The inactivation of noradrenaline and isoprenaline in dogs

Gryglewski, Ryszard J.; Vane, John R.

doi:10.1111/j.1476-5381.1970.tb10365.x

Cited by 46 publications

(15 citation statements)

References 12 publications

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“…An important contribution of extraneuronal uptake to the clearance of circulating catecholamines is consistent with other studies of the circulatory removal of isoproterenol, a substrate for extraneuronal but not neuronal uptake (Gryglewski and Vane 1970). Additionally, maximum 20 40% decreases in the plasma clearance of noradrenaline after blockade of neuronal uptake with desipramine (Esler et al 1981b;Eisenhofer et al 1989), suggest that non-neuronal mechanisms represent the predominant means for terminating the actions of circulating noradrenaline.…”

Section: Discussionsupporting

confidence: 74%

Disprocynium24, a novel inhibitor of the extraneuronal monoamine transporter, has potent effects on the inactivation of circulating noradrenaline and adrenaline in conscious rat

Eisenhofer

McCarty

Pacák

et al. 1996

Naunyn-Schmiedeberg's Arch Pharmacol

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The role of extraneuronal uptake in terminating the actions of catecholamines has been difficult to evaluate in vivo, largely because of lack of suitable inhibitors. The compound, 1,1'-diisopropyl-2,4'-cyanine iodide or disprocynium24 (D24), is a novel inhibitor of extraneuronal uptake with a high degree of potency in vitro. This study examined the actions of D24 on the inactivation and metabolism of circulating noradrenaline and adrenaline in conscious rats. Animals received i.v. infusions of 3H-labelled noradrenaline and adrenaline, and their extraneuronal O-methylated metabolites, normetanephrine and metanephrine. Plasma concentrations of endogeneous and 3H-labelled catecholamines and metanephrines were measured before and after D24. D24 caused large increases in plasma concentrations of noradrenaline and adrenaline, effects due to both decreases in their plasma clearances and increases in their rates of release into plasma. Plasma concentrations of normetanephrine and metanephrine also increased due to their decreased clearance from plasma. Increased release of normetanephrine into plasma did not contribute to increased plasma concentrations of normetanephrine. In fact, the contribution of extraneuronal O-methylation to noradrenaline clearance decreased substantially after D24. The data indicate that D24 is a potent inhibitor of the extraneuronal catecholamine transporter in vivo and that this process contributes importantly to the removal of circulating catecholamines and their O-methylated amine metabolites. Increased release of noradrenaline into plasma may reflect an increase in the proportion of transmitter that escapes from sites of release into the circulation. However, increased adrenaline release indicates that the drug also causes sympathoadrenal activation.

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Section: Discussionsupporting

confidence: 74%

Disprocynium24, a novel inhibitor of the extraneuronal monoamine transporter, has potent effects on the inactivation of circulating noradrenaline and adrenaline in conscious rat

Eisenhofer

McCarty

Pacák

et al. 1996

Naunyn-Schmiedeberg's Arch Pharmacol

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“…There are two likely sites; first, the peripheral vascular beds, where noradrenaline is removed from the circulation into sympathetic nerve terminals by the uptake, process (Whitby, Hertting & Axelrod, 1960;Whitby, Axelrod & Weil-Malherbe, 1961;Gryglewski & Vane, 1970;Iversen, 1971), and second, the lungs, where noradrenaline is removed from the circulation by an uptake process sensitive to cocaine, but which otherwise differs from uptake, (Alabaster & Bakhle, 1973;Iwasawa & Gillis, 1974 (Coffier et al, 1972). This difference in the ability of AH 5158 to antagonize systemically administered and neuronally released noradrenaline remains to be explained.…”

Section: Namentioning

confidence: 99%

Combined Α‐ and Β‐adrenoceptor Blocking Drug Ah 5158: Further Studies on Α‐adrenoceptor Blockade in Anaesthetized Animals

Kennedy

Levy

1975

British J Pharmacology

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1 AH 5158, 5-[l-hydroxy-2-[(l-methyl-3-phenylpropyl)aminolethyllsalicylamide, competitively antagonised phenylephrine-induced vasopressor responses in anaesthetized dogs, thus confirming that the drug possesses a-adrenoceptor blocking activity. 2 In contrast, AH 5158 was a relatively ineffective antagonist of vasopressor responses to noradrenaline in anaesthetized dogs. Thus, at the lowest dose-level tested (1 mg/kg) AH 5158 abolished the increase in pulse width caused by noradrenaline, but otherwise had little or no blocking effect in doses as high as 10 mg/kg. Propranolol (0.1 mg/kg) also abolished the increase in pulse width caused by noradrenaline. With both drugs this effect is thought to be a consequence of blockade of the j-adrenoceptor-mediated cardiac stimulant action of noradrenaline. 3 The interaction between AH 5158 and noradrenaline in spinal dogs, anaesthetized cats and pithed rats was very similar to that seen in anaesthetized dogs. 4 Noradrenaline pressor responses were effectively antagonized by AH 5158 in anaesthetized dogs pretreated with cocaine. The degree of block was similar to that obtained when phenylephrine was the agonist in untreated dogs. 5 These results are consistent with the hypothesis that AH 5158 blocks a cocaine-sensitive inactivation process for noradrenaline in addition to blocking a-and P-adrenoceptors. The resultant increase in the level of circulating noradrenaline would tend to counteract the adrenoceptor blocking action of the drug. 6 The implications of these findings are discussed.

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“…The kidney can remove significant amounts of ISP during i.a. infu sion in adult dogs [27,28], Our findings imply that such mechanisms for ISP uptake and excretion are well-developed in swine by the 2nd postnatal week.…”

Section: Discussionmentioning

confidence: 71%

Cardiovascular and Renal Effects of Isoproterenol Infusions in Young Swine

Buckley¹,

Brazeau²,

Charney³

et al. 1984

Neonatology

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The cardiovascular and renal effects of intravenous (i.v.) and intra-arterial (i.a.) infusions of isoproterenol (ISP, 0.1–0.2 μg/kg/min) were evaluated in 17 two-week-old swine anesthetized with pentobarbital. The glomerular filtration rate (GFR) of each kidney and blood flow and vascular resistance (RVR) of the left kidney were determined in all animals. In the 8 animals given ISP i.v., right ventricular pressure and dP/dt_max were also determined via a thoracotomy. In 9 animals, ISP was given i.a. after stabilization of constant-flow perfusion of the left kidney in situ. During i.v. infusion of ISP, the positive inotropic and chronotropic effects and the decrease in arterial pressure were maintained; renal blood flow and GFR increased and RVR decreased. During i.a. infusion of ISP in the constant-flow perfused kidney, similar changes in RVR and GFR were observed despite the higher effective concentrations of drug reaching the kidney. We conclude that, at this stage of postnatal renal development, the infusion of cardiotonic doses of ISP lowers RVR and produces a small increase in GFR.

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The inactivation of noradrenaline and isoprenaline in dogs

Cited by 46 publications

References 12 publications

Disprocynium24, a novel inhibitor of the extraneuronal monoamine transporter, has potent effects on the inactivation of circulating noradrenaline and adrenaline in conscious rat

Disprocynium24, a novel inhibitor of the extraneuronal monoamine transporter, has potent effects on the inactivation of circulating noradrenaline and adrenaline in conscious rat

Combined Α‐ and Β‐adrenoceptor Blocking Drug Ah 5158: Further Studies on Α‐adrenoceptor Blockade in Anaesthetized Animals

Cardiovascular and Renal Effects of Isoproterenol Infusions in Young Swine

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