Effects of orciprenaline on the sinoatrial and atrioventricular nodes in presence of hypoxia

Journal

of Molecular

and Cellular

Cardiology

( 1980)

Effects of Orciprenaline Atrioventricular Nodes JOCHEN SENGES, ELLEN DIETER PELZER, TETSUO The Abteilung

Innere

(Received

on the Sinoatrial and in Presence of Hypoxia

HENNIG, MIZUTANI

Meditin III Bergheimerstr.,

14 August

12, 135-l 47

JOHANNES BRACHMANN, AND WOLFGANG KUBLER

(Kardiologie), Medizinische 69 Heidelberg, Germany

1978, accepted in revisedform

Universitdtsklinik,

6 June

1979)

J. SENGES, E. HENNIG, J. BRACHMANN, D. PELZER, T. MIZUTANI AND W. K~~BLER. Effects of Orciprenaline on the Sinoatrial and Atrioventricular Nodes in Presence of Hypoxia. Journal of Molecular and Cellular Cardiology (1980) 12, 135-147. The effects of orciprenaline on the isolated, superfused sinoatrial (SA) and atrioventricular (AV) nodes of the rabbit heart were studied under normoxic and hypoxic conditions. Transmembrane action potentials were recorded simultaneously with the extracellular His bundle electrogram. At PO, 460 nmHg, orciprenaline lo-* to 4 x 10-O M increased SA nodal automaticity and shortened conduction time in the AV node. At moderate hypoxia (PO, 130 mmHg), the positive chronotropic response to orciprenaline resembled that obtained under normoxic conditions. At severe hypoxia (PO, 40 mmHg), orciprenaline 4 x 1O-6 M increased sinus rate and shortened AV conduction only during a short initial period after drug administration. Thereafter, marked sinus bradycardia and complete sinoatrial and atrioventricular block occurred associated with a pronounced decrease in action potential to amplitude of SA and AV nodal fibers. Following reoxygenation, normal A\’ conduction could be restored by administration of 4 x 10-s M orciprenaline. Intra-atria1 conduction time and atria1 action potential amplitude were not significantly affected by orciprenaline either under normoxic or under hypoxic conditions, and no rapid ectopic activity was observed. The results indicate that 4 x lOms M orciprenaline restore the reduced nodal function at moderate hypoxia but markedly potentiate the depression of automaticity and conduction in SA and AV nodes at severe hypoxia. KEY

Anoxia;

WORDS:

Sudden

Slow response; death.

Calcium-dependent

action

potentials;

Catecholamines;

1. Introduction The striking increase in mortality from asthma between 1960 and 1966, particularly in the younger age groups, has been attributed to increased use and even abuse of aerosols containing sympathomimetic drugs [9, 23, Z-21. Death occurs often sudden and unexpected in these patients and, therefore, it was suggested Address for reprints: Jochen Senges, M.D., Medizinische Universitatsklinik, 69 Heidelberg, Germany. This work was presented in part at the 1977 meeting of the Deutsche Medizin, Wiesbaden, at the International Symposium on Beta-blockade and at the Symposium on Cardiac Arrhythmias in Korfu, 1979. 0022-2828/80/010135+

13 $02.00/O

0 Academic

Bergheimer Gesellschaft fiir in Rottach-Egern,

Press Inc.

(London)

Str. 58, Innere 1977 Limited

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ET AL.

that it might result from sympathomimetic cardiac arrhythmias including ventricular tachycardias and fibrillation [23]. H owever, the electrocardiographic alterations preceding sudden death in asthmatic patients have rarely been observed [13] and increased ventricular irritability has not yet been reported to our knowledge. On the contrary, studies on the action of isoprenaline on hypoxic dogs led to the suggestion that sudden death was from cardiac asystole, rather than from ventricular fibrillation [5]. However, the cellular electrophysiological events which might facilitate bradycardias occurring in the presence of isoprenaline plus hypoxia have not yet been determined. The present experiments were performed in order to examine the combined effects of hypoxia and orciprenaline on the electrical activity of the sinoatrial and atrioventricular nodes. Orciprenaline was chosen because this sympathomimetic drug is widely used in West Germany not only for asthmatic treatment but also for the management. of bradycardias. 2. Methods Rabbits weighting 2 to 3 kg were killed by a single blow. The heart was rapidly removed and dissected in an oxygenated Tyrode’s solution of the following millimolar composition [3]: NaCl 107.7; KC1 3.48; CaCl, 1.53; MgSO, 0.69; NaHCO, 26.2; NaH,PO, 1.67; Na gluconate 9.64; glucose 5.55; sucrose 7.6. The preparation consisting of sinoatrial node, crista terminalis, pectinate muscles of the atria1 appendage, intraatrial septum, coronary sinus, atrioventricular node and His bundle [17] was mounted in a 15 ml tissue bath and superfused at a rate of 30 ml/min with Tyrode’s solution at 36 * 0.5”C. A mixture of 95:; 0, and 5% CO, was admitted directly to the chamber through a fine sintered glass disc and also to the Tyrode’s solution. Measurements of PO, (460 * 25 mmHg), PCO, (42 & 1.5 mmHg) and pH (7.4 * 0.02) were made by withdrawing samples of Tyrode’s solution from the vicinity of the tissue preparation and analyzing them with a pH/gas analyzer (radiometer Copenhagen). Transmembrane action potentials were recorded simultaneously from two sites of the preparation by means of floating microelectrodes. At each site, action potentials were recorded only from the most superficial subendocardial fibers. Earlier experiments using interstitial PO, and potassium sensitive microelectrodes have shown that under control conditions the subendocardial layers at depths above 100 [r are adequately oxygenated and demonstrate no significant variations of the extracellular K+ activities [21]. An extracellular His bundle electrogram was recorded through a close bipolar electrode. In the SA node, transmembrane action potentials were recorded from different SA nodal cells within an identifiable small area in presence of different test solutions. Atria1 transmembrane potentials were recorded from single fibers of crista terminalis near the SA node. Atrioventricular nodal action potentials were recorded from the lower (NH) regions

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ON

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137

FIBERS

according to action potential configuration and timing in relation to the extracellular His bundle electrogram. The following parameters of automaticity and conduction were measured: sinoatrial nodal rate; corrected sinus-node recovery time, i.e., the recovery interval after rapid atria1 stimulation (cycle length 280 ms; duration 1 min) in conduction times, the atrium was excess of the basic cycle [15]. F or measuring stimulated through bipolar electrodes placed on the right atria1 appendage at a constant cycle length. The stimulus was a square pulse 2 ms long and twice threshold and was suitably isolated from ground. Sinoatrial conduction could not quantitatively be determined because of the frequent appearance of diastolic prepotentials in SA nodal fibers; therefore, only the occurrence of complete sinoatrial block was evaluated. Intraatrial conduction was measured at constant atria1 cycle length (280 ms) as the interval between the stroke up of the atria1 action potential recorded tit the upper part of the crista terminalis and the extracellular atria1 electrogram near the AV node, AV nodal conduction was determined after excision of the SA node permitting the preparation to be driven at a longer cycle length (660 ms). Total Ay nodal conduction was measured as the interval between atria1 and His deflection in the extracellular His bundle electrogram. The following experimental protocol was used. In a first series of experiments, orciprenaline sulfate (Boehringer Ingelheim) was added to the control solution resulting in final concentrations of lo-*, 10e7, 10es and 4 x 10eg M. The preparation was exposed to each concentration of drug for 20 to 30 min. Thereafter, the drug was washed out for 30 min. In a second series of experiments, hypoxia was induced by substituting either 60% O,-35% N,-5% CO, or 9596 N,-59; CO, for the control gas. The pH and PCO, remained unchanged with either gas mixture. The PO, fell ta 130 i. 20 (moderate hypoxia) and 40 & 10 mmHg (severe hypoxia) in presence of 60% O,-35% N,-5% CO, and of 95O6 N,-50/, CO, respectively. The effects of hypoxia alone on the electrical parameters were determined after 60 min. In a third series of experiments, moderate or severe hypoxia was induced first for 30 min and the combined effects of hypoxia plus orciprenaline were determined during the subsequent 30 min.

3. Results Eject of orciprenaline

on oxygenated sinoatrial

and atrioventricular

nodes

Superfusion of the normally-oxygenated SA node with Tyrode’s solution ing orciprenaline in concentrations of 10-a to 4 x 1OW M increased rate at all concentrations exceeding IO-8 M (Figure 1) but failed to corrected sinus-node recovery time significantly (control 85 f 45

containthe sinus alter the ms and

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SENGES

ET

AL.

4 x 1O-6 M orciprenaline 95 -& 60 ms; n = 6). Typical recordings demonstrating the effects of 4 x 1O-s M orciprenaline at constant atria1 cycle length (280 ms) are shown in Figure 2. The retrograde sinoatrial conduction could not be evaluated because of the occurrence of abortive diastolic prepotentials in SA nodal fibers. The intraatrial conduction time remained unchanged (control 25 & 7 ms and 4 x 1O-6 M orciprenaline 25 & 8 ms, n = 6). The AV nodal conduction was shortened (Figure 2) which became, however, less apparent at slower atria1 rates. The effects of orciprenaline on automaticity and conduction are similar to those of other beta-adrenergic catecholamines and are in general agreement with the findings of others [IO, 281.

)-

l-

CON

10-8

I o-6

10-7 Orciorenaiane

4x10-6

iM)

FIGURE 1. Effects of increasing doses of orciprenaline on sinus rate in the presence of different degrees of hypoxia. Each value represents the mean value &SD. (n = 6) of the SA nodal rate. CON, control rate determined after 60 min at the respective PO, in the absence of orciprenaline. Test values at the indicated orciprenaline concentrations were obtained 30 min after administration of the drug following a preceding 30 min period at the respective PO, without orciprenaline.

Efect of orciprenaline

on automaticity

and conduction in presence of hypoxia

During hypoxia alone, sinus rate fell abruptly but then declined more gradually after 15 to 30 min (Figure 3). The hypoxic control rates determined after 60 min presence of different oxygen concentrations are shown in Figure 1. While the

ORCIPRENALINE

ON

HYPOXIC

intraatrial conduction was not significantly ventricular conduction was significantly complete SA or AV nodal block occurred.

NODAL

changed prolonged

FIBERS

139

during hypoxia, the atrio(Figure 7). However, no

Urclprenollne

200msec

FIGURE 2. Effect of 4 x 10-s M orciprenaline on sinoatrial, intraatrial and atrioventricular nodal conduction. In each section, the top trace is a record from different sinoatrial nodal fibers, the middle trace shows different atria1 action potentials recorded from the crista terminalis 1 mm within the SA node, the bottom trace is a His bundle electrogram demonstrating an initial atria1 and a following His bundle deflection. Atria1 cycle length 280 ms. Note SA nodal diastolic prepotentials, and decrease of AH interval 5 min after addition of orciprenaline.

E$ects of orciprenaline

on the hypoxic SA node

The effects of increasing concentrations of orciprenaline on the sinus rate in presence of moderate (PO, 130 & 20 mmHg) and severe hypoxia (PO, 40 f 12 mmHg) are illustrated in Figure 1. At moderate hypoxia, the doseresponse curve was shifted to lower rates but exhibited a similar course to that obtained under normoxic conditions. At severe hypoxia, orciprenaline caused consistent increase in sinus rate only at lower concentrations (IO-’ to 10e6 M). The time course of the effect of 4 x 1O-6 M orciprenaline on the sinus rate under normoxic and severe hypoxic conditions is illustrated in Figure 3 and typical records are shown in Figure 4. When orciprenaline was administered to the SA node in presence of severe hypoxia, spontaneous rate markedly increased within the initial 10 min associated with an increase in diastolic slope. However, this effect was only short-lasting and SA nodal electrical activity was severely depressed after 30 min. Slowing of spontaneous activity was accompanied by a reduction in diastolic slope, decrease in action potential amplitude and irregular faiiure of impulse initiation. Statistical evaluation of transmembrane action potential parameters was omitted since the marked positive inotropic effect of orciprenaline made it very difficult to maintain impalements of single SA nodal fibers for a prolonged period. The sinoatrial conduction was also markedly depressed after administration of

140

J. SENGES

ET

AL.

4 x 1O-6 M orciprenaline to the isolated SA node in presence of severe hypoxia. Complete sinoatrial block associated with marked depression and fragmentation of the SA nodal electrical activity was observed in 5/6 of the experiments (Figure 4, bottom right panel). A remarkable experiment is demonstrated in Figure 5 recorded 10 min after drug administration. Although the preparation was severely hypoxic, the SA nodal fiber was only moderately depressed demonstrating action

I

I

I

I

I

I

I

-30

-20

-10

0

IO

20

30

Hypoxm t

I

40 (min

4 x IO+ M Orciprenoline t

FIGURE 3. Time course of individual and combined effects of hypoxia and orciprenaline on sinus rate. Mean values fs.~. obtained from 6 experiments. 0 after a 30 min control period orciprenaline was administered under normoxic conditions at 0 min (indicated by arrow). l hypoxia was induced first at -30 min (indicated by arrow) and orciprenaline was added at 0 min.

potentials of sufficient amplitude with respect to impulse propagation and a relatively high rate of spontaneous depolarization. However, the SA nodal impulses are not conducted to the atrium which is driven by an independent pacemaker at a much slower rate. Retrograde sinoatrial conduction was also blocked as demonstrated by rapid atria1 stimulation (Figure 5)‘. Therefore, no true sinus node recovery time could be determined. However, the lower pacemaker driving the atrium showed a marked poststimulatory suppression exceeding 10 sec. Sinoatrial block was not observed in presence of moderate hypoxia plus 10-s to 4 X 10dE M orciprenaline.

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ON

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NODAL

FIBERS

141

Hypoxia

HYPOXIO

Orclprenollne

.

5 ml”

000

30 mln

msec

FIGURE 4. Combined effects of hypoxia and orciprenaline on SA nodal and atria1 action potentials and on atrioventricular conduction. In each section the top trace is a recording from different SA nodal fibers, the middle trace shows different atria1 action potentials from the upper crista terminalis and the bottom trace is a His bundle electrogram. Top left panel, control at PO, 460 mmHg. Top right panel, hypoxia 30 min at PO, 40 mmHg. Bottom panels, 3, 5 and 30 min after administration of 4 x 10-s M orciprenaline in presence of hypoxia. Note initial increase in sinus rate (bottom left panel) followed by complete AV block (bottom middle panel) and marked depression of SA nodal electrical activity including sinoatrial block (bottom right panel). Hypoxto

0

f Orciprenohe

0 ____

-8OmV

0 set

FIGURE 5. Effect of orciprenaline on sinoatrial conduction and sinus-node recovery time in presence of hypoxia (PO, 40 mmHg). The top trace is a record from a SA nodal fiber and the bottom trace shows records from an atria1 fiber. Note complete sinoatrial block 10 min after administration of 4 x 1O-B M orciprenaline to the hypoxic preparation. Rapid atria1 stimulation fails to affect the sinus rate but the poststimulatory pause of the lower atria1 pacemaker is markedly prolonged.

142

J. SENGES

Effect of orciprenaline

ET AL.

on the hypoxic atrium

The action of orciprenaline on the electrical activity of the right of severe hypoxia was less dramatic than on the SA node. The tion time was not significantly altered (hypoxic control 27 & plus 4 x 1O-6 M orciprelanine 28 & 9 ms) and the values potential amplitude were not significantly different when all marized (hypoxic control 96 & 11 mV and. hypoxia plus prenaline 100 * 10 mV; n = 6). Effect of orciprenaline

on the hypoxic atrioventricular

atrium in presence intraatrial conduc8 ms and hypoxia for atria1 action results were sum4 x 1OW M orci-

node

Similar to the action on the SA node, 4 x 1O-6 M orciprenaline markedly depressed the electrical activity of the AV node in presence of severe hypoxia. Following a short-lasting decrease in both conduction time and effective refractory period of the AV node by 20 and 5Oqb, complete intranodal block occurred in 6/6 of the experiments within 30 min. The combined effects of increasing concentrations of orciprenaline in presence of various degrees of hypoxia on the AV nodal conduction are summarized in Figure 7 and typical records obtained from the same single lower (NH) AV nodal fiber are shown in Figure 6. In contrast to the simultaneously recorded atria1 action potential, the amplitude of the AV nodal action potential was markedly depressed associated with a pronounced prolongation of the nodal conduction preceding complete Hypoma

Hypouo

/ w--’ -4 ,,’ .---ye--r

f OrclpWKllne

40 msec IJ

FIGURE 6. Effect of orciprenaline on atria1 and lower AV nodal action potentials and conduction in presence of hypoxia. In each section, the top trace shows records from an atria1 fiber from the upper crista terminalis, the middle trace is a record from the lower AV node and the bottom trace is a His bundle electrogram. All action potentials were recorded from the same respective fibers for the duration of the experiment. Atria1 cyclic length was 660 ms. Left panel, hypoxia 30 min at PO, 40 mmHg. Right panel, 15 min after administration of 4 x 10-s M orciprenaline in presence of hypoxia. Note increase in amplitude and duration of the atria1 action potential associated with normal atria1 conduction after exposure to orciprenaline but marked decrease of the AV nodal potential associated with prolongation of the AV conduction time.

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FIBERS

atrioventricular block. At moderate hypoxia, orciprenaline 4 x 1O-6 M induced 3 : 2 AV nodal blocks type Wenckebach in 316 of the experiments. At reoxygenation following severe hypoxia, complete AV block was found to persist irreversibly in absence of orciprenaline. However, when 4 x 1O-s M orciprenaline were administered to the reoxygenated AV node, block of the intranodal conduction disappeared and impulse propagation was restored to normal values although the sinus rate had markedly increased (Figure 8).

4. Discussion The present experiments were derived from the clinical observation suggesting a relationship between increase in sudden death of asthmatic patients and the excessive use of aerosols containing sympathomimetic amines [23]. The experimental results demonstrate the regular occurrence of severe bradycardias including sinus bradycardia and complete sinoatrial and atrioventricular blocks in presence of both high concentrations of orciprenaline and severe hypoxia. Basically,

I

I CON

I 10-a

I 10-7

Orciprenollne

I 10-6

I

4x10-a

(M )

FIGURE 7. Effect of increasing doses of orciprenaline on atrioventricular conduction time in presence of different degrees of hypoxia. Each value represents the mean value &s.D. (n = 6) of AV nodal conduction time obtained at a constant atria1 cycle length (660 msec). CON, control values determined after 60 min at the respective PO, in the absence of orciprenaline. Test values at the indicated orciprenaline concentrations were obtained 30 min after administration of the drug following a preceding 30 min period at the respective PO, without orciprenaline. Horizontal bar at the top of the graph indicates AV block.

144

J. SENGES

ET

AL.

similar depression of automaticity and conduction was also observed with hypoxia alone which was, however, markedly potentiated after administration of orciprenaline resulting in critical inhibition of SA and AV nodal electrical activity. The experiments provide no evidence of increased irritability or initiation of tachyarrhythmias as has been earlier suggested [23]. The degree of hypoxia was found to represent an important factor facilitating the depressant action of orciprenaline on nodal action potentials. Thus, complete SA and AV nodal blocks occurred only in presence of severe hypoxia plus orciprenaline but sinus rate was increased by orciprenaline during moderate hypoxia. Hypoxia alone regularly failed to cause complete block of conduction. Reoxygenoilon

.+----------.

Orclprenallne

---+

-c---

---+---I

200 msec

FIGURE 8. Effect of orciprenaline on complete atrioventricular nodal block during reoxygenation. In each section the top trace is a record from the SA node, the middle trace shows atria1 action potentials from the upper crista terminalis and the bottom trace is a His bundle electrogram. Left panel, complete AV block persisting 60 min after reoxygenation and washout of 4 x 10eB M orciprenaline. Right panel, increase in sinus rate, appearance of diastolic prepotentials and 1: 1 atrioventricular conduction 15 min after administration of 4 x lo-” M orciprenaline.

The PO, values obtained in these experiments were 30 to 50 mmHg when the depressant response to orciprenaline was obtained. Clinically, several authors have reported PO, levels below 40 mmHg in patients with status asthmaticus and they also demonstrated that in hypoxaemic patients the PO, may fall even further when adrenaline was administered [S, 181. It should be noted that in isolated preparations exacerbation of the hypoxic depression of the nodal electrical activity occurred only at high concentrations of orciprenaline that are not achieved in the blood of patients by inhalation. The present results cannot, therefore, be related to the clinical situation. However, studies on whole animals demonstrated death from cardiac asystole rather than from ventricular fibrillation in hypoxic dogs following administration of isoprenaline at concentrations that are comparable to therapeutic doses in men [13]. This is corroborated by an

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145

observation in a patient in status asthmaticus who developed progressive bradycardia and cardiac asystole almost immediately following administration of salbutamol aerosol [13]. In contrast to the combined effects of orciprenaline in presence of hypoxia, this drug was found to increase SA nodal automaticity and to shorten AV nodal conduction in absence of hypoxia confirming earlier reports with other betaadrenergic catecholamines [S, 10, 12, 281. That adrenaline increases the slope of diastolic depolarization of SA nodal action potentials is well known but the ionic basis for this positive chronotropic effect is still uncertain. In cardiac Purkinje fibers, adrenaline has been reported to accelerate spontaneous activity by inducing a voltage shift of the potassium outward current activation curve [2.5]. A quite different mechanism of the effects of adrenaline on membrane current underlying pacemaker activity was observed in frog atria1 fibers demonstrating (1) an increase in the outward current but with unaltered activation range and (2) a marked increase in the slow inward current [4]. In agreement with Goupil and Lenfant [7] it is suggested that the same mechanisms are involved in the orciprenalineinduced changes of sinus node automaticity observed in the present experiments. The positive dromotropic action has been atributed to a promoting effect of catecholamines on the slow inward current [26] resulting in an increase in action potential amplitude in both nodal tissues [19, 27, 29, 301. Since hypoxia markedly reduces the slow inward current-dependent action potential in SA and AV nodes [II, 211, orciprenaline should directly antagonize the hypoxic action. However, the marked depression of SA and AV nodal function following prolonged periods of orciprenaline administration in presence of severe hypoxia must be explained by additional factors. An attractive hypothesis has been advanced by Kohlhardt et al. (1977) suggesting that hypoxia reduces the driving force for slow inward current by increase in the intracellular free Ca and/or Na concentration due to a restricted cellular energy production [2, 14, 161. Thus, the orciprenaline-induced breakdown of nodal electrical activity would be the consequence of the initial enhancement of slow inward current. This would lead to further rise of intracellular free Ca and/or Na concentration and, therefore, cause a critical decrease in the driving force. Metabolic studies in anoxic ventricular muscle suggest that catecholamines stimulate the glycolytic production of ATP which may regulate the slow inward current [14], and that catecholymine-induced increase in cellular energy turnover may accelerate the hypoxic energy deficit [I, 161. An increased extracellular glucose concentration has recently been shown to restore almost to normal SA and AV nodal electrical activity in the presence of persisting severe hypoxia [22]. These results suggest that in the present preparations subjected to hypoxia plus extreme beta-adrenergic stimulation, shortage of glycolytic substrate may have been an exacerbating factor. It is interesting to note that electrical parameters dependent on the fast Na inward current, such as atria1 action potential amplitude

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ET AL.

and conduction, were much less affected by the combined effects of hypoxia and orciprenaline confirming similar results in the ventricular conducting system [ZU].

Acknorerledgement

This work was supported by a grant from the German Research Foundation within the SFB 90 “Cardiovaskulares System”. Dr Mizutani is a Research Fellow of the Alexander von Humboldt Stiftung. We are grateful to Miss Marlies Deiseroth for technical assistance. REFERENCES 1.

6.

7. 8. 9. 10.

11.

12.

13

14

BING, 0. H. L., BROOKS, W. W. & MESSER, J. V. Effects of isoproterenol on heart muscle performance during myocardial hypoxia. Journal of Molecular and Cellular Cardiology 4, 319-318 (1972). BLAUSTEIN, M. P. & HODGKIN, A. L. The effect of cyanide on the efflux of calcium from squid axons. Journal of Physiology 200, 497-527 ( 1969). BRETAG, A. Synthetic interstitial fluid for isolated mammalian tissue. Life Sciences 8, 319-329 (1969). BROWN, H. F. & NOBLE, S. J. Effects of adrenaline on membrane current underlying pacemaker activity in frog atria1 muscle. Journal of Physiology 204, 51-52 (1973). COLLINS, J. M., MCDEVITT, D. G., SHANKS, R. G. & SWANTON, J. G. The cardiotoxicity of isoprenaline during hypoxia. British Journal of Pharmacology and Chemotherapy 36, 35-45 ( 1969). DAWNES, J. J,, WOOD, D. W., STRIKER; T. W. & PITTMAN, J. C. Arterial blood gas and acid-base disorder in infants and children with status asthmaticus. Pediatrics 42, 238-249 (1967). GOUPIL, N. & LENFANT, J. The effects of amiodarone on the sinus node activity of the rabbit heart. European Journal of Pharmacology 39, 23-32 (1976). HUTTER, 0. F. & TRAUTWEIN, W. Vagal and sympathetic effects on the pacemaker fibers in the sinus venosus of the heart. Journal of General Physiology 39, 7 15-733 (1956). INMAN, W. H. H. & ADELSTEIN, A. M. Rise and fall of asthma mortality in England and Wales in relation to use of pressurised aerosols. Lancet, ii, 279-285 (1969). JEN, S. Effects of isoproterenol, dl-propranolol and d-propranolol on the A-V transmission and the A-V nodal transmembrane action potential. Japanese Heart Journal 14, 53-70 (1973). KOHLHARDT, M., MNICH, Z. & MAIER, G. Alterations of the excitation process of the sinoatrial pacemaker cell in the presence of anoxia and metabolic inhibitors. Journal of Molecular and Cellular Cardiology 9, 477-488 (1977). MATSUDA, K., HOSHI, T. & KAMEYAMA, S. Action of acetylcholine and adrenaline upon the membrane potential of the atrio-ventricular node (Tawara). Tohuku Journal of Experimental Medicine 63, 16 (1958). MCDEVITT, D. G., SHANKS, R. G. & SWANTON, J. G. Further observations on the cardiotoxicity of isoprenaline during hypoxia. British Journal of Pharmacology and Chemotherapy 50, 335-344 ( 1974). MCDONALD, T. F. & MACLEOD, D. P. Effects of manganese, glucose and isoprenaline on the action potential of anoxic ventricular muscle. Naunyn-Schmiedebergs Archiv fiir Pharmakologie und Experimentelle Pathologie 275, 169-181 (1972).

ORCIPRENALINE

15.

17.

18.

19.

20.

21.

22. 23. 2-k. 25. 26. 27. 28.

‘9.

30.

HYPOXIC

NODAL

FIBERS

147

0. S., SAMET, P. & JAVIER, R. P. Significance of the sinus-node recovery Circulation 45, 140-158 (1972). NAYLER, W. G., YEPEZ, C. E. & FASSOLD, E. Experimental Studies on the Effect qj $adrenoreceptor Antagonists on Hypoxic Heart 1Muscle. P-Blockade 1977, Thieme-Verlag. Stuttgart, 32-49 (1978). PAES De CARVALHO, A.. DE MELLO, W. C. & HOFFMAN, B. F. Electrophysiological evidence for specialized fiber types in rabbit atrium. American Journal of Physiolo,gy 196,483~488 (1959). REES, H. A.. ~IILLAR. J. S. & DONALD, K. W. A study of the clinical course and arterial blood gas tensions of patients in status asthmaticus. Quarterly Journal of Medicine 37. 5-11-561 (1968). REC'TER. H. Strom-Spannungsbeziehungen von Purkinje-Fasern bei verschiedencn extracellularen Calcium-Konzentrationen und unter Adrenalineinwirkugn. PJliigers Archit: 287, 357-367 (1966). SENGES,J., BRACHMANN. J., PELZER, D., MIZUTANI, T. & K~BLER, W. Effects of some components of ischemia on electrical activity and re-entry in the ventricular conducting system. Circulation Research 44, 864-872 (1979). SENGES,
time.

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ON