLAMINES

¹ Mead Johnson Research Center, Evansville, Indiana

Two new -adrenergic blocking agents, MJ 1999 [4- (2-isopropylamino - 1 - hydroxyethyl)- methanesulfonanilide HC1] and MJ 1998 [4-(2-methylamino-1-hydroxypropyl)methanesulfon- anilide HCl] inhibited hyperglycemia and elevation of plasma free fatty acids (FFA) induced by exogenous epinephrine or norepinephrine in the dog. MJ 1999 was the more potent agent and on occasion it alone was effective when isoproterenol was employed as the exogenous amine. The l-isomer of MJ 1999 was about 20 to 30 times more potent than the d- isomer in preventing epinephrine-induced hyperglycemia or hyperlipemia. The hyperkalemia resulting from epinephrine injection in the dog was not inhibited by effective antihyperglycemic dosage levels of MJ 1999.

In rats MJ 1999 inhibited the hyperglycemia evoked by epinephrine and isoproterenol. MJ 1998 inhibited only epinephrine-induced hyperglycemia. Neither drug affected the elevation of plasma FFA. In contrast to their lack of activity on FFA release in the intact rat, both agents inhibited catecholamine-induced release of FFA from isolated rat adipose tissue. In the rat MJ 1999 prevented the increase in active myocardial phosphorylase elicited by exogenous isoproterenol.

Comparative studies in rats and dogs showed pronethalol to be less active but similar in antihyperglycemic capabilities to M. J 1999. Pronethalol in all experiments produced marked and persistent increases in FFA precluding detection of any antihyperlipemic action it might possess.