Adrenergic Mechanisms in the Sinus Node

James, Thomas N.; Bear, Edward S.; Lang, Klaus; Green, Edward W.; Winkler, Helen H.

doi:10.1001/archinte.1970.00310030123017

Cited by 44 publications

(6 citation statements)

References 105 publications

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“…Thus it is that the special dopamine receptor has come to be accepted in general. The previous report (12), how ever, showed that the acceleration response to dopamine can be blocked by adrenergic beta-blocker. Thus, we suggest that the concentrated dopamine into the SA node area plays a physiological role as the precursor of norepinephrine.…”

Section: Methodsmentioning

confidence: 92%

Comparative Study of Chronotropic Effects of Catecholamines and Tyramine on the Sa Node of the Dog Heart in Situ

Chiba

Hashimoto

1973

Jpn.J.Pharmacol

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Abstract-The relative potency of chronotropic effects of dopamine (DA), l-nor epinephrine (NE), l-epinephrine (EP), l-isoproterenol (ISO) and tyramine (TY) was determined by direct application into the sinus node artery of the in situ canine heart (n=10), which was treated with atropine. The order of potencies of chronotropic effect of these amines was ISO>NE=EP>DA ?? TY. The ratio of doses required to produce 50% increase in sinus rate was ISO: NE: EP: DA: TY=1/30: 1: 1: 10: 10. At any dose level for inducing the same grade of sinus acceleration, the duration of action of NE and EP was almost equal and short, while that of ISO was usually long er. The duration of action of DA was short at a lower dose level but became equal to ISO with a medium dose. At a larger dose to produce a maximum response, DA acted longer than ISO, which indicates direct effect of DA with induction of indirect effect of catecholamine release. This suggest a tyramine-like action of DA.Concerning the potency of catecholamines to produce a positive chronotropic response, there are a considerable number of elaborate studies already published. These were re viewed by Trautwein (1) in 1963 and briefly summarized as follows: 1-Norepinephrine was slightly more potent than 1-epinephrine for an acceleration of the sinus pacemaker (2-6), and isoproterenol was found from 10 to 15 times more potent than 1-norepinephrine and ]-epinephrine (7). More important developments followed. James and Nadeau (8) established an unique technique for perfusion of the SA node artery of in situ heart of the dog and compared doses of epinephrine, norepinephrine and isoproterenol to pro duce a maximum tachycardia by direct application into the sinus node artery (9). In 1965, Angelakos (10) investigated the regional distribution of catecholamines in the dog heart and found that dopamine was particularly concentrated in the SA node region. Then Rolett and Black (11) in 1966 compared potencies of dopamine and norepinephrine by infusing both catecholamines into the sinus node artery of the canine heart and found that both amines produced a similar dose-dependent increase of sinus rate with dopamine be ing approx. one-tenth as potent as norepinephrine.Later similar results were obtainedby James et al. (12).Previously found that the administration of dopamine, nor epinephrine and epinephrine from 0.1 to 10 /zg often induced a deceleration of the sinus rate, while isoproterenol never induced such a deceleration response. The participation of a cholinergic mechanism in this deceleration response was confirmed by blocking it

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Section: Methodsmentioning

confidence: 92%

Comparative Study of Chronotropic Effects of Catecholamines and Tyramine on the Sa Node of the Dog Heart in Situ

Chiba

Hashimoto

1973

Jpn.J.Pharmacol

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“…Quantitative analysis of the reduced responsiveness to sympathetic stimulation was difficult to determine, since injected norepinephrine was also shown to be less active after 6-OH-DA although the responsiveness to injected norepinephrine was diminished to a lesser degree (P<0.05 only at 15,000 fig) than the responsiveness to stellate stimulation. Moreover, analysis is complicated by the fact that the concentration of neurotransmitter at the surface of the pacemaker cells in the sinus node after sympathetic stimulation could be greater than that obtained after injection of 10 fig of norepinephrine (19). The reduced responsiveness to sympathetic stimulation in the present study is in part due to reduced effect of norepinephrine and also to a decrease of the amount of norepinephrine released by nerve terminals, as suggested by other investigators (18).…”

Section: Figurementioning

confidence: 43%

Effects of 6-Hydroxydopamine on the Canine Sinus Node

Elharrar

Champlain

Nadeau

1971

Circulation Research

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The acute effects of 6-hydroxydopamine (6-OH-DA) injected directly into the sinus node artery were studied in 57 dogs. The positive chronotropic effect of 6-OH-DA was intermediate between that of norepinephrine and that of tyramine, when these substances were compared on the basis of their ED 50 . The increase in heart rate produced by 6-OH-DA was inhibited by prior intranodal injection of propranolol and desmethylimipramine. At high doses, injection of 6-OH-DA was often associated with arrhythmias such as periodic slowing of the sinus rate, atrial premature beats, atrial fibrillation, and ventricular extrasystoles. In the 72 hours following injection of 1.5 mg 6-OH-DA, the norepinephrine content of the sinus node region decreased progressively. In agreement with the norepinephrine depletion, response to intranodally injected tyramine was significantly diminished. The number of fluorescent adrenergic nerve fibers was also reduced. Impaired norepinephrine uptake and enhanced release were also demonstrated by using tritiated norepinephrine. After 6-OH-DA treatment, response to right stellate stimulation was diminished, and the response to vagal stimulation was not altered. It was concluded that the local perfusion of the sinus node with 6-OH-DA produces a marked norepinephrine depletion of the perfused region compatible with a localized degeneration of the sympathetic nerve terminals. KEY WORDSadrenergic nerve terminals cardiac arrhythmias right stellate ganglion stimulation tyramine histofluorescence uptake and release of norepinephrine • Studies on the autonomic innervation of the heart indicate that this organ is richly innervated but that innervation of the sinoatrial and atrioventricular nodes is denser than that of other cardiac regions (1, 2). The role of the adrenergic system in the control of the heart rate and contractility has been studied by various procedures such as surgical denervation, immunosympathectomy, or use of substances interfering with norepinephrine synthesis, storage mechanisms, or the action on receptors. Each of these techniques has some disadvantages in producing incomplete sympathetic denervation, requiring high technical skill, or affecting functions unrelated to the sympathetic system. Recent studies (3-5) have shown that 6-OH-DA produces a specific degeneration of adrenergic nerve terminals, without affecting surrounding Schwann cells, smooth muscle cells, and cholinergic nerve terminals. This compound constitutes a new means for producing sympathectomy and thus provides a more specific approach to evaluate the role of the sympathetic nervous system. The possibility of producing a local adrenergic denervation of the sinus node was studied by injecting 6-OH-DA into the sinus node artery. The effects of 6-OH-DA on heart rate, metabolism of norepinephrine, and disappearance of fluorescence of adrenergic nerves were 188

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“…This dopamine-induced positive chronotropic effect in heart-lung preparation has already been reported (23). Although this difference in the positive chronotropic effect of dopamine between the in vivo and heart-lung preparation is not clearly elucidative, it has been reported that the disparity between rate and contractility is not due to lack of effect of dopamine on the SA node since norepinephrine and dopamine infused into the sinus node artery of the dogs produce a similar dose-dependent rate increase though dopamine is approximately 1/10 as potent as norepinephrine (24,25).…”

Section: Resultsmentioning

confidence: 95%

A Possible Mode of Cardiovascular Actions of Dopamine in Dogs

Furukawa

Ono

Maeda

et al. 1976

Japanese Journal of Pharmacology

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Abstract-A possible mode of cardiovascular actions of dopamine was studied using ephedrine. In the dog pretreated with repeated administrations of ephedrine (total dose, 40 or 80 mg/kg, i.v.) or with combined administrations of ephedrine (total dose, 90 mg/ kg, s.c. and i.v.) and reserpine (2 mg/kg, s.c., 24 hr previously), pressor responses to dopamine were eliminated and reversed to depressor responses whereas depressor responses to dopamine were potentiated.Positive chronotropic effects of dopamine were almost eliminated. Pressor and positive chronotropic effects of tyramine were almost abolished.Sympathomimetic effect of noradrenaline and adrenaline were potentiated while those of isoprenaline were inhibited. In the heart-lung preparation of ephedrine-treated dogs (total dose, 40 mg/kg, i.v.), cardiac stimulating effects of dopamine and tyrarnine were strongly depressed, and those of noradrenaline, adrenaline and isoprenaline were reduced to some extent. In the open-chest dogs, after pretreatment with cocaine (4 mg/kg, i.v.), pressor, positive inotropic and chronotropic effects of noradrenaline were potentiated whilst those of tyramine were inhibited. Those of dopamine were not visibly altered, but depressor, negative chronotropic and inotropic effects of dopamine appeared at small doses. In the ephedrine-pretreated dogs, these sympathomimetic effects of dopamine and tyramine after cocaine were strongly de pressed and those of noradrenaline were inhibited to a certain degree. The results obtained with ephedrine suggest that dopamine differs from other catecholamines and tyramine in the mode of cardiovascular actions.Studies have shown that sympathomimetic agents can be classified in their mode of action as acting directly on the receptors, acting indirectly on the adrenergic nerve terminals and those with mixed action, these classifications being principally based on the modifications in the effects after pretreatment by chronic denervation, cocaine or reserpine (1). Concerning dopamine, other workers reported modifications in responses to dopamine by denervation or cocaine led to classification of dopamine as a directly-acting amine (2-4). As results in the reserpine-pretreated animals are considered to be of importance in order to confirm the concept of direct and indirect effect, dopamine, although it has direct sympathomimetic actions, does to some extent act indirectly (5, 6). Farmer (7) reported that the pressor effect of dopamine was slightly potentiated while the positive chronotropic effect was reduced slightly 24 hr after reserpine in the cat. We have already observed that the pressor response to dopamine was potentiated 24 hr after pretreatment with reserpine (8), whereas the re This work was funded by grants from the Ministry of Education, Japan, and from the Kanae Foundation for Medical Research

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Adrenergic Mechanisms in the Sinus Node

Cited by 44 publications

References 105 publications

Comparative Study of Chronotropic Effects of Catecholamines and Tyramine on the Sa Node of the Dog Heart in Situ

Comparative Study of Chronotropic Effects of Catecholamines and Tyramine on the Sa Node of the Dog Heart in Situ

Effects of 6-Hydroxydopamine on the Canine Sinus Node

A Possible Mode of Cardiovascular Actions of Dopamine in Dogs

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