Electrophysiological and mechanical effects of an analgesic drug (Dextromoramide) on the frog heart

ffournal of MolecularandCellularCardiology(1977) 9, 529-540

Electrophysiological and Mechanical Effects o f an Analgesic D r u g ( D e x t r o m o r a m i d e ) on the Frog H e a r t C H A N T A L M I R O N N E A U ANDJ E A N M I R O N N E A U

Laboratoire de Pharmacodynamie, U.E.R. de Mddedne et Pharmade et Laboratoire de Physiologic Animale, U.E.R. de Sciences, Universit~ de Poitiers, France (Received 22 April 1976, accepted in reoisedform 23 August 1976) C. MIRONNEAUANDJ. MmONNEAU. Electrophysiological and Mechanical Effects of an Analgesic Drug (Dextromoramide) on the Frog Heart. Journal of Molecular and Cellular Cardiology (1977) 9, 529-540. Action potential, membrane currents and contraction have been measured in naturally quiescent frog atrial trabeculae by means of a double sucrose gap method associating a photoelectrical device for recording contraction. The effects of dextromoramide (0.3- 5 rag/l) on the dectrophysiologicaland the mechanical parameters have been studied. Dextromoramide (0.3 rag/l) exerted no effect on the action potential amplitude but significantly increased the action potential duration while the rate of repetitive firing decreased. The contraction amplitude was not modified. At a higher concentration (5 rag/l), both the amplitude of action potential and contraction were decreased by dextromoramide. The TTX-sensitive fast inward current was unchanged whatever the concentration of dextromoramide. With a concentration of 5 rag/l, the manganese-sensitive slow inward current decreased and consequently the phasic contraction was also reduced. The tonic contraction was not significantly modified by dextromoramide. The delayed outward current diminished, the maximal changes being already obtained with dextromoramide in a dose of 0.3 rag/1. The results of this study indicate that large doses of dextromoramide produce a direct depressant effect on isolated heart preparations due primarily to a decrease in transmembrahe slow inward current.

KEYWoR~s: Dextromoramide; Heart muscle; Ionic currents; Contraction; Slow inward current.

1. Introduction T o t a l o r p a r t i a l anesthesia is often o b t a i n e d n o w a d a y s t h r o u g h t h e t e c h n i q u e o f n e u r o l e p t a n a l g e s i a w h i c h combines simultaneous a d m i n i s t r a t i o n o f a n e u r o l e p t i c d r u g (droperidol) a n d o f a n analgesic d r u g ( d e x t r o m o r a m i d e o r fentanyl) [20]. D e x t r o m o r a m i d e is w i d e l y used for its p r o l o n g e d a c t i o n causing significant a n a l gesia d u r i n g t h e p o s t - o p e r a t i v e stage [ 1 / ] . H o w e v e r , m o r e i m p o r t a n t c a r d i o v a s c u l a r s e c o n d a r y effects t h a n w i t h o t h e r analgesic d r u g s c a n b e observed. I n fact, a decrease in b l o o d pressure w i t h p e r i p h e r a l v a s o d i l a t a t i o n was shown b y CaneUas et al. [7] a n d B l o n d e a u [3]. As the p r i m a r y a c t i o n o f analgesic d r u g s h a p p e n s to b e m o r e effective a t t h e cell m e m b r a n e level t h a n a t t h e i n t r a c e l l u l a r level [2], the effects o f d e x t r o m o r a m i d e h a v e b e e n a n a l y z e d o n c a r d i a c m e m b r a n e s . T o investigate t h e c h a n g e s o c c u r r i n g i n m e m b r a n e c u r r e n t s d u e to t h e a c t i o n o f

530

c. M m O ~ U

AND J. mRormv_.AU

dextromoramide, the double sucrose gap technique [23] was used on frog atrial trabeculae. These variations were correlated with the modifications noticed in the action potential and contractility produced by the drug.

2. M a t e r i a l s

and Methods

Experimental arrangement and measurements Isolated atrial trabeculae from the heart of Rana esculenta (70-100 ~tm in diameter and 3-4 m m in length) were placed in a double sucrose gap apparatus as previously described [23]. This technique allows the simultaneous measurements of action potential (or membrane currents) and contraction. The nomenclature used to express the results was as follows: V (mV), variation of the membrane potential, the resting potential being taken as zero (positive values of Vrepresent a depolarization, negative values a hyperpolarization); I (A), membrane currents (positive values correspond to an outward current, negative values to an inward current). Inward currents were estimated by subtracting the currents obtained in the presence of specific inhibitors (tetrodotoxin or manganese chloride) from those in the normal solution. T h e space constant in the frog heart is about 690 ~m [6] and the test gap (100 ~ma) is narrow enough so that a reasonably uniform potential can be applied even during the active state (space constant reduced to approximately one-third of its resting value). At the beginning of each experiment, the action potential was always recorded across each sucrose gap. When the total amplitude of the two action potentials exceeded 90 mV, indicating a short-circuiting factor of 0.8 or more, the bundle was accepted for further experimentation. A certain variability in the quality of temporal voltage clamp control can be attributed to the series resistances [13, 26]. T h e values of the series and membrane resistances were estimated from current-voltage relations for small depolarizing steps (5-10 mV positive to the resting potential). When the ratio between the series resistances ( 8 + 4 k.Q, n ~ 38) and the membrane resistance (4204-170 k.Q, n = 70) was about 1 to 50, our measurements were thought to be trustworthy. As a matter of fact, uncertainties in the imposed voltage may occur due to the series resistances during the inward current phase, when the membrane resistance is lowered. When control measurements were performed with intracellular microelectrodes, a minimal error of 10% was obtained between the imposed potential and the true membrane potential, at the peak inward current. Similar results were reported by De Hemptinne [8]. T h e bundles presenting this moderate error of 10% were selected for voltage clamp analysis. Under these conditions, the results presented in this paper should be regarded as a comparison between a control and an experimental state, the errors in both states remaining almost identical.

D E X T R O M O R A M I D E O N H E A R T MUSCLE

531

The "gap potential" was estimated in the following way: the preparation in the test gap was perfused with an isotonic potassium solution (K +, 117 m_~) and the electronic set-up was connected for current clamp. Then, the potassium solution was changed for the normal solution (K+, 2.5 m_~). The preparation repolarized at --70 to --80 mV, a value which is close to the resting potential usually recorded with intracellular microelectrodes [9]. The pacemaker activity was triggered in quiescent frog atrial trabeculae in response to depolarizing current pulses of relatively low magnitude and of several seconds duration. For such an activity there were unvariably upper and lower limits of membrane potential above and below which pacemaking would not occur and an optimal level at which maximal frequency developed [4]. This optimal potential level was employed to study the effects of dextromoramide on rhythmic activity. The contraction of the atrial trabeeulae in the test gap of the double sucrose gap apparatus was evaluated by means of a photoelectrical device [17]. Our results were taken into account only when the contraction of the heart muscle was confined in the test gap. The contraction was measured as a change in the light intensity appearing on the photomultiplier. The amplitude of the contraction was expressed as a percentage between the contraction observed under voltage clamp conditions and the maximal contraction triggered by an action potential.

The composition of the normal solution was as follows (mM) : NaC 1, 110; KC 1, 2.5; CaC 12, 1.8; ~rris (hydroxymethyl)aminomethane-HC 1, 5.3. The pH was adjusted to 7.8 and the experiments were performed at 18-20~ The following inhibitors of permeability were used: tetrodotoxin (TTX), 10 -3 rn~ and manganese chloride (MnCI,), 2.5 rout. Dextromoramide (Delalande, Paris) was employed at 0.3 a n d 5 rag/1. In all experiments, our measurements were made only when the preparations reached a steady state (that is after 8-10 m-in in the test solution).

Statistics Statistics were calculated on the differences observed between control a n d test data using a paired t-test.

3. Results Effects on action potential, contraction and rhythmic activity The effects of dextromoramide (0.3 and 5 mg/1) were analyzed in frog sinoatrial fibres. The results obtained 10 rain after its addition, expressed as changes in

532

c. ~XgOm,mAU AND j. ~ o t , ~ , m A u

percentage, are shown in Table 1. Significant experimental data concerning the action potential, the contraction and the rhythmic activity can be summarized as follows. (1) At 0.3 mg/1, the amplitude of the action potential as well as the resting potential was not significantly impaired. However, the action potential duration (measured when repolarization had reached 90% of its value) increased. This variation is statistically significant (P < 0.001). When recorded simultaneously TABLE 1. Effect of dextromoramide on different electrophysiological variables mad contraction (percentage change) Concentrations ofdextromoramide (rag/l) 0.3 5 Resting potential Action potential amplitude Action potential.)'20% repolarization duration [.90% repolarization Rhythmic activity (maxima/rate) Contraction amplitude

3 :k 2 (9) 2 • 1 (9) 5 • 3 (9) 10 ~: 1.5 (9)t -- 11 ~ 3 (8)* 2 :t: 2.5 (7)

3.5 ~= 2 (7) - 9 . 5 =E 2 (7)*

- 2 0 ~: 3 (7)t 8 ~: 2 (7)* -]3

=/: 3 (8)*

- 2 5 ~: 5 (7)*

* P < O.O1;t P < 0.001. Mean values 4- s,r.m; in brackets"number ofpreparat/ons.

with the action potential, no appreciable change in the amplitude of the contraction occurred. (2) At 5 rag/l, the amplitude of the action potential decreased and the plateau was lowered. In fact, the duration of the action potential at 20% of repolarization decreased while it increased at 90% of repolarization. Finally, the amplitude of the contraction diminished (25 4-5%) without major modification in its time to peak and duration. Maximal rhythmic activity was also significantly reduced by dextromoramide. Examples of the results are shown in Figure 1(a) and (b).

Reversible alterations in the action potential parameters and in the contraction time course were always observed under our experimental conditions.

Effects on ionic currents

Manganese ions are known to inhibit the slow inward current (related to calcium plus sodium ions) of the frog heart [24]. Dextromoramide (0.3-5 rag/l) in the presence of MnCl~ (2.5 m•) did not alter the amplitude of the fast inward current (Table 2). No significant variation of the reversal potential was observed through the analysis of the current-voltage relations. An example of current-voltage relationships obtained in reference solution and after addition ofdextromoramide is shown in Figure 2(a). In the same way, T T X is considered a highly selective substance causing inhibition of the fast sodium inward current [14]. In the presence of T T X (10 -3 raM), the slow inward current was not modified by dextromoramide

533

D E X T R O M O R A M I D E ON H E A R T MUSCLE

(a] t ~ "N V" ~

I2omV ~ i ) I0"oms (i~

"SFA

Z---

O)

V....I

k, S

~.

FIGURE 1. Effects ofdextromoramide on the action potential, contraction and rhythmic activity of the frog atrial trabeculae. (a) Action potential and contraction (in arbitrary units) are recorded in the normal solution (i) and in the presence of dextromoramide at two different concentrations, with two different preparations: 0.3 mg/l (ii) and 5 mg/l (iii). (b) Maximal rhythmic activity elicited by a depolarizing current at a given intensity, in the normal physiological solution (i), and in the presence of dextromoramide (5 my/I) (ii). The frequency and amplitude of the responses appear diminished by the analgesic drug. (V: potential; I: current; C: contraction.) (0.3 mg/1). H o w e v e r , d e x t r o m o r a m i d e (5 mg/1) d e c r e a s e d t h e m a x i m a l v a l u e o f the slow i n w a r d c u r r e n t intensity ( 2 3 ~ 4 % ; see T a b l e 2). A n e x a m p l e is shown in F i g u r e 2 (b). N a t u r a l l y , t h e t i m e to p e a k r e m a i n s u n c h a n g e d even if there is a slight r e d u c t i o n in t h e d e c r e a s i n g p h a s e o f the slow i n w a r d current. D e x t r o m o r a m i d e d i d TABLE 2. Effect of dextromoramide on different ionic current parameters and contraction (percentage change) Concentrations of dextromoramide (rag/l) 0.3 5 f m a x i m a l intensity Fast inward current Lreversal potential S. . . . ( m a x i m a l intensity lOWlnwarQ currenc -i , 9, kreversai potential Delayed outward current, maximal intensity'~ at+100mV J Phasic contraction (% maximal contraction) Tonic contraction (% maximal contraction)

2 2 2 2

• • • •

1.5 2.5 1.5 2

(5) (5) (6) (6)

--42• (9)* 4 -4- 3 (8) 0.5 • 1 (7)

* P < 0.01;t P < 0.001. Mean value -4-s.s in brackets: number of preparations.

1.5 • 2

(9)

2.5 • 1.5 (9)

- 2 3 ' • 4. (7)* 1.5 • 1

(7)

-26 •

(7)t (7)t

-2.5 •

(5)

-46 • 7

534

C. ~ O ~ U

(o1

AND j. ~ m o ~ n ~ . A u

(b)

(r !ZOmV

o ,,

.y,,.o.-

5ms I--

0

i

50 mV

I

100

i

( iii ) ~ ' " - ' - ' - - " (Itii)

I~

0

'

-.0.1 ,,-0.2 0

|

I

50

I00 mV

FIGURE 2. Effectsof dextromoramide on inward currents. (a) Effects of dextromoramide on the fast kinetics inward current: current-voltage relationship found in the reference solution (MnC12, 2.5 mu, filled circles) and in the presence of dextromoramide (5 rag/l, open circles).The current amplitude is not modified by the analgesic drug. (b) Effects of dextromoramide on the maximal value of the slow kinetics inward current, in the reference solution [ T r x , (i)] and in the presence of dextromoramide [0.3 mg[l, (ii); 5 rag[l, (ih')]. T h e maximal current amplitude is diminished by 234-4% in the case of the 5 mg/1concentration. (c) Current-voltage relationships obtained under the same conditions as (b). At 5 mg/l (iii), the flow inward current is diminished without an appreciable shift of the revenal potential (Jr). (V: potential; I: current.) not influence the reversal potential (Table 2) while diminishing the amplitude of the slow inward current in a wide range of m e m b r a n e potentials as shown in the current-voltage relationships illustrated in Figure 2 (c). Dextromoramide (0.3 rag/l) reduced the delayed outward current for potenH~h higher than + 40 InV. This reduction reached 42 4-9% and is statistically significant (Table 2). An example is shown in Figure 3(a). T h e current-voltage relationships [Figure 3(b)] show that dextromoramide had no effect on the anomalous rectification but decreased the delayed rectification. T h e modification in the amplitude of the outward current reached 464-7% with 5 mg/1, indicating that the maximal effect was practically obtained with 0.3 mg/l dextromoramide. T h e reversal potential of the outward current can be evaluated as follows: after a large initial depolarization, inducing the phenomenon of delayed conductance, the preparation is repolarized at different levels until the value of the reversal potential is reached (that is when there is no tail current). Dextromoramide had no effect on the reversal potential of the two components [4] of the outward current which were respectively + 54-2 m V and + 304-10 m V (n = 12) referring to the resting potential as zero. With depolarizing steps activating the outward current at its maximal value, it is then possible to extrapolate the values of the tail currents measured at the end of the pulse (using semi-logarithmic plots of currents vca~us time), see Brown and Noble [5]. T h e plot of the maximal tail currents values at 0 time corresponds to the changes existing in the activation of the two componeJal~ of the outward current. Complete activation curves of the outward current were obtained from 5 frog atrial trabeculae. Dextromoramide lowered the maximal values (obtained with + 100 m V depolarizations) of components I and I I resl~:-

DEXTROMORAMIDE

(a)

(f)

ON HEART

535

MUSCLE

(iiJ

ISOmV

, -,-*'sV

I"-

Is (b)

04

/

<

tc,/2)

a2t mV ~

,o'o

-~ -e'~ o

7

u 50 mv

,,~.,o-o(i),,.~ n IOO

FIGURE 3. Effects ofdextromoramide on the delayed outward current. (a) The delayed outward current is recorded in the normal solution (i) and in the presence of dextromoramide [0.3 rag/l, (ii)] for (i) + 95 mV depolarization lasting 7.5 s. (b) Current-voltage relationships obtained in the normal solution (filled circles) and in the presence of dextromoramide (0.3 rag/l, open circles). The outward current intensity is decreased by the analgesic drug for depolarizing currents superior to + 40 mV. (c) Effects of dextromoramide on the activation curves of the delayed outward current./1: Activation curve of component I, in the normal solution (i) and in the presence of dextromoramide [0.3 rag/l, (ii)]./z: Activation curve of component II, under the same conditions as for I1. Maximal values of components I and II of the delayed outward current are respectively decreased by 284-7% and 174-4% by the analgesic drug. (V: potential; I: current.) tively b y 28-4-7% (P < 0.02) a n d 1 7 4 - 4 % (P < 0.02). For a n e x a m p l e of these results see Figure 3(c).

Effects on contraction I n the frog heart there are at least two types of contraction which differ in both their time a n d voltage dependence [17, 28]. Short-lasting depolarizations (100 ms) cause a n inward flow of calcium ions which can trigger a phasic c o m p o n e n t in the contraction. Both the slow inward current a n d the phasic contraction increase as a function of the m e m b r a n e potential; after a m a x i m a l value, they decline for strong depolarizations. I n T T X a n d manganese-containing solution, or in calcium-free solution, long-lasting depolarizations (0.5-1 s) produce a second c o m p o n e n t in the contraction which is independent from the slow inward current. T h e m a g n i t u d e of this tonic contraction increases with depolarization. T h e presence of this second m e c h a n i s m of activation m a y go along with the hypothesis that calcium is released from intraceUular stores, from which it can be in effect displaced b y long-lasting depolarizations or b y the intracellular sodium ions [28]. During a n action potential, the phasic contraction [29] is rapidly activated a n d represents a b o u t 70% o f the

536

c. Mmox'~a~u AND J. MXRO~raAU

total contraction, while the tonic contraction develops slower a n d is only responsible for 3 0 % o f the total contraction. D e x t r o m o r a m i d e (5 mg/1) decreased the phasic contraction obtained with depolarizations o f I00 ms duration ( 2 6 4 - 4 % ; T a b l e 2). A typical experiment is shown in Figure 4(a). This decrease in contraction can be c o m p a r e d with the reduction of the slow inward current ( 2 3 4 - 4 % ; T a b l e 2). These results indicate that the negative inotropic effect of d e x t r o m o r a m i d e is d e p e n d e n t on a diminution in the slow i n w a r d current, even t h o u g h the change in the contraction a n d t h e slow inward current (calcium plus sodium) is not exactly the same. T h e presence o f sodium ions as a c o m p o n e n t o f the slow inward current could explain this slight difference. W h e n the inward currents were blocked (due to the action of T T X plus MnCls), the tonic contraction was not significantly modified b y dextromoramide. T h e relation between peak contraction and voltage did not reveal a n y variation with or without d e x t r o m o r a m i d e [Figure 4(b) ]. (o)

~ o

(b)

I ?-.J"

0

50

I

/j

,

/

I00

mV

/ 0 0

O .Ir 8 ~

I 50I I00 mV

FIGURE 4. Effects of dextromoramide on the different components of the contraction. (a) Relatiomhips between the maximal amplitude of the slow inward current and the peak of the contraction as a function of voltage in the reference solution [TTX, (i)] and in the presence of dextromoramide [5 rag/l, (ii)]. The ordinates are expressed as a ratio of the maximal contraction (triggered by an action potential) and of the maximal inward current. Contraction and current are decreased for all the potential values. (b) Maximal amplitude of the contraction recorded with 0.5 s depolarizations, in the refere~ace solution (TTX + MnCls, filled circles) and when dextromoramide (5 mgfl, open circles) is added. The second component of the contractile response is not modified by the analgesic drug whatev~ the concentration used. (C: contraction; I: current.) 4. D i s c u s s i o n

Electrophysiological activity and dosage of dextromoramide I n order to explain the electrophysiological effects of d e x t r o m o r a m i d e , it is necessary to c o m p a r e the d a t a at similar concentrations. A dose o f 0.05 to 0.2 m g / k g is usually employed to induce neuroleptanalgesia [16, 22]. Since d e x t r o m o r a m l d e is not largely b o u n d b y tissues [/], a concentration of 0.3 rag/1 m a y be regarded as a

DEXTROMO~E

ON I-IF,A R T MUSCLE

537

therapeutic concentration. Under these conditions, the fast and slow inward currents are not noticeably changed by dextromoramide but the delayed outward current is significantly decreased. A similar conclusion can be reached with fentanyl on the action potential of dog Purkinje fibres [30]. Our results show that dextromoramide clearly antagonizes the rhythmic activity and this effect may be correlated, in part, with the increase in the action potential duration. More drastic modifications in action potential amplitude and slow inward current are obtained at a higher concentration (5 rag/l). This concentration, in exceeding the therapeutic plasma concentration of the drug, can be compared with the large doses of other analgesic drugs (morphine, fentanyl) used on isolated hearts [10, 15, 25]. Under these conditions, the slow inward current is markedly reduced while the decrease in the outward current (observed at 0.3 rag/l) is not amplified. How dextromoramide acts on cardiac membranes is revealed when voltage clamp data are analyzed. As previously described by Hodgkin and Huxley [12], the decrease of art ionic current can be related to: (a) a reduction in the maximal conductance, or (b) a decrease of the driving force for movements of ions (shift of the reversal potential towards less positive values of voltage). The most obvious effect ofdextromoramide seems to be its ability to inhibit the outward current, even at a low concentration (0.3 rag/l). The diminution in the outward current intensity cannot be related to a variation of the reversal potentials of the two components I and II which remains at stable values in the presence of dextromoramide. Our results tend to show that dextromoramide is essentially acting on the delayed conductance since the maximal activation of the two components is respectively reduced by 28-4-7% and 174-4%. The outward current, primarily carried by potassium ions [5], is one of the membrane currents which determine the repolarization phase of the action potential. At the end of the plateau, the outward current is decreased by dextromoramide, and this reduction could explain the effects of the drug on the action potential duration. In the same way, the reduction in the slow inward current intensity, at a high concentration (5 rag/l), may be explained by a decrease in the membrane conductance since the reversal potential is not appreciably modified by the analgesic drug. As the snow inward current is responsible for the amplitude and the plateau of the cardiac action potential, and since it is affected by dextromoramide, our results illustrate this phenomenon. In frog atria, two ionic mechanisms are probably involved in the development of the rhythmic activity induced by long-lasting depolarization pulses [4, 18] : (a) a slow inward current responsible for the rate of rise and plateau of the responses and (b) a delayed outward current involved in the repolarization and in the diastolic depolarization. According to this analysis, the diastolic depolarization is mainly due to a decline in the component I of the delayed conductance [4]. Our results demonstrate that in fact dextromoramide (5 rag/l) decreases both the outward current and the slow inward current. The decrease in the outward current intensity accounts for the fact that a relatively longer time than in the control solution is

538

c. m a ~ o m ~ z A u AND J. ~ o N t , t ~ ^ u

needed so that the membrane can repolarize again during the diastolic phase. The bradycardia and the anti-arrhythmic effect of dextromoramide can be related t o the inhibition of the diastolic depolarization and the increase in the action potential duration. Similar results in anesthetized dogs have been previously reported [16].

Negative inotropic effect of dextromoramide The action of analgesic drugs on myocardial contractility has been described having either no effect, or negative or positive inotropic effects [10, 15, 21, 25, 27]. Our results show that dextromoramide (0.3 mg/1) has no effect on the contraction triggered by an action potential. Similar results were obtained with equi-analgesic doses of morphine (1-10 rag/l, 25) and fentanyl (0.02 rag/l, 21) on mammalian hearts. However, at larger doses, dextromoramide (5 mg/l) decreased the phasic but not the tonic contraction. The slow inward current carried primarily by calcium ions [24] is considered as responsible for the phasic contraction. Dextromoramide (5 mg[l) decreased both the slow inward current and the phasic contraction. This action could explain the negative inotropic effect of the analgesic. Similar data indicating a depressing effect on isolated heart were reported with other central analgesics [10]. According to Strauer [25], and Krishna and Paradise [15], the usual depressing effects of analgesics could be simply related to the high concentrations employed in relation to equianalgesic potency (e.g. morphine, 200-500 mg/1, 10, 15; fentanyl, 5 mg/1, 25). It can be concluded that dextromoramide acts directly on the cardiac membrane, as previously demonstrated for the neuroleptic drug droperidol [19]. At a therapeutic concentration, dextromoramide increases the action potential duration but reduces the rate of repetitive firing, while marked cardiovascular alterations, such as a negative inotropic activity involving primarily a decrease in calcium influx, are usually observed at high concentratiom.

REFERENCES 1. ATrmso, M. Une m~thode de recherche et de dosage du dextromoramide (Pyrrolamidol ou R.875) dans les milieux biologiques. Application ~t l'~tude exp~rimentale d e l'accumulation du R.875 chez le rat. TMrapie14, 650-660 (1959). 2. Bra~usa'Em,M. P. & GOLDMAN,D. E. Action of anionic and cationic nerve-blocking agents: experiment and interpretation. Science153, 429-432 (1966). 3. BLO~mEAU,P. Note compl~mentaire sur le dextromoramide en anesth~sie. La m~thode rapide. Anesttdsie,Analgesic,Rtanimation21, 681-684 (1964). 4. BROWN,H. F. & Nomm, S.J. Membrane currents underlying delayed rectification pacemaker activity in frog atrial muscle. JournalofPhysiolog~204, 717-736 (1969). 5. BROWN,H. F. & NOB~, S.J. A quantitative analysis of the slow component ofdelay~l rectification in frog atrium. Journalof Physiolog~204, 737-747 (1969).

DEXTROMORAMIDE

ON HEART

MUSCLE

539

6. BROWN,H. F., NOBLe, D. & NOBLe, S. J. The influence of non-uniformity on the analysis of potassium currents in atrial muscle, oTournalof Physlology245, 89-90p (1975). 7. GAZ~Lt~S,J., LE BARS, H., ROQtmBEt~T, J. & SASATI~S, M. Au sujet des effets chollnergiqnes dn dextromoramide. Bulletin de la Socitt~ de Pharmacie de Bordeaux 102, 105-110 (1963). 8. DE H~MPTtm~, A. Voltage clamp analysis in isolated cardiac fibres as performed with two different perfusion chambers for double sucrose gap. PfliigersArchly EuropeanJournal of Physiology363, 87-95 (1976). 9. GLn'Sc~, H. G., I-Ix~, H. G. & TaAtrrws~, W. The effect of adrenaline on the K and Na fluxes in the frog's atrium. Archivfiir experimentelle Pathelogie und Pharmakologie 250, 59-71 (1965). 10. GOLDBERG,A. H. ~; PADGET,C. H. Comparative effects of morphine and fentanyl on isolated heart muscle. Anesthesia and Analgesia 48, 978-982 (1969). 11. GU~.RXN,J. Contribution ~ l'~tude du R 875 ou dextromoramide en ancsth~siologie. Th}se de Mgdecine, Universitfi de Bordeaux (1961). 12. HODGKn~,A. L. & HUXLEY,A. F. A quantitative description of membrane current and its application to conduction and excitation in nerve. Journal of Physiology 117, 500-544 (1952). 13. JOHNSON,E. A. & L m B z ~ , M. Heart: excitation and contraction. Annual Review of Physiology33, 479-532 (1971). 14. KAO, C. Y. Tetrodotoxin, saxitoxin and their significance in the study of excitation phenomena. PharmacologicalReview 18, 997-1049 (1966). 15. KRXSHNA,G. & PARArme, R. R. Effect of morphine on isolated human atrial muscle. Anesthesiology40, 147-151 (1974). 16. LAums, M., CANELLAS,J., ROQtmBERT,J. & DamcX-mL,P. Action du dextromoramide sur les performances et la comommation en oxygene du coeur. Journal de Pharmacologic 4, 171-180 (1973). 17. L~OTY, C. & RAYMOND,G. Mechanical activity and ionic currents in frog atrial trabeculae. PfliigersArchly EuropeanJournal of Physiology334, 114--128 ( 1972). 18. LSNFANT,J., MmONNEAU,J. & AKA,J. K. Activit~ rfip~titive de la fibre sino-auriculaire de grenouille: analyse des courants membranaires responsables de l'automatisme cardiaque. Journal de Physiologie64, 5-18 (1972). 19. MmONNEAV,C., Mmomc~AU,J. & GROSSET,A. Action du drop~ridol sur les courants ioniques et la contraction de la fibre sino-auriculaire de grenouille. Etude des propri~t~ antiarythmiques. Journal de Physiologic70, 27-39 (1975). 20. NXLSSON,E. & JANSSEN, P. A. J. Neuroleptanalgesia--an alternative to general anesthesia. Acta AnaesthesiologicaScandinavica 5, 73-84 (1961). 21. OSTHSV, mR, G. W., SHA~AHAN,E. A., Gv-rroN, R. A., DAGOET,W. M. & LOWE~STEIn, E. Effects of fentanyl and droperidol on canine left ventricular performance. Anesthesiology42, 288-291 (1975). 22. ROQUEBERT,J., CANELLAS,J., DUMARTIN,A. & SAeATHm, M. Etude exp~rimentale comparative des effets secondaires du dextromoramide, du fentanyl et de la ph~_nop~ridine. ArchivesInternationalesde Pharmacodynamieet de TMrapie 167, 297-307 (1967). 23. ROUGIER,O., VASSORT,G. & ST~a'FLI, R. Voltage clamp experiments on frog atrial heart muscle fibres with the sucrose-gap technique. Pfliigers Archly fiir die gesamte Physiologicdes Menschenund der Tiere 301, 91-108 (I 968). 24. ROUGIER,O., VASSORT,G., GARNIER,D., GAROOUIL,Y. M. ~: CORABOEUI~,E. Existence and role of a slow inward current during the frog atrial action potential. Pfliigers Archivfiir die gesamtePhysiologledes Mensehen und der Tiere 308, 91-110 ( 1969). 25. STaAUER, B. E. Contractile responses to morphine, piritramide, meperidine and

540

26. 27. 28. 29. 30.

(]. MIRONNEAUAND J. MIRONNEAU fentany1: a comparative study of effects on the isolated ventricular myocardlum. A,~t~ology 37, 304-310 (1972). TARZ, M. & TRANK,J. M..An assessment of the double sucrose gap voltage clamp technique as applied to frog atrial muscle. Biophysicalffourna114,627-643 (1974). VAsao, J. S., I-IENN~Y,R. P., BRAWL~Y,R. K., OLDHAM, H. N. & MORROW, A. G. Effects of morphine on ventricular function and myocardial contractile force. Amer/r 3ournal of Physiology210, 329-334 (1966). VASSORT,G. Influence of sodium ions on the regulation of frog myocardial contractility. PfliigersArrhiv EuropeanJournal of Physiology339, 225--240 (1973). VASSORT,G. & ROUOIER,O. Membrane potential and slow inward current dependence of frog cardiac mechanical activity. Pfliigers Arehiv EuropeanJournal of Physiology 331, 191-203 (1972). WoyrozAK, J. & BERES~.WICZ,A. Electrophysiologieal effects of the neuroleptanalgesic drugs on the canine cardiac tissue..Naun.yn.Schmiedebergs Archiv fiir experimentdlr Pathologieund Pharmakologie286, 211-220 (1974).