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Quinidine and quinine effects on the slow wave activity of colonic circular muscle
European Journal of Pharmacology, 163 (1989) 137-140
137
Elsevier EJP 20343 Short communication
Quinidine and quinine effects on the slow wave activity of colonic circular muscle Carlos B a r a j a s - L 6 p e z a n d J a n D. H u i z i n g a * Intestinal Disease Research Unit and Department of Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada
Received 24 January 1989, accepted 31 January 1989
The slow wave plateau phase has an important role in the regulation of contractile activity in the canine colon. Quinidine (ECs0 - 5 /~M) and quinine (ECs0 - 13 /IM) inhibited in a concentration dependent manner the plateau phase. Quinidine and quinine decreased the plateau amplitude, and increased the plateau potential; whereas, they did not affect the upstroke amplitude, and the average rate of rise of the slow waves. Their specific effect on the slow wave plateau suggests that the plateau phase depolarization is mediated by a quinidine- and quinine-sensitive inward current. Quinidine and quinine will be useful experimental tools to further characterize the ionic conductances responsible for the plateau depolarization. Quinidine; Quinine; Colon electrophysiology; Interstitial cells of Cajal; Slow waves; Pacemaker activity
1. Introduction
In the circular muscle of the dog colon, the membrane potential threshold for contraction generation (mechanical threshold) is about - 4 5 mV (Barajas-L6pez and Huizinga, in press). The membrane potential periodically passes this threshold through slow waves (pacemaker activity) and spike potentials, generating contraction (Barajas-Lbpez and Huizinga, 1988; in press). Slow waves are generated in cells at the submucosal surface (Barajas-Lbpez and Huizinga, 1988; Smith et al., 1987); the slow wave amplitude decreases through the thickness of the circular layer (Smith et al., 1987) and a plateau potential gradient exists between the cells from both surfaces of this layer, the plateau potential being 15 mV lower in the submucosal surface cells (Barajas-L6pez and Huizinga, 1988; in press). These observations indi* To whom all correspondenceshould be addressed: McMaster University, Health Science Center 3N5C, 1200 Main Street West, Hamilton, Ontario, Canada, LSN 3Z5.
cate passive propagation of slow waves toward the myenteric plexus surface cells, and they suggest that a specific conductance, responsible for the large depolarization during the plateau, is present exclusively in cells closer to the submucosal surface, likely in the pacemaker cells (BarajasL6pez and Huizinga, in press). The present study characterizes the quinidine and quinine effects on the spontaneous slow wave activity of the circular smooth muscle of the dog colon. Our data show that quinidine and quinine inhibit selectively the slow wave plateau at the submucosal surface cells of the circular layer, probably by acting on the interstitial cells of Cajal.
2. Materials and methods
Dogs, either male or female, were anaesthetized using pentobarbital (35 m g / k g ) given i.v. The colon was exposed by a midline abdominal incision. A - 10 cm segment of proximal colon was removed, 5 cm distal to the ileocecal junction. The
0014-2999/89/$03.50 © 1989 ElsevierSciencePublishers B.V. (BiomedicalDivision)
138
details of the methods and equipment used to record the electrical activity have been described previously (Barajas-L6pez and Huizinga, in press). The strip was mounted in a recording chamber with its submucosal surface upward. The electrical activity was measured only from the superficial cells at the submucosal surface, less than 100 /~m below the surface of the layer. All experiments were carried out in prewarmed (36.5-37.0°C) Krebs solution and equilibrated with 95% 02-5% CO 2. The composition of the solution was (mM): NaC1 120.3; KC1 5.9; CaC12 2.5; MgC12 1.2; N a H C O 3 20.0; NaH2PO 4 1.2 and glucose 11.5, pH 7.3-7.35. Quinidine or quinine (Sigma Co.) were added to the Krebs solution to reach the desired concentration. Experiments were performed in the presence of tetrodotoxin (5 × 10 -7 M; Sigma Co.) to prevent nerve mediated responses. The following parameters were measured in 2 min periods, during the control situation and approximately 5 min after each concentration of quinidine or quinine: resting membrane potential,
~---
3.1. Quinidine effects As previously described (Barajas-L6pez and Huizinga, 1988, in press; Durdle et al., 1983; Smith et al., 1987), superficial cells at the submucosal surface exhibited an omnipresent and
[QUINIDINE
~ 2 5
"-'~ 40~rnV 1 2s
3. Results
CONTROL
-
-72 mV~'~-" 7
slow wave frequency, mean duration of slow waves and of the plateau phase, mean upstroke and plateau amplitude, the membrane potential during the plateau phase (plateau potential), and the average rate of rise. The duration was measured at half-maximal plateau amplitude of the slow wave. Data within one dose response curve were obtained usually from recordings of the same cell or from a neighbor cell. Control data were compared with those recorded in the presence of quinidine or quinine using the paired Student's t-test. A difference was considered significant with P < 0.05. Data were expressed as means + S.E.
B
(~i)
10
-
~u 100
< 0. < ku t~ Ill "rph O k-
Z
CONTROL
2 4
20 }JM [QUININE l
50 40 mV
I
i~
-
:'i
2 2
,J!
,,
I'!-
CONTROL
5
10 20
C) [QUINIDINE]; •
5 0 100
[QUININE]
(juM)
JL_ 1 min
Fig. 1. (A) Concentration dependence of quinidine- and quinine-induced inhibition of the plateau phase in the colonic circular muscle. Cumulative concentrations of both drugs were used. Two to five different concentrations were used in each muscle strip. Circles represent the mean values and the bars the standard error. Lines were calculated using simple regression analysis. Concentration for the half maximal response (ECs0) was calculated using these lines. N u m b e r s in parentheses denote number of strips in which a particular concentration was tested. Inset: Representative slow waves recorded in normal Krebs solution, and in different quinidine concentrations. (B) Quinine effects on the intracellular electrical activity. All recordings were performed in the same cell, upper tracing before quinine was added, middle tracing 5 min after start of quinine perfusion, and lower tracing 10 rain after wash out of the substance. The dashed line between slow waves indicates the - 40 mV membrane potential.
139
spontaneous slow wave activity (fig. 1). Table 1 summarizes the quinidine effects on the spontaneous electrical activity. In the presence of 5 /tM quinidine, the slow wave duration was significantly decreased, this effect was due to inhibition of the plateau phase (fig. 1). The plateau amplitude was also decreased, whereas the plateau potential and the slow wave frequency were increased. A small decrease in the resting membrane potential was observed. No significant effect was observed on the upstroke amplitude, and average rate of rise. The maximal effect of quinidine on the plateau phase, was observed within 5 rain after addition of the drug, this effect was concentration dependent, with an ECs0 of about 5/~M (fig. 1A). Quinidine effects were reversible, recovery was obtained within 20 min after washout.
3.2. Quinine effects Quinine effects on the slow wave activity were very similar to the actions of quinidine (table 1, and fig. 1A). Significant effects were observed on the frequency, and duration of the slow wave activity. Similar to quinidine, quinine always blocked the plateau phase of the slow waves, with an ECs0 of 13 /~M. Quinine effects were also reversible (fig. 1B).
4. Discussion
The present observations show that quinidine and quinine inhibited specifically and in a concentration dependent fashion the flow wave plateau, suggesting that the depolarization during the plateau phase is mediated by a quinidine and quinine sensitive conductance. In agreement with this, quinidine also decreased the plateau amplitude and decreased the depolarization during the plateau phase. The inhibition of the plateau is likely independent of the well known actions of quinidine and quinine and potassium conductances (Glavinovic and Trifaro, 1988; Imaizumi and Giles, 1987; Nawrath, 1981), since other potassium conductance blockers, like tetraethylammonium, prolonged rather than decreased the plateau phase (Barajas-Lbpez and Huizinga, 1988). Calcium influx blockage, by either D600 or by decreasing the extracellular calcium concentration also inhibited the plateau phase, decreased the plateau amplitude, and decreased the depolarization during the plateau, which suggested that the conductance responsible for the plateau phase is calcium influx dependent (Barajas-L6pez and Huizinga, 1988). In support of this hypothesis, the membrane potential during the plateau is low enough ( - - 4 0 mV) to activate a voltage depen-
TABLE 1 Quinidine and quinine effects (at ECs0 ) on the intracellular electrical activity. Membrane potential
Slow wave
(mV)
Plateau potential (mV)
Plateau amplitude (mV)
Upstroke amplitude (mV)
Rate of rise (mV/s)
Duration (s)
Frequency (cpm)
Control Quinidine
- 72 ± 1.0 - 71 ± 1.1
(5 ~ M )
b
-36±1.0 -38±0.8 b
35±1.2 33±1.5 b
~±1.5 40±1.6 NS
91±12 90±12 NS
6.6±0.6 4 +0.3 c
4.4±0.2 5.1±0.2 c
n=7 Control Quinine (20 # M )
- 72 ± 2.0 - 72 ± 1.7 NS
-35±1.5 -37±1.3 NS
36±1.1 35±1.2 NS
41±1.3 41±1.7 NS
8 6 ± 5.5 97±10 NS
6.4±0.5 3.2±0.2 c
4.0±0.2 4.6±0.2 b
n=9
a
n, number of strips; b p < 0.05; c P < 0 . ~ 5 ;
NS, n o t s i g n i f i c ~ t l y d i f f e r e n t ; P v a l u e s o b t a i n e d w i t h t h e p a i r e d S t u d e n t ' s t - t e s t .
140
dent calcium current (Langton et al., 1988) and to pass the mechanical threshold in the colonic circular muscle cells (Barajas-L6pez and Huizinga, in press). Thus, it is possible that quinidine and quinine inhibited the plateau phase by blocking a calcium conductance, as observed in heart muscle fibers (Nawrath, 1981). Voltage dependent calcium currents (Langton et al., 1988) will also be expected to be activated during the upstroke depolarization. Indeed D600 reduced the upstroke suggesting that at least part of the upstroke is calcium influx mediated (Barajas-L6pez and Huizinga, 1988). Quinidine and quinine however, did not affect the upstroke amplitude. These observations suggest that the calcium conductance activated during the upstroke and the one responsible for the depolarization during the plateau phase, are different. Slow wave activity of the circular muscle of the dog colon is a consequence of membrane conductance changes (Barajas-L6pez et al., in press b) and probably generated in the network of interstitial cells of Cajal (ICC) close to the submucosal surface (Barajas-L6pez and Huizinga, 1988; Barajas-L6pez et al., in press a; Berezin et al., 1988; Durdle et al., 1983; Smith et al., 1987). In support of this hypothesis it has been shown that the slow wave activity can be recorded in these cells (Barajas-L6pez et al., in press a), and that slow waves disappear after the removal of the network of ICC (Durdle et al., 1983; Smith et al., 1987). Thus, the plateau conductance is only expressed by the cells close to the submucosal surface of this circular muscle (Barajas-L6pez and Huizinga 1988; in press) probably only by the ICC, (Barajas-L6pez and Huizinga, 1988; in press). Therefore, it is likely that the ICC are mediating the quinidine and quinine effects on the slow wave activity. In conclusion, our results indicate that quinidine and quinine block specifically a conductance responsible for the depolarization during the plateau phase. This conductance is calcium influx dependent and therefore could be either a calcium conductance or a calcium activated conductance. Quinidine and quinine will be useful experimental
tools to further characterize the ionic conductances in single cell studies, and to identify the cells that generate a conductance sensitive to these substances, which likely are the ICC.
Acknowledgements This work was supported by grants from the Medical Research Council of Canada. J.D. Huizinga is a MRC scholar; Carlos Barajas-Lrpez is a MRC fellow.
References Barajas-L6pez, C. and J.D. Huizinga, 1988, Heterogeneity in spontaneous and tetraethylammonium induced intracellular electrical activity in colonic circular muscle, Pfliigers Arch. 412, 203. Barajas-Lrpez, C., I. Berezin, E.E. Daniel and J.D. Huizinga, Role of the interstitial cells of Cajal (ICC) in generation of pacemaker activity, FASEB (Abstract) (in press a). Barajas-L6pez, C., E. Chow, A. Den Hertog and J.D. Huizinga, Role of the sodium pump in pacemaker generation in dog colonic smooth muscle, J. Physiol. London (in press b). Barajas-Lrpez, C. and J.D. Huizinga, Different mechanisms of contraction generation in circular muscle of canine colon, Am. J. Physiol. 256G (in press). Berezin, I., J.D. Huizinga and E.E. Daniel, 1988, Interstitial cells of Cajal canine colon: a special communication network at the inner border of the circular muscle, J. Comp. Neurol. 273, 42. Durdle, N.G., Y.J. Kingma, K.L. Bowes and M.M. Chambers, 1983, Origin of slow waves in the canine colon, Gastroenterology 84, 375. Glavinovic, M.I. and J.M. Trifaro, 1988, Quinine blockade of currents through Ca2+-activated K + channels in bovine chromaffin ceils, J. Physiol. London 399, 139. Imaizumi, Y. and W.R. Giles, 1987, Quinidine-induced inhibition of transient outward current in cardiac muscle, Am. J. Physiol. 253, H704. Langton, P.D., E.P. Burke and K.M. Sanders, 1988, Characteristics of calcium current in circular smooth muscle cells of canine proximal colon, Gastroenterology 95, 876 (Abstract). Nawrath, H., 1981, Action potentials, membrane currents and force of contraction in mammalian heart muscle fibers treated with quinidine, J. Pharmacol. Exp. Ther. 216, 176. Smith, T.K., J.B. Reed and K.M. Sanders, 1987, Origin and propagation of electrical slow waves in circular muscle of canine proximal colon, Am. J. Physiol. 252, C215.
137
Elsevier EJP 20343 Short communication
Quinidine and quinine effects on the slow wave activity of colonic circular muscle Carlos B a r a j a s - L 6 p e z a n d J a n D. H u i z i n g a * Intestinal Disease Research Unit and Department of Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada
Received 24 January 1989, accepted 31 January 1989
The slow wave plateau phase has an important role in the regulation of contractile activity in the canine colon. Quinidine (ECs0 - 5 /~M) and quinine (ECs0 - 13 /IM) inhibited in a concentration dependent manner the plateau phase. Quinidine and quinine decreased the plateau amplitude, and increased the plateau potential; whereas, they did not affect the upstroke amplitude, and the average rate of rise of the slow waves. Their specific effect on the slow wave plateau suggests that the plateau phase depolarization is mediated by a quinidine- and quinine-sensitive inward current. Quinidine and quinine will be useful experimental tools to further characterize the ionic conductances responsible for the plateau depolarization. Quinidine; Quinine; Colon electrophysiology; Interstitial cells of Cajal; Slow waves; Pacemaker activity
1. Introduction
In the circular muscle of the dog colon, the membrane potential threshold for contraction generation (mechanical threshold) is about - 4 5 mV (Barajas-L6pez and Huizinga, in press). The membrane potential periodically passes this threshold through slow waves (pacemaker activity) and spike potentials, generating contraction (Barajas-Lbpez and Huizinga, 1988; in press). Slow waves are generated in cells at the submucosal surface (Barajas-Lbpez and Huizinga, 1988; Smith et al., 1987); the slow wave amplitude decreases through the thickness of the circular layer (Smith et al., 1987) and a plateau potential gradient exists between the cells from both surfaces of this layer, the plateau potential being 15 mV lower in the submucosal surface cells (Barajas-L6pez and Huizinga, 1988; in press). These observations indi* To whom all correspondenceshould be addressed: McMaster University, Health Science Center 3N5C, 1200 Main Street West, Hamilton, Ontario, Canada, LSN 3Z5.
cate passive propagation of slow waves toward the myenteric plexus surface cells, and they suggest that a specific conductance, responsible for the large depolarization during the plateau, is present exclusively in cells closer to the submucosal surface, likely in the pacemaker cells (BarajasL6pez and Huizinga, in press). The present study characterizes the quinidine and quinine effects on the spontaneous slow wave activity of the circular smooth muscle of the dog colon. Our data show that quinidine and quinine inhibit selectively the slow wave plateau at the submucosal surface cells of the circular layer, probably by acting on the interstitial cells of Cajal.
2. Materials and methods
Dogs, either male or female, were anaesthetized using pentobarbital (35 m g / k g ) given i.v. The colon was exposed by a midline abdominal incision. A - 10 cm segment of proximal colon was removed, 5 cm distal to the ileocecal junction. The
0014-2999/89/$03.50 © 1989 ElsevierSciencePublishers B.V. (BiomedicalDivision)
138
details of the methods and equipment used to record the electrical activity have been described previously (Barajas-L6pez and Huizinga, in press). The strip was mounted in a recording chamber with its submucosal surface upward. The electrical activity was measured only from the superficial cells at the submucosal surface, less than 100 /~m below the surface of the layer. All experiments were carried out in prewarmed (36.5-37.0°C) Krebs solution and equilibrated with 95% 02-5% CO 2. The composition of the solution was (mM): NaC1 120.3; KC1 5.9; CaC12 2.5; MgC12 1.2; N a H C O 3 20.0; NaH2PO 4 1.2 and glucose 11.5, pH 7.3-7.35. Quinidine or quinine (Sigma Co.) were added to the Krebs solution to reach the desired concentration. Experiments were performed in the presence of tetrodotoxin (5 × 10 -7 M; Sigma Co.) to prevent nerve mediated responses. The following parameters were measured in 2 min periods, during the control situation and approximately 5 min after each concentration of quinidine or quinine: resting membrane potential,
~---
3.1. Quinidine effects As previously described (Barajas-L6pez and Huizinga, 1988, in press; Durdle et al., 1983; Smith et al., 1987), superficial cells at the submucosal surface exhibited an omnipresent and
[QUINIDINE
~ 2 5
"-'~ 40~rnV 1 2s
3. Results
CONTROL
-
-72 mV~'~-" 7
slow wave frequency, mean duration of slow waves and of the plateau phase, mean upstroke and plateau amplitude, the membrane potential during the plateau phase (plateau potential), and the average rate of rise. The duration was measured at half-maximal plateau amplitude of the slow wave. Data within one dose response curve were obtained usually from recordings of the same cell or from a neighbor cell. Control data were compared with those recorded in the presence of quinidine or quinine using the paired Student's t-test. A difference was considered significant with P < 0.05. Data were expressed as means + S.E.
B
(~i)
10
-
~u 100
< 0. < ku t~ Ill "rph O k-
Z
CONTROL
2 4
20 }JM [QUININE l
50 40 mV
I
i~
-
:'i
2 2
,J!
,,
I'!-
CONTROL
5
10 20
C) [QUINIDINE]; •
5 0 100
[QUININE]
(juM)
JL_ 1 min
Fig. 1. (A) Concentration dependence of quinidine- and quinine-induced inhibition of the plateau phase in the colonic circular muscle. Cumulative concentrations of both drugs were used. Two to five different concentrations were used in each muscle strip. Circles represent the mean values and the bars the standard error. Lines were calculated using simple regression analysis. Concentration for the half maximal response (ECs0) was calculated using these lines. N u m b e r s in parentheses denote number of strips in which a particular concentration was tested. Inset: Representative slow waves recorded in normal Krebs solution, and in different quinidine concentrations. (B) Quinine effects on the intracellular electrical activity. All recordings were performed in the same cell, upper tracing before quinine was added, middle tracing 5 min after start of quinine perfusion, and lower tracing 10 rain after wash out of the substance. The dashed line between slow waves indicates the - 40 mV membrane potential.
139
spontaneous slow wave activity (fig. 1). Table 1 summarizes the quinidine effects on the spontaneous electrical activity. In the presence of 5 /tM quinidine, the slow wave duration was significantly decreased, this effect was due to inhibition of the plateau phase (fig. 1). The plateau amplitude was also decreased, whereas the plateau potential and the slow wave frequency were increased. A small decrease in the resting membrane potential was observed. No significant effect was observed on the upstroke amplitude, and average rate of rise. The maximal effect of quinidine on the plateau phase, was observed within 5 rain after addition of the drug, this effect was concentration dependent, with an ECs0 of about 5/~M (fig. 1A). Quinidine effects were reversible, recovery was obtained within 20 min after washout.
3.2. Quinine effects Quinine effects on the slow wave activity were very similar to the actions of quinidine (table 1, and fig. 1A). Significant effects were observed on the frequency, and duration of the slow wave activity. Similar to quinidine, quinine always blocked the plateau phase of the slow waves, with an ECs0 of 13 /~M. Quinine effects were also reversible (fig. 1B).
4. Discussion
The present observations show that quinidine and quinine inhibited specifically and in a concentration dependent fashion the flow wave plateau, suggesting that the depolarization during the plateau phase is mediated by a quinidine and quinine sensitive conductance. In agreement with this, quinidine also decreased the plateau amplitude and decreased the depolarization during the plateau phase. The inhibition of the plateau is likely independent of the well known actions of quinidine and quinine and potassium conductances (Glavinovic and Trifaro, 1988; Imaizumi and Giles, 1987; Nawrath, 1981), since other potassium conductance blockers, like tetraethylammonium, prolonged rather than decreased the plateau phase (Barajas-Lbpez and Huizinga, 1988). Calcium influx blockage, by either D600 or by decreasing the extracellular calcium concentration also inhibited the plateau phase, decreased the plateau amplitude, and decreased the depolarization during the plateau, which suggested that the conductance responsible for the plateau phase is calcium influx dependent (Barajas-L6pez and Huizinga, 1988). In support of this hypothesis, the membrane potential during the plateau is low enough ( - - 4 0 mV) to activate a voltage depen-
TABLE 1 Quinidine and quinine effects (at ECs0 ) on the intracellular electrical activity. Membrane potential
Slow wave
(mV)
Plateau potential (mV)
Plateau amplitude (mV)
Upstroke amplitude (mV)
Rate of rise (mV/s)
Duration (s)
Frequency (cpm)
Control Quinidine
- 72 ± 1.0 - 71 ± 1.1
(5 ~ M )
b
-36±1.0 -38±0.8 b
35±1.2 33±1.5 b
~±1.5 40±1.6 NS
91±12 90±12 NS
6.6±0.6 4 +0.3 c
4.4±0.2 5.1±0.2 c
n=7 Control Quinine (20 # M )
- 72 ± 2.0 - 72 ± 1.7 NS
-35±1.5 -37±1.3 NS
36±1.1 35±1.2 NS
41±1.3 41±1.7 NS
8 6 ± 5.5 97±10 NS
6.4±0.5 3.2±0.2 c
4.0±0.2 4.6±0.2 b
n=9
a
n, number of strips; b p < 0.05; c P < 0 . ~ 5 ;
NS, n o t s i g n i f i c ~ t l y d i f f e r e n t ; P v a l u e s o b t a i n e d w i t h t h e p a i r e d S t u d e n t ' s t - t e s t .
140
dent calcium current (Langton et al., 1988) and to pass the mechanical threshold in the colonic circular muscle cells (Barajas-L6pez and Huizinga, in press). Thus, it is possible that quinidine and quinine inhibited the plateau phase by blocking a calcium conductance, as observed in heart muscle fibers (Nawrath, 1981). Voltage dependent calcium currents (Langton et al., 1988) will also be expected to be activated during the upstroke depolarization. Indeed D600 reduced the upstroke suggesting that at least part of the upstroke is calcium influx mediated (Barajas-L6pez and Huizinga, 1988). Quinidine and quinine however, did not affect the upstroke amplitude. These observations suggest that the calcium conductance activated during the upstroke and the one responsible for the depolarization during the plateau phase, are different. Slow wave activity of the circular muscle of the dog colon is a consequence of membrane conductance changes (Barajas-L6pez et al., in press b) and probably generated in the network of interstitial cells of Cajal (ICC) close to the submucosal surface (Barajas-L6pez and Huizinga, 1988; Barajas-L6pez et al., in press a; Berezin et al., 1988; Durdle et al., 1983; Smith et al., 1987). In support of this hypothesis it has been shown that the slow wave activity can be recorded in these cells (Barajas-L6pez et al., in press a), and that slow waves disappear after the removal of the network of ICC (Durdle et al., 1983; Smith et al., 1987). Thus, the plateau conductance is only expressed by the cells close to the submucosal surface of this circular muscle (Barajas-L6pez and Huizinga 1988; in press) probably only by the ICC, (Barajas-L6pez and Huizinga, 1988; in press). Therefore, it is likely that the ICC are mediating the quinidine and quinine effects on the slow wave activity. In conclusion, our results indicate that quinidine and quinine block specifically a conductance responsible for the depolarization during the plateau phase. This conductance is calcium influx dependent and therefore could be either a calcium conductance or a calcium activated conductance. Quinidine and quinine will be useful experimental
tools to further characterize the ionic conductances in single cell studies, and to identify the cells that generate a conductance sensitive to these substances, which likely are the ICC.
Acknowledgements This work was supported by grants from the Medical Research Council of Canada. J.D. Huizinga is a MRC scholar; Carlos Barajas-Lrpez is a MRC fellow.
References Barajas-L6pez, C. and J.D. Huizinga, 1988, Heterogeneity in spontaneous and tetraethylammonium induced intracellular electrical activity in colonic circular muscle, Pfliigers Arch. 412, 203. Barajas-Lrpez, C., I. Berezin, E.E. Daniel and J.D. Huizinga, Role of the interstitial cells of Cajal (ICC) in generation of pacemaker activity, FASEB (Abstract) (in press a). Barajas-L6pez, C., E. Chow, A. Den Hertog and J.D. Huizinga, Role of the sodium pump in pacemaker generation in dog colonic smooth muscle, J. Physiol. London (in press b). Barajas-Lrpez, C. and J.D. Huizinga, Different mechanisms of contraction generation in circular muscle of canine colon, Am. J. Physiol. 256G (in press). Berezin, I., J.D. Huizinga and E.E. Daniel, 1988, Interstitial cells of Cajal canine colon: a special communication network at the inner border of the circular muscle, J. Comp. Neurol. 273, 42. Durdle, N.G., Y.J. Kingma, K.L. Bowes and M.M. Chambers, 1983, Origin of slow waves in the canine colon, Gastroenterology 84, 375. Glavinovic, M.I. and J.M. Trifaro, 1988, Quinine blockade of currents through Ca2+-activated K + channels in bovine chromaffin ceils, J. Physiol. London 399, 139. Imaizumi, Y. and W.R. Giles, 1987, Quinidine-induced inhibition of transient outward current in cardiac muscle, Am. J. Physiol. 253, H704. Langton, P.D., E.P. Burke and K.M. Sanders, 1988, Characteristics of calcium current in circular smooth muscle cells of canine proximal colon, Gastroenterology 95, 876 (Abstract). Nawrath, H., 1981, Action potentials, membrane currents and force of contraction in mammalian heart muscle fibers treated with quinidine, J. Pharmacol. Exp. Ther. 216, 176. Smith, T.K., J.B. Reed and K.M. Sanders, 1987, Origin and propagation of electrical slow waves in circular muscle of canine proximal colon, Am. J. Physiol. 252, C215.