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Electrophysiological effects of low pH in human atrial fibres
j Mol Cell Cardio118, 109 112 (1986)
RAPID COMMUNICATION
Electrophysiological Effects o f Low pH in H u m a n Atrial Fibres (Received 19 April 1985, accepted16 August 1985) In the s t u d i e s o f the e l e c t r o p h y s i o l o g i c a l p r o p e r t i e s o f h u m a n a t r i a l f i b r e s o b t a i n e d at c a r d i a c s u r g e r y , it h a s o f t e n b e e n r e p o r t e d t h a t the d i a s t o l i c p o t e n t i a l , the m a x i m u m u p s t r o k e v e l o c i t y o f the p h a s e 0 d e p o l a r i z a t i o n ( IYmx) a n d t h e a m p l i t u d e o f a c t i o n p o t e n t i a l a r e r e l a t i v e l y l o w [4, 5, 10, 11, 13]. T h e s a m e f i n d i n g s w e r e also o b t a i n e d in o u r p r e v i o u s s t u d y {8l w h e n the t i s s u e p r e p a r a t i o n s w e r e p e r f u s e d w i t h a T y r o d e s o l u t i o n w h i c h , as u s u a l l y d e s c r i b e d in l i t e r a t u r e s on c a r d i a c cell s t u d i e s [1, 4, 5, 11, 13] h a d a N a H C O 3 c o n c e n t r a t i o n o f 12 mM a n d w a s a e r a t e d w i t h a gas m i x t u r e o f 95% 0 2 - 5% CO 2 at 37~ R e c e n t l y w e f o u n d t h a t the r e l a t i v e l y p o o r e l e c t r i c a l a c t i v i t i e s o f the h u m a n a t r i a l f i b r e s w e r e r e l a t e d to the low p H v a l u e ( a r o u n d 7.06) o f the p e r f u s a t e used. R a i s i n g the p H v a l u e o f the p e r f u s a t e e i t h e r b y i n c r e a s i n g the N a H C O 3 c o n c e n t r a t i o n o r b y r e d u c i n g the CO 2 in the b u b b l i n g gas m i x t u r e s i g n i f i c a n t l y i m p r o v e d the e l e c t r i c a l a c t i v i t i e s o f the fibres. T h e r e is evid e n c e t h a t the s u p p r e s s i v e effect o f low p H on the e l e c t r i c a l a c t i v i t i e s is d u e to the hindering a c t i o n o f H + on the t r a n s p o r t a t i o n o f o t h e r c a t i o n s a c r o s s the p l a s m a membrane. Specimens of human atrial appendage were obtained from the hearts of 12 patients (32 __+ 7 years old, mean __+ s.E.~.) undergoing open-heart surgery. Prior to surgery, informed consent was obtained. The tissue was immersed in cold Tyrode solution immediately after excision from the right atrium as part of the routine atriotomy procedure. Strands of atrial trabecular muscle fibres with a diameter of 0.5 to 1.5 mm were removed and placed in a tissue bath perfused with Tyrode solution at 37~ The compositions of control Tyrode solution in mM is NaCI, 125; KCI, 4; NaHCO3, 24; NaH2PO4, 0.5; MgC12, 0.5; CaC12, 2.7 and dextrose, 5.5. This control solution was oxygenated with a gas mixture of 95% 02 5% CO2, yielding a pH of 7.38 __+0.01 (n = 6) in tissue bath. The low pH solution (7.06 __+0.02, n = 6) were prepared by decreasing the N a H C O 3 concentration from 24 to 12 mM with a compensatory increase of NaC1 from 125 to 137 m~. In certain experiments, the pH of low N a H C O 3 0022-2828/86/010109 + 04 $03.00/0
solution was increased to 7.31 ___0.02 (n = 4) by saturating the low NaHCO3 solution with a gas mixture of 98% 0 2 - 2 % CO 2. The preparations were initially driven at a cycle length of 1000 ms. Transmembrane potentials were detected by means of glass microelectrodes filled with 3 M KC1. The action potential and its first derivative were displayed continually on a chart recorder (Gould 2400S) and a digitizing oscilloscope (Tektronix 5223). Occasionally the recordings were stored on magnetic tape (Gould 6500) for future playback. The preparations in the present experiments were divided into two main groups on the basis of their electrical activities. One group of atrial fibres (n = 5). responded to electrical stimulation with a Vmax of phase 0 depolarization faster than 180 V/s (fast response) in control Tyrode solution. The other group (n = 7) had a /?max less than 30 V/s (slow response) in the same experimental conditions. Figure l(a) shows the effect of a 9 1986 Academic Press Inc. (London) Limited
110
Rapid c o m m u n i c a t i o n : Z-Y. Hou et aL 5 0 0 ms
(o) Oi
~
+4~176
"
!
J
X__\
!
V/s C02 (HC03-) pH
~
5 24 7.38
i
5 12 7.06
L 2% 12 mu
7.31
(bl
0.Ss
x.____.
~
-
mV
coV -
5
(HE03-) 241 DH 7.38
0
~ 19_
7.06
7.38
F I G U R E 1. Effects of pH on h u m a n atrial fibres showing fast response action potential. In (a), oscilloscopic recordings of action potential (upper trace) and its first derivative (d V/dt, lower trace) were recorded after 13-rain perfusion in Tyrode solution containing 24 mM (left panel) or 12 mM N a H C O a (middle and right panels), T h e perfusates were either aerated with a gas mixture of 95% 0 2 5% CO 2 (left and middle panels) or 98% 0 2 - 2 % C O e (right panel). In (b) the dots above the slow-speed chart recordings show the time at which the oscilloscopic recordings in top panels have been recorded in sequence. The pH of perfusate was decreased by reducing N a H C O 3 concentration from 24 to 12 mM as indicated, T h e break in chart recordings was 212 s. T h e pH values of the perfusates at tissue bath were measured by an ABL 3 Radiometer. The preparations were driven at 60 cycles per rain. In (a) the d F/dt for phase 0 depolarization had been retouched.
reduced pH on an atrial fibre with a maximum diastolic potential (MDP) of - 8 6 m V and a l?max of 355 V/s in control Tyrode solution oxygenated with 95% 0 2 - 5 % C O 2. When the perfusate was shifted to a low N a H C O 3 solution for 13 rains and pH was reduced from 7.38 to 7.06, the action potential duration was increased and the M D P was shifted to a more positive value (--81 mV), but the T)'max and the amplitude of action potential remained unchanged. When low NaHCO3 solution was saturated with 98% O z - 2 % CO2 and p H was increased to 7.31, the M D P was returned to a more negative value ( - 8 4 mV) while the Vmax and the action potential duration changed very little. Similar results were observed in three other preparations. In the last atrial preparation with a Dma. of 180 V/s and a lower level of M D P ( - 6 3 mV), however, exposure to the low p H solution induced a pronounced depolarization (to - 4 4 mV) and the fibre eventually became inexcitable within 2 rains [Fig. l(b)]. The deteriorating effects were readily
reversible after washout with control Tyrode solution. The average ;)max and M D P for these five atrial preparations showing fast response action potentials in control perfusate were 252 + 35 V/s and --71 -t- 5 mV, respectively. The respective values were 215 4- 62 V/s and - 6 4 + 6 mV during exposure to low p H perfusate. The differences in Vm~x ( - 3 7 4` 32 V/s) and M D P ( + 6 . 6 4- 4.4 mV) were not found to be statistically significant (P > 0.2). However, the increase in action potential duration at 50% repolarization ( + 6 7 4-11 ms, from 166 4- 10 to 233 + 10 ms) was significant (P < 0.01) by paired Student's t test. In atrial preparations showing slow response action potenials (either active spontaneously or driven electrically), low p H solution induced significant change in Vmax and MDP, as illustrated in Figure 2. In seven preparations from seven patients, the M D P was shifted f r o m - 5 3 4- 4 t o - 4 2 + 3mV (-t-11.04-2.1 mV, P < 0.01). The ~-max was also decreased significantly (--6.7 + 2.4 V/s,
L o w p H a n d H u m a n Atrial M e m b r a n e P o t e n t i a l (a)
0.5 s
111
accumulation of potassium in the extracellu-
lar spaces of the Purkinje fibres [1]. An alternative explanation is that acidosis induces a - 5 o ~ L . . . . . 4 L..... decrease in m e m b r a n e potassium conduc+2o~ ~ ~~ tance and the subsequent m e m b r a n e depolarV/s ization [3, 6]. HC03-) 24 12 24 mM In rabbit atrial muscle ceils, a reduction of pH 7.37 7.07 7.57 p H from 7.5 to 6.1 was associated with a (b) 0.5 s decrease in [K] i and an increase in [K]0 and caused a positive shift in resting m e m b r a n e potential and equilibrium potential for potassium (E~) [12]. Thus the reduction of mV 20 s resting potential could be explained by an inhibition of the N a - K pump. Increasing "" "~JJ~""~V ,, lljii,l~l; [K]0 from 3.6 to 5 m~ produced a similar ,!11 !~lH!" depolarizing effect [12]. Results of the present experiments show that, in h u m a n atrial fibres, ( HCO3-) 24~_~,2 ~ mu t a moderate reduction o f p H from 7.38 to 7.06 PHIZ~ J'~'~'~ L K5.4 m~ J. K4 m~ was capable of producing an approximately FIGURE 2. Effects of pH on human atrial fibres 10 m V depolarization and inhibiting the showing slow response action potential. In (a) oscil- repolarization process. Increasing [K] 0 from 4 loscopic recordings of action potential (upper trace) and its first derivative (lower trace) were recorded in control to 5.4 to 6 mM during low p H perfusion could solution (left panel), in low NaHCO 3 Tyrode solution reverse the m e m b r a n e depolarization. Similar (middle panel) and again in control solution (right repolarizing effects of increasing [K] 0 have panel). The preparation was driven at 60 cyclesper rain. been observed in dog Purkinje fibres during In (b), another preparation was allowed to discharge spontaneously. The dots above the the slow-speed chart low p H perfusion [6] or during strophanthirecordings show the time at which fast-speed recordings din intoxication [9]. T h u s the low p H depoin top panels have been recorded in sequence. The pH of larization in h u m a n atrial fibres appears to be perfusate was decreased by reducing NaHCO 3 from 24 to similar to a low [K]o depolarization [7] and 12 mM. During low pH perfusion, [/('J0 was increased from 4 to 5.4 mM for 3.5 min. The breaks in slow speed could be due to a decrease in m e m b r a n e potassium conductance. T h e prolongation of recordings were 422 and 128 s, respectively. action potential duration was associated with m e m b r a n e depolarization and could also be fromlT_2to I1 + 3 V / s , P < 0 . 0 5 ) . F i g u r e explained by a reduction in potassium con2(b) also shows that the depolarizing effects of ductance. low p H could be antagonized by increasing It has been shown that both sodium and [/f]0 from 4 to 5.4 raM. I n three experiments, calcium conductances of frog atrial fibres were increasing I/f]0 from 4 to 5.4-6 m M shifted depressed in acidic media [2]. In our study in the M D P from - 4 3 • 3 to - - 5 3 + 7 inV. h u m a n atria, significant suppression of rate of Decreasing the C O 2 in gas mixture from 5% rise of action potential was observed only in to 2% induced similar repolarizing effect on fibres showing slow responses ( Vmax< 30 V/s). M D P ( - 3 . 1 - 1 - 0 . 4 mV, from --63__+8 to These slow response action potentials were - 6 6 4- 8 mV) (P < 0.02, n = 4). characterized by a low level of m a x i m u m Studies of the effects of acid solutions on diastolic potential (around --53 mV). It electrical activities of m a m m a l i a n cardiac has been proposed that at m a x i m u m tissues have been concentrated on ventricular diastolic potentials less than - 6 0 mV, the Purkinje fibres, using either buffers [1, 63 or rapid inward current responsible for phase 0 C O 2 [3]. It has been shown that p H depolarization is largely inactivated and the reductions could induce m e m b r a n e depolaraction potential is initiated by a slow inward ization and slow response action potentials in current [4]. T h e differential suppressive effect Purkinje fibres [3, 6]. O n e possible explanaof low p H on the upstroke velocity of the slow tion fbr the H +-induced depolarization is that response v. the fast response action potential proton inhibits sodium pump, leading to an suggest a greater inhibition o f H + on the slow mvO[~
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~
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112
Rapid communication: Z-Y. Hou
i n w a r d c u r r e n t t h a n o n t h e fast i n w a r d current. Further studies with voltage-clamp t e c h n i q u e a r e r e q u i r e d to clarify this p o i n t .
et aL
t h e m a n u s c r i p t , to D r G u a n g - M i n g S h i a o for t h e use o f A B L 3 R a d i o m e t e r a n d to M s I - N i n g C h u a n g for t e c h n i c a l assistance.
Acknowledgements This work was supported by grant from Academia Sinica, Taipei, R.O.C. Dr Hou was a Research Fellow from the Division of Cardiology, D e p a r t m e n t of Medicine, Veterans G e n e r a l H o s p i t a l . T h e a u t h o r s a r e g r a t e f u l to p r o f e s s o r H s i n - H s i a n g L u for h e l p i n w r i t i n g
Zone-Yuan Hou, Cheng-I L i n l * , Benjamin N. Chiang and Kwok-Kei Cheng Clinical Research Centre, Veterans General Hospital, Taipei, and aDepartment of Pharmacology, National Defense Medical Center, P.O. Box 8244, Taipei, Taiwan, Republic of China
KEY WORDS: Atria; pH, Low; Vmax ; Acidosis.
References 1 BROWN, R. H., Jr, COHEN, I., NOBLE, D. The interactions of protons, calcium and potassium ions on cardiac Purkinje fibres.J Physiol [Lond] 282,345 352 (1978). 2 CHESNAIS,J. M., CORABOEUF,E., SAUVIAT,M. P., VASSAS,J. M. Sensitivity to H, Li and Mg ions of the slow inward sodium current in frog atrial fibres.J Mol Cell Cardiol 7, 627 642 (1975). 3 CORABOEUF,E., DEROUBAIX,E., HOERTER,J. Control of ionic permeabilities in normal and ischemic heart. Circ Res38 [Suppl I], 192 197 (1976). 4 HORDOF,A.J., EmE, R., MALM,J. R., HOFFMAN,B. F., ROSEN, M. R. Electrophysiologic properties and response to pharmacologic agents of fibers from diseased human atria. Circulation 54, 774-779 (1976). 5 HORDOr, A. J., SPOTNITZ,A., MARY-RABINE,L., ED1E, R. N., ROSEN, M. R. The cellular electrophysiologic effects of digitalis on human atrial fibers. Circulation 57,223 229 (1978). 6 LAUER,M. R., RusY, B. F., DAVIS,L. D. H+-induced membrane depolarization in canine cardiac Purkinje fibers. Am J Physio1247, H312 H321 (1984). 7 LEE, C. O., FOZZARD, H. A. Membrane permeability during low potassium depolarization in sheep cardiac Purkinje fibers. A m J Physio1237, C156-C165 (1979). 8 LIN, C. I., C m A ~ , B. N., CHENG, K. K. Positive inotropic effect of acetylcholine in isolated human atrial fibers. IntJ Cardiol 6, 743 746 (1984). 9 LIN,C. I., VASSALLE,M. The antiarrhythmic effect of potassium and rubidium in strophanthidin toxicity. E u r J Pharmaco162, 1-15 (1980). 10 MARY-RABINE,L., ALBERT,A., PHAM,T. D., HORDOF,A., FENOOLIO,J. J., Jr, MALM,J. R., Rosen, M. R. The relationship of human atrial cellular electrophysiology to clinical function and ultrastructure. Circ Res 52, 188 199 (1983). 11 MARY-RABINE,L., HORDOE, A.J., DANILO, P., Jr, MALM,J. R., ROSEN, M. R. Mechanisms for impulse initiation in isolated human atrial fibers. Circ Res 47, 267-277 (1980). 12 SKINNER,R. B., Jr, KUNZE, D. L. Changes in extracellular potassium activity in response to decreased pH in rabbit atrial muscle: Circ Res 39, 67~683 (1976). 13 TEN LICK, R. E., SIN~ER, D. H. Electrophysiological properties of diseased human atrium. I. Low diastolic potential and altered cellular response to potassium. Circ Res 44, 545 557 (1979).
* To whom correspondence should be addressed.
RAPID COMMUNICATION
Electrophysiological Effects o f Low pH in H u m a n Atrial Fibres (Received 19 April 1985, accepted16 August 1985) In the s t u d i e s o f the e l e c t r o p h y s i o l o g i c a l p r o p e r t i e s o f h u m a n a t r i a l f i b r e s o b t a i n e d at c a r d i a c s u r g e r y , it h a s o f t e n b e e n r e p o r t e d t h a t the d i a s t o l i c p o t e n t i a l , the m a x i m u m u p s t r o k e v e l o c i t y o f the p h a s e 0 d e p o l a r i z a t i o n ( IYmx) a n d t h e a m p l i t u d e o f a c t i o n p o t e n t i a l a r e r e l a t i v e l y l o w [4, 5, 10, 11, 13]. T h e s a m e f i n d i n g s w e r e also o b t a i n e d in o u r p r e v i o u s s t u d y {8l w h e n the t i s s u e p r e p a r a t i o n s w e r e p e r f u s e d w i t h a T y r o d e s o l u t i o n w h i c h , as u s u a l l y d e s c r i b e d in l i t e r a t u r e s on c a r d i a c cell s t u d i e s [1, 4, 5, 11, 13] h a d a N a H C O 3 c o n c e n t r a t i o n o f 12 mM a n d w a s a e r a t e d w i t h a gas m i x t u r e o f 95% 0 2 - 5% CO 2 at 37~ R e c e n t l y w e f o u n d t h a t the r e l a t i v e l y p o o r e l e c t r i c a l a c t i v i t i e s o f the h u m a n a t r i a l f i b r e s w e r e r e l a t e d to the low p H v a l u e ( a r o u n d 7.06) o f the p e r f u s a t e used. R a i s i n g the p H v a l u e o f the p e r f u s a t e e i t h e r b y i n c r e a s i n g the N a H C O 3 c o n c e n t r a t i o n o r b y r e d u c i n g the CO 2 in the b u b b l i n g gas m i x t u r e s i g n i f i c a n t l y i m p r o v e d the e l e c t r i c a l a c t i v i t i e s o f the fibres. T h e r e is evid e n c e t h a t the s u p p r e s s i v e effect o f low p H on the e l e c t r i c a l a c t i v i t i e s is d u e to the hindering a c t i o n o f H + on the t r a n s p o r t a t i o n o f o t h e r c a t i o n s a c r o s s the p l a s m a membrane. Specimens of human atrial appendage were obtained from the hearts of 12 patients (32 __+ 7 years old, mean __+ s.E.~.) undergoing open-heart surgery. Prior to surgery, informed consent was obtained. The tissue was immersed in cold Tyrode solution immediately after excision from the right atrium as part of the routine atriotomy procedure. Strands of atrial trabecular muscle fibres with a diameter of 0.5 to 1.5 mm were removed and placed in a tissue bath perfused with Tyrode solution at 37~ The compositions of control Tyrode solution in mM is NaCI, 125; KCI, 4; NaHCO3, 24; NaH2PO4, 0.5; MgC12, 0.5; CaC12, 2.7 and dextrose, 5.5. This control solution was oxygenated with a gas mixture of 95% 02 5% CO2, yielding a pH of 7.38 __+0.01 (n = 6) in tissue bath. The low pH solution (7.06 __+0.02, n = 6) were prepared by decreasing the N a H C O 3 concentration from 24 to 12 mM with a compensatory increase of NaC1 from 125 to 137 m~. In certain experiments, the pH of low N a H C O 3 0022-2828/86/010109 + 04 $03.00/0
solution was increased to 7.31 ___0.02 (n = 4) by saturating the low NaHCO3 solution with a gas mixture of 98% 0 2 - 2 % CO 2. The preparations were initially driven at a cycle length of 1000 ms. Transmembrane potentials were detected by means of glass microelectrodes filled with 3 M KC1. The action potential and its first derivative were displayed continually on a chart recorder (Gould 2400S) and a digitizing oscilloscope (Tektronix 5223). Occasionally the recordings were stored on magnetic tape (Gould 6500) for future playback. The preparations in the present experiments were divided into two main groups on the basis of their electrical activities. One group of atrial fibres (n = 5). responded to electrical stimulation with a Vmax of phase 0 depolarization faster than 180 V/s (fast response) in control Tyrode solution. The other group (n = 7) had a /?max less than 30 V/s (slow response) in the same experimental conditions. Figure l(a) shows the effect of a 9 1986 Academic Press Inc. (London) Limited
110
Rapid c o m m u n i c a t i o n : Z-Y. Hou et aL 5 0 0 ms
(o) Oi
~
+4~176
"
!
J
X__\
!
V/s C02 (HC03-) pH
~
5 24 7.38
i
5 12 7.06
L 2% 12 mu
7.31
(bl
0.Ss
x.____.
~
-
mV
coV -
5
(HE03-) 241 DH 7.38
0
~ 19_
7.06
7.38
F I G U R E 1. Effects of pH on h u m a n atrial fibres showing fast response action potential. In (a), oscilloscopic recordings of action potential (upper trace) and its first derivative (d V/dt, lower trace) were recorded after 13-rain perfusion in Tyrode solution containing 24 mM (left panel) or 12 mM N a H C O a (middle and right panels), T h e perfusates were either aerated with a gas mixture of 95% 0 2 5% CO 2 (left and middle panels) or 98% 0 2 - 2 % C O e (right panel). In (b) the dots above the slow-speed chart recordings show the time at which the oscilloscopic recordings in top panels have been recorded in sequence. The pH of perfusate was decreased by reducing N a H C O 3 concentration from 24 to 12 mM as indicated, T h e break in chart recordings was 212 s. T h e pH values of the perfusates at tissue bath were measured by an ABL 3 Radiometer. The preparations were driven at 60 cycles per rain. In (a) the d F/dt for phase 0 depolarization had been retouched.
reduced pH on an atrial fibre with a maximum diastolic potential (MDP) of - 8 6 m V and a l?max of 355 V/s in control Tyrode solution oxygenated with 95% 0 2 - 5 % C O 2. When the perfusate was shifted to a low N a H C O 3 solution for 13 rains and pH was reduced from 7.38 to 7.06, the action potential duration was increased and the M D P was shifted to a more positive value (--81 mV), but the T)'max and the amplitude of action potential remained unchanged. When low NaHCO3 solution was saturated with 98% O z - 2 % CO2 and p H was increased to 7.31, the M D P was returned to a more negative value ( - 8 4 mV) while the Vmax and the action potential duration changed very little. Similar results were observed in three other preparations. In the last atrial preparation with a Dma. of 180 V/s and a lower level of M D P ( - 6 3 mV), however, exposure to the low p H solution induced a pronounced depolarization (to - 4 4 mV) and the fibre eventually became inexcitable within 2 rains [Fig. l(b)]. The deteriorating effects were readily
reversible after washout with control Tyrode solution. The average ;)max and M D P for these five atrial preparations showing fast response action potentials in control perfusate were 252 + 35 V/s and --71 -t- 5 mV, respectively. The respective values were 215 4- 62 V/s and - 6 4 + 6 mV during exposure to low p H perfusate. The differences in Vm~x ( - 3 7 4` 32 V/s) and M D P ( + 6 . 6 4- 4.4 mV) were not found to be statistically significant (P > 0.2). However, the increase in action potential duration at 50% repolarization ( + 6 7 4-11 ms, from 166 4- 10 to 233 + 10 ms) was significant (P < 0.01) by paired Student's t test. In atrial preparations showing slow response action potenials (either active spontaneously or driven electrically), low p H solution induced significant change in Vmax and MDP, as illustrated in Figure 2. In seven preparations from seven patients, the M D P was shifted f r o m - 5 3 4- 4 t o - 4 2 + 3mV (-t-11.04-2.1 mV, P < 0.01). The ~-max was also decreased significantly (--6.7 + 2.4 V/s,
L o w p H a n d H u m a n Atrial M e m b r a n e P o t e n t i a l (a)
0.5 s
111
accumulation of potassium in the extracellu-
lar spaces of the Purkinje fibres [1]. An alternative explanation is that acidosis induces a - 5 o ~ L . . . . . 4 L..... decrease in m e m b r a n e potassium conduc+2o~ ~ ~~ tance and the subsequent m e m b r a n e depolarV/s ization [3, 6]. HC03-) 24 12 24 mM In rabbit atrial muscle ceils, a reduction of pH 7.37 7.07 7.57 p H from 7.5 to 6.1 was associated with a (b) 0.5 s decrease in [K] i and an increase in [K]0 and caused a positive shift in resting m e m b r a n e potential and equilibrium potential for potassium (E~) [12]. Thus the reduction of mV 20 s resting potential could be explained by an inhibition of the N a - K pump. Increasing "" "~JJ~""~V ,, lljii,l~l; [K]0 from 3.6 to 5 m~ produced a similar ,!11 !~lH!" depolarizing effect [12]. Results of the present experiments show that, in h u m a n atrial fibres, ( HCO3-) 24~_~,2 ~ mu t a moderate reduction o f p H from 7.38 to 7.06 PHIZ~ J'~'~'~ L K5.4 m~ J. K4 m~ was capable of producing an approximately FIGURE 2. Effects of pH on human atrial fibres 10 m V depolarization and inhibiting the showing slow response action potential. In (a) oscil- repolarization process. Increasing [K] 0 from 4 loscopic recordings of action potential (upper trace) and its first derivative (lower trace) were recorded in control to 5.4 to 6 mM during low p H perfusion could solution (left panel), in low NaHCO 3 Tyrode solution reverse the m e m b r a n e depolarization. Similar (middle panel) and again in control solution (right repolarizing effects of increasing [K] 0 have panel). The preparation was driven at 60 cyclesper rain. been observed in dog Purkinje fibres during In (b), another preparation was allowed to discharge spontaneously. The dots above the the slow-speed chart low p H perfusion [6] or during strophanthirecordings show the time at which fast-speed recordings din intoxication [9]. T h u s the low p H depoin top panels have been recorded in sequence. The pH of larization in h u m a n atrial fibres appears to be perfusate was decreased by reducing NaHCO 3 from 24 to similar to a low [K]o depolarization [7] and 12 mM. During low pH perfusion, [/('J0 was increased from 4 to 5.4 mM for 3.5 min. The breaks in slow speed could be due to a decrease in m e m b r a n e potassium conductance. T h e prolongation of recordings were 422 and 128 s, respectively. action potential duration was associated with m e m b r a n e depolarization and could also be fromlT_2to I1 + 3 V / s , P < 0 . 0 5 ) . F i g u r e explained by a reduction in potassium con2(b) also shows that the depolarizing effects of ductance. low p H could be antagonized by increasing It has been shown that both sodium and [/f]0 from 4 to 5.4 raM. I n three experiments, calcium conductances of frog atrial fibres were increasing I/f]0 from 4 to 5.4-6 m M shifted depressed in acidic media [2]. In our study in the M D P from - 4 3 • 3 to - - 5 3 + 7 inV. h u m a n atria, significant suppression of rate of Decreasing the C O 2 in gas mixture from 5% rise of action potential was observed only in to 2% induced similar repolarizing effect on fibres showing slow responses ( Vmax< 30 V/s). M D P ( - 3 . 1 - 1 - 0 . 4 mV, from --63__+8 to These slow response action potentials were - 6 6 4- 8 mV) (P < 0.02, n = 4). characterized by a low level of m a x i m u m Studies of the effects of acid solutions on diastolic potential (around --53 mV). It electrical activities of m a m m a l i a n cardiac has been proposed that at m a x i m u m tissues have been concentrated on ventricular diastolic potentials less than - 6 0 mV, the Purkinje fibres, using either buffers [1, 63 or rapid inward current responsible for phase 0 C O 2 [3]. It has been shown that p H depolarization is largely inactivated and the reductions could induce m e m b r a n e depolaraction potential is initiated by a slow inward ization and slow response action potentials in current [4]. T h e differential suppressive effect Purkinje fibres [3, 6]. O n e possible explanaof low p H on the upstroke velocity of the slow tion fbr the H +-induced depolarization is that response v. the fast response action potential proton inhibits sodium pump, leading to an suggest a greater inhibition o f H + on the slow mvO[~
~llV
~
- ~ ~ . . _ - ~
112
Rapid communication: Z-Y. Hou
i n w a r d c u r r e n t t h a n o n t h e fast i n w a r d current. Further studies with voltage-clamp t e c h n i q u e a r e r e q u i r e d to clarify this p o i n t .
et aL
t h e m a n u s c r i p t , to D r G u a n g - M i n g S h i a o for t h e use o f A B L 3 R a d i o m e t e r a n d to M s I - N i n g C h u a n g for t e c h n i c a l assistance.
Acknowledgements This work was supported by grant from Academia Sinica, Taipei, R.O.C. Dr Hou was a Research Fellow from the Division of Cardiology, D e p a r t m e n t of Medicine, Veterans G e n e r a l H o s p i t a l . T h e a u t h o r s a r e g r a t e f u l to p r o f e s s o r H s i n - H s i a n g L u for h e l p i n w r i t i n g
Zone-Yuan Hou, Cheng-I L i n l * , Benjamin N. Chiang and Kwok-Kei Cheng Clinical Research Centre, Veterans General Hospital, Taipei, and aDepartment of Pharmacology, National Defense Medical Center, P.O. Box 8244, Taipei, Taiwan, Republic of China
KEY WORDS: Atria; pH, Low; Vmax ; Acidosis.
References 1 BROWN, R. H., Jr, COHEN, I., NOBLE, D. The interactions of protons, calcium and potassium ions on cardiac Purkinje fibres.J Physiol [Lond] 282,345 352 (1978). 2 CHESNAIS,J. M., CORABOEUF,E., SAUVIAT,M. P., VASSAS,J. M. Sensitivity to H, Li and Mg ions of the slow inward sodium current in frog atrial fibres.J Mol Cell Cardiol 7, 627 642 (1975). 3 CORABOEUF,E., DEROUBAIX,E., HOERTER,J. Control of ionic permeabilities in normal and ischemic heart. Circ Res38 [Suppl I], 192 197 (1976). 4 HORDOF,A.J., EmE, R., MALM,J. R., HOFFMAN,B. F., ROSEN, M. R. Electrophysiologic properties and response to pharmacologic agents of fibers from diseased human atria. Circulation 54, 774-779 (1976). 5 HORDOr, A. J., SPOTNITZ,A., MARY-RABINE,L., ED1E, R. N., ROSEN, M. R. The cellular electrophysiologic effects of digitalis on human atrial fibers. Circulation 57,223 229 (1978). 6 LAUER,M. R., RusY, B. F., DAVIS,L. D. H+-induced membrane depolarization in canine cardiac Purkinje fibers. Am J Physio1247, H312 H321 (1984). 7 LEE, C. O., FOZZARD, H. A. Membrane permeability during low potassium depolarization in sheep cardiac Purkinje fibers. A m J Physio1237, C156-C165 (1979). 8 LIN, C. I., C m A ~ , B. N., CHENG, K. K. Positive inotropic effect of acetylcholine in isolated human atrial fibers. IntJ Cardiol 6, 743 746 (1984). 9 LIN,C. I., VASSALLE,M. The antiarrhythmic effect of potassium and rubidium in strophanthidin toxicity. E u r J Pharmaco162, 1-15 (1980). 10 MARY-RABINE,L., ALBERT,A., PHAM,T. D., HORDOF,A., FENOOLIO,J. J., Jr, MALM,J. R., Rosen, M. R. The relationship of human atrial cellular electrophysiology to clinical function and ultrastructure. Circ Res 52, 188 199 (1983). 11 MARY-RABINE,L., HORDOE, A.J., DANILO, P., Jr, MALM,J. R., ROSEN, M. R. Mechanisms for impulse initiation in isolated human atrial fibers. Circ Res 47, 267-277 (1980). 12 SKINNER,R. B., Jr, KUNZE, D. L. Changes in extracellular potassium activity in response to decreased pH in rabbit atrial muscle: Circ Res 39, 67~683 (1976). 13 TEN LICK, R. E., SIN~ER, D. H. Electrophysiological properties of diseased human atrium. I. Low diastolic potential and altered cellular response to potassium. Circ Res 44, 545 557 (1979).
* To whom correspondence should be addressed.