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

Abstract

Abstract-The relative potency of chronotropic effects of dopamine (DA), <I>l</I>-nor epinephrine (NE), <I>l</I>-epinephrine (EP), <I>l</I>-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&gt;NE=EP&gt;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

Pharmacologic analysis of positive chronotropic and inotropic responses to octopamine.

“…Therefore, positive chronotropic and inotropic responses to octopamine were mainly due to its indirect effect on the heart. Furthermore, effects of octopamine were not influenced by tetrodotoxin which blocks effects of nicotine as reported previously (Chiba et al 1973). As tyramine effects were not prevented by tetrodotoxin (Hashimoto and Chiba 1969;Chiba 1975a, b), the indirect effect of octopamine may be due to a tyramine-like action.…”

“…The duration of action of octopamine was significantly longer than that of dopamine or norepinephrine. Previously Chiba et al (1973) demonstrated that dopamine given into the cannulated sinus node artery induced much longer sinus acceleration than norepinephrine or epinephrine. Then, it was demonstrated in the in situ and isolated atrium preparations that dopamine-induced positive chronotropic and inotropic effects were signfiicantly suppressed by treatment with desmethylimipramine (Chiba et al 1974;Chiba 1975a, b).…”

Effect of desmethylimipramine on the canine SA node.

“…When tyramine was administered into the sinus node artery, sinus accelera tion was dose-dependently induced as reported previously (James and Nadeau 1964; Chiba et al 1973). It is well known that this tyramine action is blocked by DMI treatment.…”

EFFECTS OF DOPAMINE ON SINUS RATE AND VENTRICULAR CONTRACTILE FORCE OF THE DOG HEART in vitro AND in vivo

“…These observations indicate that the sinus node preparation is more resistant to the blocking effect of DMI on the neuronal uptake of the amines (Iversen, 1967) as well as to depletion of NA by reserpine: the effect of dopamine on the sinus node is fundamentally not different from that on the papillary muscle. Thus, findings with reserpine and DMI support the view (Bejrablaya et al, 1958;Lee & Yoo, 1964;Farmer, 1966;Tsai et al, 1967;Chiba, Hashimoto & Hashimoto, 1973;Neuvonen & Westermann, 1973) that both the positive inotropic and the positive chronotropic responses to dopamine are mediated partially by a direct and partially by an indirect stimulant effect on ,B-adrenoceptors.…”