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210 A species difference in metabolism of myocardial catecholamines
Abstracts 209 The Effects of Drugs Uptake into the
on the Heart.
Noradrenaline
E.
MUSCHOLL
(Germany). The effects of drugs, known to modify the action of sympathomimetic amines, on the noradrenaline uptake into the heart were studied in the pithed rat. Noradrenaline (5-20 pg per rat in 20 min) was infused intravenously and the heart racised 5 min later. Infusion of 5 and 20 i*g of noradrcnalinc caused an increase in heart noradrenaline concentration by 39 and 69 per cent, respectively. Rescrpine’“’ and cocaine’“, 3, are known to block the noradrenaline uptake into the heart. The specificity of the action of cocaine (0.15-20 mg/kg) With infusions of .j and 20 has been investigated. pg of noradrenaline, the doses of cocaine needed for 50 per cent inhibition of net uptake of noradrenaline were 0.7 and IO mgjkg, respectively. For a given dose of cocaine, there was a significant correlation between increase of the pressor response to a test close of noradrenaline and inhibition of the noradrenaline uptake into the heart. Drugs chemically related to cocaine such as alpha-cocaine, tetracaine and atropine (IO-20 mg/ kg), did not alter the noradrenaline uptake or cause supersrnritivity towards noradrenaline. Noradrenaline uptake was unchanged after dibenamine (50 mg:kg‘i, but completely blockrd by dichloroisoprcnaline (WI, 30 mg/kg). It is concluded that injected noradrenaline not only combines with adrcnergic receptors but is storrd at other sites as well. Cocaine prevents uptake into these sites, thereby increasing the amount of noradrenaline available for combination with adrcnergic receptors. DC1 blocks both the uptake into stores and the combination with receptors. -
2. MLXHOLL, E. (1960), Ibid., 240, 8. 3. AIELROD,J., WHITBY, L. G. and HERTTING, G. (19601, .hbtrtre (Land.), 187, 604. 210 A Species cardial
Difference in Metabolism of MyoCatecholamines. F. E. SHIDEWIAN and
N. 13. GOLDBERG
(U.S.A.).
We previously demonstrated a depletion of myocardial catecholamines (LlCA) in one species (cat) and an increase in concentration of SlCA in another species (rat) in nivo by the monoamine oxidase inhibitor (MAOI), Z-trans-phenylcyclopropylamine (SKF 3851. A positive inotropic effect is produced This by SKF 385 on isolated atria of both species. action is blocked by pretreatment with dichloroisoproterenol or trimethyl (2-(2 :6-xylyloxy)-propyl)ammonium chloride and abolished or greatly reduced in preparations from reserpine-treated animals. This evidence suggests the inotropic
of Papers
65
response is effected by a release of catecholamines (CA) in both species. It is conceivable that the comparable physiological effects of SKF 385 on heart muscle from the cat and rat and the observed difference in response of MCA to administration of this MAO1 might be explained by a difference in the metabolic mechanisms available for its biotransformation in the two species. .4 study of the in Stro metabolism of norepincphrine (NE) by heart homogenates disclosed a rapid rate of metabolism by rat heart but little or no metabolism by cat heart unless ATP and r_-methionine were added. These additions did not enhance metabolism of NE by rat heart. Disappearance of NE in rat heart homogenates containing added ATP and Lmethionine was inhibited by SKF 385 but not SKF 385 did not affected significantly by catechol. inhibit metabolism of KE by cat heart homogenates supplemented with ATP and I~-rnethio~lin~ but catechol did. These results indicate that thr predominant CA inactivating enzyme in the myocardium of the rat is MAO and in the cat is catecholO-methyl transferase. 21 I The
Potentiation of Adrenaline and Noradrenaline by Cocaine on the Innervated and the Denervated Nictitating Membrane ofthe Cat. W. R. KUKOVETZ anclF. 1m.m~~~
(Austria). Consecutive doses of O.l-10.0 ug/kg adrenalin? and noradrenaline were injected intravenously to spinal cats. Contractions of both nictitating mcmbrancs one of which had been denervated one week prior to the experiment were recorded. Subsequently, 3 mg/kg ofcocaine wer,e given and the same On doses of catecholamines were Injected again. the innervated membrane the well-known potentiation of the catechol effect by cocaine occurred. On the denervated nictitating membrane, however, cocaine completely failed to potentiate the effect of adrenaline or noradrenaline. These results are in agreement with the observation of Hcrtting et al. (1961) who found that denervated tissue did not take up “H-noradrenaline. Cocaine, which presumably exerts its potcntiating effect on the action of catecholamines by blocking their unspecific receptor sites around the nerve endings and hereby making available more ratccholamines to the specific receptors, would as a result of the denervation br deprived of its substrate and, thereforc, not be able to produce potentiation. 212 The Inlluence of Isolated Artery. fCanadaj.CL
of Reserpine on the Reactivity Rabbit Aorta and Carotid N. GILLIS and C:. hf. YATES
Pretreatment of rabbits on each of 2 days before use with reserpine (2 mg/kg i.p. first day and 2 mg/ kg i.v. second day), completely abolished the secondary contraction of rabbit aorta and carotid artery which normally follows the cessation of an
on the Heart.
Noradrenaline
E.
MUSCHOLL
(Germany). The effects of drugs, known to modify the action of sympathomimetic amines, on the noradrenaline uptake into the heart were studied in the pithed rat. Noradrenaline (5-20 pg per rat in 20 min) was infused intravenously and the heart racised 5 min later. Infusion of 5 and 20 i*g of noradrcnalinc caused an increase in heart noradrenaline concentration by 39 and 69 per cent, respectively. Rescrpine’“’ and cocaine’“, 3, are known to block the noradrenaline uptake into the heart. The specificity of the action of cocaine (0.15-20 mg/kg) With infusions of .j and 20 has been investigated. pg of noradrenaline, the doses of cocaine needed for 50 per cent inhibition of net uptake of noradrenaline were 0.7 and IO mgjkg, respectively. For a given dose of cocaine, there was a significant correlation between increase of the pressor response to a test close of noradrenaline and inhibition of the noradrenaline uptake into the heart. Drugs chemically related to cocaine such as alpha-cocaine, tetracaine and atropine (IO-20 mg/ kg), did not alter the noradrenaline uptake or cause supersrnritivity towards noradrenaline. Noradrenaline uptake was unchanged after dibenamine (50 mg:kg‘i, but completely blockrd by dichloroisoprcnaline (WI, 30 mg/kg). It is concluded that injected noradrenaline not only combines with adrcnergic receptors but is storrd at other sites as well. Cocaine prevents uptake into these sites, thereby increasing the amount of noradrenaline available for combination with adrcnergic receptors. DC1 blocks both the uptake into stores and the combination with receptors. -
2. MLXHOLL, E. (1960), Ibid., 240, 8. 3. AIELROD,J., WHITBY, L. G. and HERTTING, G. (19601, .hbtrtre (Land.), 187, 604. 210 A Species cardial
Difference in Metabolism of MyoCatecholamines. F. E. SHIDEWIAN and
N. 13. GOLDBERG
(U.S.A.).
We previously demonstrated a depletion of myocardial catecholamines (LlCA) in one species (cat) and an increase in concentration of SlCA in another species (rat) in nivo by the monoamine oxidase inhibitor (MAOI), Z-trans-phenylcyclopropylamine (SKF 3851. A positive inotropic effect is produced This by SKF 385 on isolated atria of both species. action is blocked by pretreatment with dichloroisoproterenol or trimethyl (2-(2 :6-xylyloxy)-propyl)ammonium chloride and abolished or greatly reduced in preparations from reserpine-treated animals. This evidence suggests the inotropic
of Papers
65
response is effected by a release of catecholamines (CA) in both species. It is conceivable that the comparable physiological effects of SKF 385 on heart muscle from the cat and rat and the observed difference in response of MCA to administration of this MAO1 might be explained by a difference in the metabolic mechanisms available for its biotransformation in the two species. .4 study of the in Stro metabolism of norepincphrine (NE) by heart homogenates disclosed a rapid rate of metabolism by rat heart but little or no metabolism by cat heart unless ATP and r_-methionine were added. These additions did not enhance metabolism of NE by rat heart. Disappearance of NE in rat heart homogenates containing added ATP and Lmethionine was inhibited by SKF 385 but not SKF 385 did not affected significantly by catechol. inhibit metabolism of KE by cat heart homogenates supplemented with ATP and I~-rnethio~lin~ but catechol did. These results indicate that thr predominant CA inactivating enzyme in the myocardium of the rat is MAO and in the cat is catecholO-methyl transferase. 21 I The
Potentiation of Adrenaline and Noradrenaline by Cocaine on the Innervated and the Denervated Nictitating Membrane ofthe Cat. W. R. KUKOVETZ anclF. 1m.m~~~
(Austria). Consecutive doses of O.l-10.0 ug/kg adrenalin? and noradrenaline were injected intravenously to spinal cats. Contractions of both nictitating mcmbrancs one of which had been denervated one week prior to the experiment were recorded. Subsequently, 3 mg/kg ofcocaine wer,e given and the same On doses of catecholamines were Injected again. the innervated membrane the well-known potentiation of the catechol effect by cocaine occurred. On the denervated nictitating membrane, however, cocaine completely failed to potentiate the effect of adrenaline or noradrenaline. These results are in agreement with the observation of Hcrtting et al. (1961) who found that denervated tissue did not take up “H-noradrenaline. Cocaine, which presumably exerts its potcntiating effect on the action of catecholamines by blocking their unspecific receptor sites around the nerve endings and hereby making available more ratccholamines to the specific receptors, would as a result of the denervation br deprived of its substrate and, thereforc, not be able to produce potentiation. 212 The Inlluence of Isolated Artery. fCanadaj.CL
of Reserpine on the Reactivity Rabbit Aorta and Carotid N. GILLIS and C:. hf. YATES
Pretreatment of rabbits on each of 2 days before use with reserpine (2 mg/kg i.p. first day and 2 mg/ kg i.v. second day), completely abolished the secondary contraction of rabbit aorta and carotid artery which normally follows the cessation of an