Inhibition of catecholamine uptake in the isolated rat heart by haloalkylamines related to phenoxybenzamine

Abstract

Summary1. Twenty-one haloalkylamine derivatives were tested as inhibitors of both the neuronal uptake of 3H-noradrenaline (NA) by the Uptake, mechanism and the extraneuronal uptake of 3H-NA by the Uptake2 mechanism in the isolated rat heart.2. At a concentration of 50 ,M most of the compounds tested caused a significant inhibition of both uptake processes, although there were wide differences in the relative effects on Uptake1 and Uptake2. Some tentative structure activity relationships for uptake inhibition were formulated from these results. were significantly more potent than phenoxybenzamine as Uptake2 inhibitors, and were all less potent than phenoxybenzamine as Uptake, inhibitors. The compound SKF 550 is the most potent and selective inhibitor of Uptake2 so far described. It has an IC50 for Uptake2 of 0-08 /.M, and an IC50 for Uptake1 of approximately 40 0 zuM. 5. Comparison of the present results with the known activities of these blocking agents suggests that no correlation exists between adrenoceptor blocking activity and ability of the substances to act as inhibitors of Uptake2 or Uptake1. IntroductionCatecholamines are accumulated by two different uptake mechanisms in the rat heart. There is an uptake of catecholamine into adrenergic nerve terminals

Assessment of the 18F-Labeled PET Tracer LMI1195 for Imaging Norepinephrine Handling in Rat Hearts

“…Recently, the transporter OCT3 has been identified to be the mediator of the nonneural uptake-2 mechanism (29,30). Potent inhibitors for this mechanism include metanephrine (31,32), steroids (33), and phenoxybenzamine (17,34). The substance we used in our experiments, phenoxybenzamine, is based on a haloalkylamide structure and is reported to be a highly potent and irreversible inhibitor of the uptake-2 mechanism; however, phenoxybenzamine also blocks the neural uptake-1 mechanism simultaneously (17).…”

“…Moreover, low tracer uptake in the liver is beneficial for evaluating the inferior wall tracer uptake without scatter artifact. 18 F-LMI1195 is also specific for cardiac norepinephrine uptake, as proven by blocking studies with phenoxybenzamine, a nonselective norepinephrine uptake-1 and -2 blocker (16,17). However, different from the previously reported studies with rabbit and nonhuman primate hearts (10), we found no reduction of cardiac 18 F-LMI1195 uptake by selective neural uptake-1 blocker (12) pretreatment with desipramine in rats, suggesting a significant contribution of the nonselective uptake-2 mechanism to cardiac 18 F-LMI1195 uptake in the rat heart.…”

“…Potent inhibitors for this mechanism include metanephrine (31,32), steroids (33), and phenoxybenzamine (17,34). The substance we used in our experiments, phenoxybenzamine, is based on a haloalkylamide structure and is reported to be a highly potent and irreversible inhibitor of the uptake-2 mechanism; however, phenoxybenzamine also blocks the neural uptake-1 mechanism simultaneously (17). Therefore, to characterize the 18 F-LMI1195 uptake mechanism, we combined the nonselective phenoxybenzamine blocking experiments with selective neural uptake-1 blocking with desipramine to further elucidate the contribution of the uptake-2 mechanism.…”

Effects of Sympathetic Innervation and Temperature on the Properties of Rat Heart Adrenoceptors

“…Haloalkylamines can inhibit the uptake of NA into adrenergic nerve endings (Iversen, Salt & Wilson, 1972), which could contribute to the potentiation of myocardial responses to NA by these drugs. The receptor protection experiments presented above showed that the potentiating effect of Pbz is present at all temperatures, but is masked by its a-adrenoceptor blocking action at 170C.…”

Electrocortical Changes Induced by the Perfusion of Noradrenaline, Acetylcholine and Their Antagonists Directly Into the Dorsal Raphé Nucleus of the Cat

“…NA invariably produced some degree of electrocortical desynchrony when perfused in concentrations of 10-5-10-3 M. When considered in terms of the total amount of NA applied during the 5 min perfusion period, these concentrations represent relatively substantial doses. However, similar perfusion studied within the mesencephalic reticular formation have shown that only a fraction of the applied NA, in the order of 0.39-119.2 ng respectively, will actually penetrate into the brain tissue (Key, 1975 (Kowstowski, Giacalonne, Garattini & Valzelli, 1969;Morgane & Stern, 1972;Jouvet, 1973 (Potter, Chubb, Put & Schaepdryver, 1971), or inhibit the uptake of catecholamines into adrenergic nerve terminals (Iversen, Salt & Wilson, 1972 (Alexander, Davis & Lefkowitz, 1975). In addition, phentolamine is known to produce non-specific inhibitory effects on certain fl-adrenergic physiological responses (Moran & Perkins, 1961) and on fl-adrenoceptor-coupled adenylate cyclase activity (Vatner & Lefkowitz, 1974).…”