Absence of Acute Cardiac Effect of Triiodothyronine in Isolated, Blood-Perfused Canine Atrium
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Absence of Acute Cardiac Effect of Triiodothyronine in Isolated, Blood-perfused Canine Atrium Miyoharu KOBAYASHI, M.D., Yasuyuki FURUKAWA, M.D., and Shigetoshi CHIBA, M.D. SUMMARY Effects of triiodothyronine (T3) on SA node pacemaker activity, atrial contractility and on chronotropic and inotropic responses to nor- epinephrine were investigated, using 9 isolated, blood-perfused dog atrium preparations. T3 (0.001pg-0.1ƒÊg) did not cause a significant direct action injected into the cannulated sinus node artery. When T3 (10pg/ min, 40pg/min, 0.1ƒÊg/min, or 0.4ƒÊg/min) was continuously infused into the sinus node artery, both positive chronotropic and inotropic actions of norepinephrine (0.03ƒÊg-0.3ƒÊg) were not influenced. From these results, it is concluded that T3 has neither acutely direct chronotropic nor inotropic effects, and also T3 does not have an acute ef- fect on responses to norepinephrine in the isolated, blood-perfused canine atrium. Additional Indexing Words: Isolated canine atrium Triiodothyronine Norepinephrine Chronotropic effect Inotropic effect T has been known for many years that clinical manifestations of hyper- thyroidism are similar to those caused by overactivity of the sympathetic nervous system. However, considerable controversy still remains whether the cardiovascular manifestations of hyperthyroidism are due to a direct action of thryroid hormones or due to a sensitization to catecholamines. Cairoli and Crout1) reported that tachycardia in hyperthyroidism was attributed to a direct effect of thyroid hormone on pacemaker cells. Murayama and Goodkind2) reported that the enhanced developed tension of isolated atrial muscle from hyperthyroid guinea pigs was produced by a direct effect of thyroid hormone on the heart. In clinical study, Teoh et al3) postulated that sinus tachycardia in hyperthyroid patients was due to combined effects of an increased amount of thyroid homones and increased adrenergic activity of catecholamines on the heart. In contrast, Wahlberg et al4) examined that T3 caused no direct effect on the isolated cat heart, although they acutely From the Department of Pharmacology, Faculty of Medicine, Shinshu University, Matsumoto- 390,Japan. Received for publication July 11, 1978. Manuscript revised August 19, 1978. 219 I Jap.M Heart J. 220 KOBAYASHI, FURUKAWA, AND CHIBA arch, 1979 examined its direct action. In 1962, Folkman and Edmunds5) reported that thyroid hormone caused a sensitization of the myocardium to catecholamines. Furthermore, Mc- Neil and Brody6) suggested that pretreatment with T3 potentiated effect of catecholamines on rat hearts. On the other hand, Buccino et al7) reported that hyperthyroid cat papillary muscles were not hypersensitive to exogenous norepinephrine. Wilson et al8) also confirmed that thyroid hormone did not augment the hemodynamic responses to catecholamine. The present investigation was undertaken to study direct effects of T3 and influences of T3 on responses to norepinephrine in the isolated, blood-perfused canine atria. MATERIALS AND METHODS Nine mongrel dogs weighing from 10 to 20Kg were anesthetized with sodium pentobarbital, 30mg/Kg i.v. After treatment with 2,000 unit of sodium heparin i.v., the right atrium was excised and immerged into a cold Tyrode solution at 4•K- 10•Ž. The sinus node artery was cannulated via the right coronary artery and perfused with arterial blood conducted from the carotid artery of the donor dog by the aid of a peristaltic pump (Harvard Apparatus Model 505-1200). The per- fusion pressure was maintained at 100mmHg. The atrium was suspended in the bath filled with blood at a constant temperature of 37•Ž. The upper part of the crista terminalis of the atrium was connected directly to a force displacement trans- ducer (Grass FTO3B) by a silk thread. The donor dogs weighing 12 to 25Kg were also anesthetized with 30mg/Kg of sodium pentobarbital i.v. Sodium heparin, Table I. Effect of T3 on the Responeses to Norepinephrine in Pacemaker Results are given as mean•}S.E.M. Control sinus rate was 99•}3beats/min in 5 preparations. Vol.20 No.2 T3 ON SA NODE AND CONTRACTILITY 221 500units/Kg, was intravenously administered at the beginning of the perfusion and 2,000 units were added at 1-hr intervals. The flow rate at 100mmHg of the perfusion pressure was 4.5-5.0ml/min. Bipolar platinum electrodeswere placed in contact with atrial epicardium. The atrial rate was measured with a cardiotacho- graph triggered by the signal from the atrial depolarization of an electrogram. The isometric tension development was recorded on an ink-writing rectigraph (Sanei Sokki Instrument) through a carrier preamplifier (Nihon Kohden RP-3), RC circuit and a high amplifier (Nihon Kohden RPH-2). Details of the iso- lated, blood-perfused canine atrial preparations were described in previous pa- pers9),10). The systemic arterial blood pressure and heart rate of the donor dog were measured from a cannulated femoral artery with a pressure transducer (Nihon Kohden RP-2) and a cardiotachograph triggered by the pulse pressure, respec- tively. The drugs used in these experiments were sodium-L-triiodothyronine (Takeda, kindly furnished by Dr. M. Miyakawa, Department of Surgery, Faculty of Medicine, Shinshu University, Matsumoto), (•})-norepinephrine hydrochloride (Sankyo). The volume of drug solution injected into the sinus node artery was 0.01 to 0.03ml and given by a microsyringe (Terumo Co) in a period of 4sec. T3 was continuously infused into the sinus node artery with an infusion pump (Harvard Apparatus 901). T3 was also administered into the jugular vein of the donor dog. RESULT ‚r 1. Absence of chronotropic and inotropic responses to T3 injected into the sinus node artery: T3 has neither direct chronotropic nor inotropic action on SA node when Activity and Contractility in 5 Isolated Dog Atrial Preparations All values were not significant when compared with control values (t-test). Jap. Heart J. 222 KOBAYASHI, FURUKAWA, AND CHIBA March, 1979 Fig. 1. Chronotropic and inotropic responses to increasing doses of triiodothyronine (T3) when injected into the sinus node artery of an isolated, blood-perfused atrium preparation of the dog. Fig. 2. Absence of potentiation of responses to norepinephrine (NE) by an infusion of triiodothyronine (T3) on an isolated, blood-perfused atrial muscle of the dog. T3 was injected into the cannulated sinus node artery in a dose range of 0.001ƒÊg to 0.1ƒÊg in all 6 experiments. In 2 out of 6 preparations, T3 pro- duced a negative inotropic action over the dose of 0.3ƒÊg or 1 to 3ƒÊg (Fig. 1). The maximum decrease was approximately 20% when compared with values of control tension. On the other hand, in chronotropism, a larger amount of T3 caused a slight negative chronotropic effect but not usually. As shown in Fig. 1, 3ƒÊg of T3 produced a clear decrease in atrial rate in this case, but in other 5 cases, 3ƒÊg of T3 did not induce so distinct negative chronotropic effect. 2. Absence of potentiation of responses to norepinephrine by a continuous infusion of T3: When T3 was continuously infused into the cannulated sinus node artery with an infusion rate of 10pg, 40pg, 0.1ƒÊg, or 0.4ƒÊg/min, both sinus rate and developed tension did not show any change. As shown in Fig. 2, nore- pinephrine-induced positive chronotropic and inotropic effects were not in- fluenced by a continuous infusion of T3. Summarized data are demonstrated in Fig. 3 and Table I. The positive chronotropic responses to norepinephrine were slightly depressed during an infusion of T3 but not significantly. On the other hand, the positive ones were rather slightly potentiated by an infusion Vol.20 No.2 T3 ON SA NODE AND CONTRACTILITY 223 Fig. 3. Effects of a continuous infusion of triiodothyronine (T3) on norepinephrine (NE) dose-response curve in 5 isolated dog atria. •œ-•œ =NE only • -• =NE+T3 infusion (10pg/min) •¤-•¤ =NE+T3 infusion (40pg/min) •¡-•¡ =NE+T3 infusion (0.1beg/min) =NE+T3 infusion (0.4beg/min) Control sinus rate was 99•}3beats/min in 5 preparations. Standard errors were not shown for clarity. of relatively larger doses of T3 but not significantly. 3. Chronotropicand isotropic responsesof isolated atria when T3 was injected into the jugular vein of the donor dog: When T3 was administered into the jugular vein of the donor dog, a slight decrease of the systemic blood pressure was observed in 2 experiments. As shown in Fig. 4, 30pg/Kg of T3 caused a slight decrease in the arterial blood pressure of the donor dog. In this case, a decrease in the developed tension of the isolated atrium occurred approximately 2min after the onset of detectable hypotension of the donor dog since the time to pass through the Jap. Heart J. M 224 KOBAYASHI, FURUKAWA, AND CHIBA arch, 1979 Fig. 4. Chronotropic and inotropic responses on an isolated, blood- perfused atrial preparation when 30ƒÊg/Kg of triiodothyronine (T3) was ad- ministered into the jugular vein of the donor dog. circuit was 2min. Any change in atrial rate, however, did not occur. DISCUSSION The present results showed that, in the isolated, blood-perfused canine atrium, T3 when injected into the cannulated sinus node artery produced neither significant chronotropic nor inotropic effects, and an infusion of T3 never significantly potentiated the positive chronotropic and inotropic re- sponses to norepinephrine. In acute experiments, there were a few available reports on effects of T3 on heart function. Wahlberg et al4) reported that T3 did not have any direct inotropic nor chronotropic effects of its own on isolated cat heart preparations when T3 was given acutely. In the present experiments, we also agreed with their results, using the isolated dog atrial preparations, although extremely larger doses of T3 occasionally produced slightly negative chronotropic and inotropic effects. On the other hand, in the observation of chronic animals or human beings, there have been a lot of reports on the effects of T3.