l-Bunolol and propranolol: oral and intravenous beta-adrenoceptor blocking activity in rats compared to dogs and humans.

To determine the pharmacological significance of reported differences between species in l-bunolol metabolism, oral and intravenous beta-adrenoceptor blocking activity against an isoproterenol-induced tachycardia was compared in dogs, rats, and humans. Propranolol was similarly studied in rats and dogs. Species differences in intravenous potency were minimal for both compounds in contrast to oral dose studies. Oral to intravenous ratios of doses causing a comparable degree of beta-adrenoceptor blockade after l-bunolol were: rat, 212; dog 4; and human, 5. For propranolol, the oral to intravenous dose ratios were 210 and 32 for the rat and dog, respectively. These pharmacological findings show major differences in the rat compared to dogs and humans and may be explained in part by differences in the urinary excretion patterns of l-bunolol in the various species.

Levo-bunolol and propranolol: further evaluation of oral beta-blocking activity in conscious dogs.

The oral beta-adrenoceptor blocking activity of bunolol, propanolol, and their levo-isomers was compared against isoproterenol- and treadmill exercise-induced tachycardias in normal conscious dogs. Relative potencies against isoproterenol were (ascending order): propranolol=1, levo-propranolol=2, bunolol=40, and levo-bunolol=102. Large oral doses of levo-bunolol and propranolol suppressed exercise tachycardia by only 18% (range 10 to 22%). Compared to the isoproterenol response, the tachycardia associated with severe exercise in the healthy trained dog was largely resistant to beta-receptor blockade showing factors other than beta-receptor stimulation to be involved. Differences in duration of beta-blockade were observed at equiactive doses of levo-bunolol and propranolol. The isoproterenol response had returned to greater than 50% of control by 12 hr after propranolol but was less than 10% of control at 12 hr after levo-bunolol. The time to 50% recovery of the exercise tachycardia was 24 hr after levo-bunolol and 6 to 9 hr after propranolol. The results show oral levo-bunolol to be considerably more potent and to have a longer duration of action than propranolol in inhibiting both isoproterenol and exercise-induced tachycardias in conscious dogs.

Sympathomimetic drugs: evaluation for acute central hypotensive activity in alpha-chloralose-anesthetized dogs and cats intravertebral artery administration,.

dl-Amphetamine, phentermine and their para-chloro derivatives were tested for acute central hypotensive activity after intra-vertebral artery (iva) infusions in alpha-chloralose-anesthetized cats and intact and carotid sinus denervated dogs. Iva clonidine (reference standard) caused immediate reductions in blood pressure and heart rate and carotid sinus denervation (CSD) enhanced the clonidine response. dl-Amphetamine and phentermine did not cause acute hypotensive responses in the dog or cat whereas their para-chloro derivatives did. The vasodepressor response to para-chloramphetamine was inconsistent and transient and not modified by CSD. The magnitude and duration of the chlorphentermine vasodepressor response was minimal in the intact and CSD dog compared to clonidine. In contrast, chlorphentermine in the cat (140-300 mug/kg) caused an acute hypotensive response comparable in magnitude to clonidine (0.6-1.0 mug/kg). The bradycardias observed after iva chlorphentermine were much less pronounced than those associated with iva clonidine at comparable vasodepressor doses. By the i.v. route, each drug caused only pressor responses in the dog and cat. Suppression of the pressor response (resulting from "spill-over" of these alpha-stimulants into the systemic circulation after iva dosing) in the dog with small doses of i.v. phenoxybenzamine did not unmask or enhance the vasodepressor or bradycardic actions to iva administration of drugs. Methysergide prevented the hypotensive response to chlorphentermine in the cat and partially suppressed the response to clonidine; the reverse was true after piperoxan. Lilly 110140 and para-chlorophenylalanine reduced or abolished the effects of iva chlorphentermine. In summary, (1) iva chlorphentermine and clonidine were the only alpha-sympathomimetics tested which were effective as hypotensive substances; (2) the cat was considerably more responsive to iva chlorphentermine than the intact or CSD dog; (3) iva clonidine was more bradycardic than iva chlorphentermine; and (4) both adrenergic and serotonergic components appear to be among the mechanisms involved in the acute iva hypotensive response to chlorphentermine in the cat.