RELATIVE BETA ADRENERGIC RECEPTOR BLOCKING ACTIVITY IN DOGS AFTER INTRAVENOUS AND INTRAPORTAL VEIN ADMINISTRATION: BUNOLOL, PROPRANOLOL, THEIR LEVO ISOMERS AND SOTALOL

¹ Warner-Lambert Research Institute, Department of Pharmacology, Morris Plains, New Jersey

Changes in the heart rate response to isoproterenol and cardioaccelerans nerve stimulation were compared before and after i.v. and intraportal vein (pv) doses of dl- or l-bunolol, dl- or l-propranolol and dl-sotalol. Equiactive i.v. doses of the antagonists did not cause equivalent degrees of beta adrenergic receptor blockade after pv administration. dl- and l-Propranolol were less active (P < .05) than the other antagonists after pv administration. Route- and dose-dependent differences were quantitated for individual antagonists by comparing i.v. and pv pA₂ and slope values. The reduced activity of pv dl- and l-propranolol was most pronounced after the levo isomer and associated primarily with low cumulative doses. Pretreatment with large pv doses of d-propranolol did not significantly alter the pv response to a low dose of dl-propranolol. SKF 525A pretreatment did not change the relative pv activities of bunolol and propranolol. Carbon tetrachloride pretreatment (hepatotoxic doses): 1) caused a shift in the pv response of propranolol toward that observed after a pv dose of bunolol in normal dogs; 2) had minimal effects on the pv response to bunolol; and 3) prolonged the normally abbreviated pv response of sotalol. It was concluded that the descending order of pharmacologic inactivation after pv administration was: l-propranolol > propranolol >> sotalol > l-bunolol > bunolol. This difference may contribute significantly to l- and dl-bunolol's (and to a lesser degree to sotalol's) favorable oral-to-i.v. dose relationship over propranolol.