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CARDIOVASCULAR

Papaverine Blocks hKv1.5 Channel Current and Human Atrial Ultrarapid Delayed Rectifier K⁺ Currents

Department of Physiology, Ulsan University College of Medicine, Seoul, South Korea (Ha.C.); Departments of Pharmacology (Y.-K.L. Y.-T.L., J.-H.K., S.-W.C., Y.-G.K.), Anesthesiology (Hu.C., S.-H.K.), Pediatrics (C.-U.J. and M.-H.K.), and Thoracic and Cardiovascular Surgery (G.-S.K.), and Institute of Cardiovascular Research (S.-W.C., Y.-G.K.), Chonbuk National University Medical School, Chonju, South Korea; and Departments of Pharmacology, Woosuk University College of Pharmacy, Wanju, South Korea (J.-S.E.)

Received August 4, 2002; accepted October 3, 2002.

	Abstract

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Papaverine, 1-[(3,4-dimethoxyphenyl)methyl]-6,-7-dimethoxyisoquinoline, has been used as a vasodilator agent and a therapeutic agent for cerebral vasospasm, renal colic, and penile impotence. We examined the effects of papaverine on a rapidly activating delayed rectifier K⁺ channel (hKv1.5) cloned from human heart and stably expressed in Ltk^– cells as well as a corresponding K⁺ current (the ultrarapid delayed rectifier, I_Kur) in human atrial myocytes. Using the whole cell configuration of the patch-clamp technique, we found that papaverine inhibited hKv1.5 current in a time-and voltage-dependent manner with an IC₅₀ value of 43.4 µM at +60 mV. Papaverine accelerated the kinetics of the channel inactivation, suggesting the blockade of open channels. Papaverine (100 µM) also blocked I_Kur in human atrial myocytes. These results indicate that papaverine blocks hKv1.5 channels and native hKv1.5 channels in a concentration-, voltage-, state-, and time-dependent manner. This interaction suggests that papaverine could alter cardiac excitability in vivo.

Kv channels represent a structurally and functionally diverse group of membrane proteins. These channels play an important role in determining the length of the cardiac action potential and are the targets for antiarrhythmic drugs (Colatsky et al., 1990). Multiple Shaker-like K⁺ channel and subunit genes have been cloned from human myocardium and contribute to its electrical activity (Deal et al., 1996). One of these, Kv1.5, is one of the more cardiovascular-specific Kv channel isoforms identified to date, although it has been found in other tissues (Tamkun et al., 1991; Overturf et al., 1994; Mays et al., 1995; Deal et al., 1996). Cloned from human heart, it forms the molecular basis for an ultrarapid delayed rectifier K⁺ current (I_Kur). hKv1.5 currents expressed in heterologous expression systems are similar in their biophysical and pharmacological properties to I_Kur recorded in human atrial myocytes (Wang et al., 1993; Deal et al., 1996; Feng et al., 1997). Thus, hKv1.5 may form an important molecular target for the treatment of atrial tachyarrhythmias, which represent a major clinical problem with serious morbidity (Cobbe, 1994).

In the present study, we found that papaverine blocked hKv1.5 channel current stably expressed in Ltk^– cells and I_Kur current in human atrial myocytes in a concentration-, time-, voltage-, and state-dependent manner.

	Materials and Methods

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Isolation of Human Atrial Myocytes. Specimens of human right atrial appendage were obtained from the hearts of four patients (range 1– 4 years) undergoing cardiopulmonary bypass surgery. The procedure for obtaining the tissue was approved by the Ethics Committee of the Chonbuk National University Hospital. Samples were immersed in nominally Ca²⁺-free Tyrode's solution (100% O₂, 37°C) of the following composition: 136.0 mM NaCl, 5.4 mM KCl, 1.0 mM MgCl₂, 0.33 mM NaH₂PO₄, 10 mM dextrose, and 10 mM HEPES, pH adjusted to 7.4 with NaOH. The myocardial specimens were chopped with scissors into cubic pieces and placed in a 25-ml flask containing 10 ml of the Ca²⁺-free Tyrode's solution. The tissue was gently agitated by continuous bubbling with 100% O₂. After an initial 5 min in this solution, the pieces were reincubated in a similar solution containing 200 U/ml collagenase (CLS II; Worthington Biochemicals, Freehold, NJ) and 4 U/ml protease (type XXIV; Sigma Korea, Seoul, South Korea). The first supernatant was removed after 45 min and was discarded. The pieces were then incubated in a fresh enzymecontaining solution. Microscopic examination of the medium was performed every 15 min to determine the number and the quality of isolated cells. When the yield seemed to be maximal, the cells were suspended in a storage solution of the following composition: 20 mM KCl, 10 mM KH₂PO₄, 10 mM glucose, 70 mM glutamic acid, 10 mM -hydroxybutyric acid, 10 mM taurine, 10 mM EGTA, and 0.1% albumin, pH adjusted to 7.4 with KOH, and gently pipetted. Only quiescent rod-shaped cells showing clear cross-striations were used.

Cell Culture and Transfection. The method used to establish hKv1.5 expression in a clonal mouse Ltk^– cell line is the same as that described previously (Snyders et al., 1992, 1993). The expression vector contains a dexamethasone-inducible murine mammary-tumor virus promoter that controls transcription of the inserted cDNA and a gene that confers neomycin resistance driven by the simian virus 40 early promoter. The cells used for the experiments reported in the present study displayed hKv1.5-specific mRNA expression after dexamethasone induction as evidenced by Northern blot analysis (Tamkun et al., 1991). Transfected cells were cultured in Dulbecco's modified Eagle's medium supplemented with 10% horse serum and 0.25 mg/ml G418 under 5% CO₂ atmosphere. The cultures were passaged every 3 to 5 days by the use of a brief trypsin treatment. Before experiments, subconfluent cultures were incubated with 2 µM dexamethasone for 12 h to induce expression of hKv1.5 channels. The cells were removed from the dish with a rubber policeman, a procedure that left the majority of the cells intact. The cell suspension was stored at room temperature (20 –22°C) and was used within 12 h for all the experiments reported.

Electrical Recording. The intracellular pipette filling solution contained 100 mM KCl, 10 mM HEPES, 5 mM K₄BAPTA, 5 mM K₂ATP, and 1 mM MgCl₂ and was adjusted to pH 7.2 with KOH, yielding a final intracellular K⁺ concentration of 145 mM. The bath solution contained 130 mM NaCl, 4 mM KCl, 1.8 mM CaCl₂, 1 mM MgCl₂, 10 mM HEPES, and 10 mM glucose and was adjusted to pH 7.35 with NaOH. All chemicals were purchased from Sigma Korea. Experiments were performed in a small volume (0.5 ml) bath mounted on the stage of an inverted microscope (model TE300; Nikon, Tokyo, Japan), perfused continuously at a flow rate of 1 ml/min. I_Kur in human atrial myocytes and hKv1.5 currents in Ltk^– cells were recorded at room temperature (20 –22°C) using the whole cell configuration of the patch-clamp technique (Hamill et al., 1981) with an Axopatch 200B patch-clamp amplifier (Axon Instruments, Inc., Foster City, CA). Currents were recorded at room temperature (21–23°C) and sampled at 1 to 10 kHz after anti-alias filtering at 0.5 to 5 kHz. Data acquisition and command potentials were controlled by pClamp 6.0.3 software (Axon Instruments, Inc.). To ensure voltage-clamp quality, electrode resistance was kept below 3 M. Junction potentials were zeroed with the electrode in the standard bath solution. Gigaohm seal formation was achieved by suction and, after establishing the whole cell configuration, the capacitive transients elicited by symmetrical 10-mV voltage-clamp steps from –80 mV were recorded at 50 kHz for calculation of cell capacitance. We selected cell lines for current levels in the range of 1.5 to 5 nA (at +60 mV). To ensure adequate voltage-clamp control, we calculated the residual access resistance (total access resistance minus amount of analog compensation) for each experiment individually (range, 0.3–3 M) and excluded cells in which the series resistance error exceeded 5 mV.

Pulse Protocols and Analysis. The holding potential was –80 mV, and the cycle time for the protocols was 20 s. The standard protocol to obtain current-voltage relationships and activation curves consisted of 250-ms pulses that were imposed in 10-mV increments between –80 and +60 mV. The steady-state currents were obtained at the end of 250-ms depolarizations. Deactivating tail currents were recorded at –50 mV. The activation curve was obtained from the ratio of tail current amplitudes measured immediately after decay of the capacitive transients. The voltage dependence of channel opening (activation curve) was fitted with a Boltzmann equation

(1)

where k represents the slope factor and E_h represents the voltage at which 50% of the channels are open. The voltage dependence of block was described with the use of the Woodhull (1973) model and was fitted to the equation

(2)

where z, F, R, and T have their usual meaning; represents the fractional electrical distance, i.e., the fraction of the transmembrane electrical field sensed by a single charge at the receptor site, [D] is the papaverine concentration; and K_D^* represents the apparent dissociation constant at the reference potential (0 mV). Concentrationresponse curve was fitted with the following logistic equation using Origin 5.0 software (Origin LabCorp, Northampton, MA)

(3)

where IC₅₀ is the concentration of papaverine resulting in 50% inhibition, and n is the Hill coefficient.

The results are expressed as mean ± S.E.M. The Student's t test was used to calculate the statistical significance of the differences between two populations. Values of p < 0.05 were considered to indicate statistical significance.

	Results

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Figure 1 shows superimposed tracings of potassium current through hKv1.5 channels expressed in mouse Ltk^– cells in control conditions and in the presence of papaverine. The membrane potentials were held at –80 mV and depolarizing pulses from –80 to +60 mV in 10-mV steps were applied every 20 s. Outward currents were followed by decaying outward tail currents upon repolarization to –50 mV. Under control conditions, depolarizations positive to –40 mV elicited outward currents that progressively increased with further depolarizations. The rate of activation was faster at more depolarized levels. The activation time constant was 1.4 ± 0.1 ms at +60 mV (n = 15). At +60 mV, after the current reached the maximum, it declined slowly during the maintained depolarization. Outward tail currents exhibited a dominant time constant of deactivation of 26.7 ± 3.2 ms (n = 15), as has been described previously (Snyders et al., 1992, 1993).

View larger version (30K): [in this window] [in a new window]   Fig. 1. Effect of papaverine on hKv1.5 currents expressed in Ltk– cell line. hKv1.5 current traces were recorded before (A) and 20 min after exposure to 100 µM papaverine (B). Voltage protocol consisted of 250-ms depolarizing pulses from –80 to +60 mV with 10-mV increments from a holding potential of –80 mV and repolarization to –50 mV for 400 ms. Steps were repeated at 20-s intervals. C, resultant I-V relationship of steady-state current taken at the end of the depolarizing pulses in the absence () and the presence (•) of 100 µM papaverine (n = 6). The current at the end of the depolarizing pulses were normalized to the current at +60 mV before papaverine and plotted as relative current. *, significantly different (p < 0.05) from current before papaverine. D, activation curves in the absence () and the presence (•) of 100 µM papaverine (n = 6). The activation curve was obtained from deactivating tail current amplitudes at –50 mV after 250-ms depolarizing steps to the potentials between –60 to +20 mV in steps of 10 mV from a holding potential from –80 mV. The tail current was normalized to the largest value in each group and plotted against membrane potential. Data were fitted with eq. 1. Each point with vertical bar denotes the mean ± S.E.M. *, p < 0.05, significantly different from current before papaverine.

In the presence of papaverine (100 µM), both outward current during depolarizing steps and tail current were reduced compared with control condition (Fig. 1B). Figure 1C shows the effect of papaverine (100 µM) on the steady-state current-voltage (I-V) relationship for the hKv1.5 channel constructed by plotting the current amplitudes at the end of 250-ms depolarizations as a function of the test pulse voltage. Papaverine (100 µM) reduced the peak current and the steady-state current elicited by pulses to +60 mV by 51 ± 3% (n = 6) and 68 ± 6% (n = 6), respectively. The washout of papaverine by perfusion of drug-free solution was obtained within 5 min, and currents were recovered to 93 ± 2% (n = 6) of control levels (data not shown).

Drugs that block ion channels often alter the voltage dependence. Therefore, we analyzed the voltage dependence of activation from the peak amplitude of the decaying tail currents in the absence or presence of papaverine (100 µM) (Fig. 1D). The sigmoidal voltage dependence was fitted with eq. 1, resulting in half-activation voltages of –16.7 ± 1.2 mV (n = 6) and –26.3 ± 1.5 mV (n = 6; p < 0.01), without and with papaverine (100 µM), respectively. The slope factors were not significantly different (6.2 ± 0.5 mV for control and 5.9 ± 0.7 mV for papaverine; n = 6).

The block of hKv1.5 by papaverine in a concentration-dependent manner was shown in Fig. 2A. Steady-state currents were measured at the end of depolarizing pulse of +60 mV to construct the concentration-response curve (Fig. 2B). Plots of steady-state current as a function of papaverine concentration were fitted to the Hill equation. For papaverine-induced block, a half-maximal inhibitory concentration (IC₅₀) and Hill coefficient were 43.4 ± 4.6 and 1.4 ± 0.2 µM, respectively (n = 6).

View larger version (15K): [in this window] [in a new window]   Fig. 2. Concentration-dependent block of hKv1.5 current by papaverine. A, current traces recorded with depolarizing steps to +60 mV from a holding potential of –80 mV in the absence and the presence of various concentrations of papaverine. Currents were recorded after achieving steady-state block by repetitive pulses to +50 mV. Concentrations of papaverine were (from above) 0, 30, 100, and 300 mM, respectively. B, concentration-response relationships of hKv1.5 block by papaverine. Steady-state currents taken at the end of the depolarizing pulse were normalized to control values. Data were fitted with eq. 3 with IC50 value of 43.4 µM and a Hill coefficient of 1.38 (n = 6).

Figure 3 shows superimposed recordings of 250-ms depolarizations of +60 mV followed by repolarizing pulse of –50 mV in the absence and in the presence of papaverine (100 µM). Under control conditions, hKv1.5 current decay was well fitted to a single exponential function with a time constant of 126 ± 12 ms (n = 6). In the presence of papaverine (100 µM), a new component of rapid inactivation was added (Fig. 3A). The time constant of the rapid component was concentration-dependent and was 41 ± 10 ms (n = 6). In contrast, the time constant of slow inactivation was not modified by papaverine.

View larger version (14K): [in this window] [in a new window]   Fig. 3. Effects of papaverine on kinetics of hKv1.5 channel. A, time-dependent block during a depolarization to +60 mV followed by the repolarizing pulse of –50 mV in the presence of 100 µM papaverine. The tracings were normalized to each peak current. B, voltage-dependent block of hKv1.5 by papaverine. Relative currents expressed as Ipapaverine/Icontrol at each depolarizing potential from data obtained in the absence and the presence of papaverine (100 µM). Steady-state current amplitude, normalized to control, is plotted as a function of test potentials. This voltage dependence was fitted (continuous line) with eq. 2, which yielded z values of 0.14 (n = 6). The dashed line represents activation curves in the absence of papaverine. It was superimposed to show that the activation is saturated at the potential range, suggesting the shallow voltage dependence is not due to the intrinsic gating of the channel but the effect of papaverine (see text).

To quantify the voltage dependence of papaverine block, the relative current I_papaverine/I_control was plotted as a function of membrane potential (Fig. 3B). In the presence of papaverine (100 µM), the blockade increased steeply between –30 mV and 0 mV, which corresponds to the voltage range of channel opening (Snyders et al., 1993). These data suggest that papaverine binds primarily to the open state of the hKv1.5 channel. Between 0 and +60 mV, the block of hKv1.5 channel continued to increase with a shallow voltage dependence. It is unlikely that the shallow voltage dependence of block observed at membrane potentials positive to 0 mV was due to channel gating, because hKv1.5 activation had reached saturation over this voltage range (Snyders et al., 1992, 1993). At physiological pH, papaverine is predominantly present in the charged form with a pK_a value of 8.07. Thus, this shallow voltage dependence could be due to the influence of the transmembrane electrical field on the interaction between the charged form of papaverine and the channel receptor. The fractional electrical distance () that is the fraction of electrical field sensed by a single charge at the receptor site was calculated from Woodhull (1973) model. The solid line in Fig. 3B represents a fit of this Boltzmann equation to the data points positive to 0 mV. Using this analysis, we obtained _z value of 0.13 ± 0.02 (n = 6) in the presence of papaverine (100 µM).

We next examined the effects of papaverine on I_Kur in human atrial myocytes. These currents display a number of similarities to those of hKv1.5 (Fedida et al., 1993; Wang et al., 1993). I_Kur was obtained by 250-ms depolarizing pulses ranging from –80 to +60 mV from a holding potential of –50 mV and then repolarizing to 0 mV at 30-s interval. A 100-ms prepulse was introduced 10 ms before each depolarizing pulse to inactivate transient outward current (Wang et al., 1993). Depolarizing pulses applied to atrial myocytes elicited I_Kur, and this current showed outward rectification (Fig. 4A). These currents were inhibited by papaverine (100 µM) in a voltage-dependent manner (Fig. 4B). The I-V relation for I_Kur in five cells is shown in Fig. 4C and indicates voltage-dependent block by papaverine. In Fig. 4D, the normalized current decrease with papaverine is plotted as a function of the voltage.

View larger version (34K): [in this window] [in a new window]   Fig. 4. Effects of papaverine (100 µM) on the sustained outward current (IKur) in human atrial myocytes. A and B, representative IKur current tracings in the absence (A) and the presence of papaverine (B). IKur was obtained by 250-ms depolarizing pulses ranging from –80 to +60 mV from a holding potential of –50 mV, and then repolarizing to 0 mV at 30-s intervals. C, I-V relationship of IKur in the absence () and the presence (•) of papaverine, as determined at the end of the pulse at each voltage. The current were normalized to the current at +60 mV before papaverine and plotted as relative current. *, significantly different (p < 0.05) from current before papaverine. D, voltage-dependent inhibition of IKur by papaverine. Normalized inhibition is shown as relative current (Ipapaverine/Icontrol) from data in C. Data represent means ± S.E.M. of five cells.

	Discussion

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The current generated by hKv1.5 channels is similar in voltage dependence, kinetics, and pharmacological sensitivity to the very rapidly activating delayed rectifier K⁺ current recorded in human atrial myocytes (I_Kur) (Wang et al., 1993), dog ventricle (Jeck and Boyden, 1992), and rat atria (Boyle and Nerbonne, 1991). In fact, the hKv1.5 channel protein has been located in human atrial and ventricular myocardium (Mays et al., 1995). However, electrophysiological studies have indicated the absence of hKv1.5-like current in human ventricular myocytes (Konarzewska et al., 1995; Li et al., 1996). All these results suggest that I_Kur is the native counterpart to hKv1.5 channels in human atria (Tamkun et al., 1991; Snyders et al., 1993; Wang et al., 1993; Deal et al., 1996). In particular, selective block of hKv1.5-like current in human atrial myocytes results in a significant prolongation of the action potential (Wang et al., 1993). Block of cardiac K+ channels increases the action potential duration (Colatsky et al., 1990; Hondeghem and Snyders, 1990; Roden, 1993). However, it is noteworthy that there is a difference in the shape of the steady I-V plots between hKv1.5 (Fig. 1C) and I_Kur (Fig. 4C). Also there is a difference in the shape of percentage of block between hKv1.5 (Fig. 3B) and I_Kur (Fig. 4D). It seems that I_Kur was contaminated by leak current as indicated by the slope in the I-V curve before the activation of the channels. It is also possible that there is more than one type of K⁺ current in the atrial cells and that papaverine is blocking more than just the Kv1.5 current. Therefore, it is likely that the voltage dependence in Fig. 4D may be contaminated by other currents.

Papaverine induced an initial fast decline of the hKv1.5 current during a depolarization in addition to the slow inactivation process that characterizes this current at positive potentials (Fig. 3A), suggesting that papaverine binds to the open state of hKv1.5 channels. Moreover, the interaction of papaverine with the hKv1.5 channels was voltage-dependent (Fig. 3B), reaching a higher degree of block at more positive membrane potentials. These results are also consistent with an open channel block mechanism, because the probability of opening increases at more positive membrane potentials. The _z value based on Woodhull's voltage-dependent block obtained for papaverine is very similar to those described previously for other hKv1.5 blocking agents (Snyders et al., 1992; Rampe et al., 1993a,b; Valenzuela et al., 1995, 1996, 1997; Yang et al., 1995; Delpon et al., 1996; Caballero et al., 1997; Franqueza et al., 1998), which suggests that all these compounds share the same receptor site in hKv1.5 channels. Open channel blockers mimic fast inactivation. Papaverine resulted in earlier activation of hKv1.5 current and shifted the midpoint of activation (Fig. 1D), similar to the effects of Kv subunits on hKv1.5 currents (England et al., 1995a,b; Uebele et al., 1996). This effect may result from the charge of papaverine, because a simple accumulation of positive charges at the inner surface of the channel reduces the effective membrane potential (Gilbert and Ehrenstein, 1969).

Papaverine has been shown to prolong QT interval and ventricular tachycardia (Inoue et al., 1994). Many commonly used drugs, including antiarrhythmic, antihistamine, anti-psychotic, and antibiotic agents are associated with drug-induced LQTS. Most of these drugs either block human ether-a-go-go-related gene-dependent K⁺ current (IKr) in ventricular myocytes or inhibit liver enzymes that are important for metabolic degradation of other drugs that block IKr. Indeed, papaverine blocks human ether-a-go-go-related gene current with somewhat higher IC₅₀ value than that for Kv1.5 (H. Choe, Y. K. Lee, and Y. G. Kwak, unpublished data). Therefore, it is most likely that papaverine may induce arrhythmia through block of IKr in ventricular myocytes. Nonetheless, it is also true that selective block of hKv1.5-like current in human atrial myocytes results in significant prolongation of the action potential (Wang et al., 1993). Thus, the block of hKv1.5 and I_Kur by papaverine could affect cardiac excitability (Cobbe, 1994). In summary, this report is the first to detail the effects of papaverine on voltage-gated K⁺ channels in the heart. We find that papaverine blocks both a cloned cardiac channel (hKv1.5) expressed in Ltk^– cells and a rapidly I_Kur in human atrial cells. The effects of papaverine on these currents were shown to be concentration-, time-, voltage-, and state-dependent in a qualitatively similar manner.

	Acknowledgements

 
We thank Jeong-Ah Park for excellent technical assistance.

	Footnotes

 
This work was supported by Grant R05-2000-000-00199-0 from the Basic Research Program of the Korea Science and Engineering Foundation.

DOI: 10.1124/jpet.102.042770.

ABBREVIATIONS: Kv channel, voltage-gated K⁺ channel; I_Kur, ultrarapid delayed rectifier; I-V, current-voltage; IKr, human ether-a-go-go-related gene-dependent K⁺ current.

Address correspondence to: Dr. Yong-Geun Kwak, Department of Pharmacology, Chonbuk National University Medical School, Chonju, Chonbuk 561-180, South Korea. E-mail: ygkwak{at}moak.chonbuk.ac.kr

	References

Top Abstract Materials and Methods Results Discussion References

 

Boyle WA and Nerbonne JM (1991) A novel type of depolarization-activated K⁺ current in isolated adult rat atrial myocytes. Am J Physiol 260: H1236 –H1247.

Brading AF, Burdyga TV, and Scripnyuk ZD (1983) The effects of papaverine on the electrical and mechanical activity of the guinea-pig ureter. J Physiol (Lond) 334: 79 – 89.[Abstract/Free Full Text]

Caballero R, Delpon E, Valenzuela C, Longobardo M, Franqueza L, and Tamargo J (1997) Effect of descarboethoxyloratadine, the major metabolite of loratadine, on the human cardiac potassium channel Kv1.5. Br J Pharmacol 122: 796 –798.[CrossRef][Medline]

Cobbe SM (1994) Incidence and risks associated with atrial fibrillation. Pacing Clin Electrophysiol 17: 1005–1010.[CrossRef][Medline]

Colatsky TJ, Follmer CH, and Starmer CF (1990) Channel specificity in antiarrhythmic drug action. Mechanism of potassium channel block and its role in suppressing and aggravating cardiac arrhythmias. Circulation 82: 2235–2242.[Abstract/Free Full Text]

Deal KK, England SK, and Tamkun MM (1996) Molecular physiology of cardiac potassium channels. Physiol Rev 76: 49 – 67.[Abstract/Free Full Text]

Delpon E, Valenzuela C, Perez O, Franqueza L, Gay P, Snyders DJ, and Tamargo J (1996) Mechanisms of block of a human cloned potassium channel by the enantiomers of a new bradycardic agent: S-16257-2 and S-16260-2. Br J Pharmacol 117: 1293–1301.[Medline]

England SK, Uebele VN, Kodali J, Bennett PB, and Tamkun MM (1995a) A novel K⁺ channel -subunit (hKv1.3) is produced via alternative mRNA splicing. J Biol Chem 270: 28531–28534.[Abstract/Free Full Text]

England SK, Uebele VN, Shear H, Kodali J, Bennett PB, and Tamkun MM (1995b) Characterization of a voltage-gated K⁺ channel subunit expressed in human heart. Proc Natl Acad Sci USA 92: 6309 – 6313.[Abstract/Free Full Text]

Fedida D, Wible B, Wang Z, Fermini B, Faust F, Nattel S, and Brown AM (1993) Identity of a novel delayed rectifier current from human heart with a cloned K⁺ channel current. Circ Res 73: 210 –216.[Abstract]

Feng J, Wible B, Li GR, Wang Z, and Nattel S (1997) Antisense oligodeoxynucleotides directed against Kv1.5 mRNA specifically inhibit ultrarapid delayed rectifier K⁺ current in cultured adult human atrial myocytes. Circ Res 80: 572–579.[Abstract/Free Full Text]

Flemming KD, Brown RD Jr, and Wiebers DO (1999) Subarachnoid hemorrhage. Curr Treat Options Neurol 1: 97–112.[Medline]

Franqueza L, Valenzuela C, Delpon E, Longobardo M, Caballero R, and Tamargo J (1998) Effects of propafenone and 5-hydroxy-propafenone on hKv1.5 channels. Br J Pharmacol 125: 969 –978.[CrossRef][Medline]

Franz N, Modersohn D, Romaniuk P, and Linss G (1991) Coronary reserve determination by intracoronary papaverine: effects of various doses on coronary circulation and hemodynamics. Z Gesamte Inn Med 46: 15–17.[Medline]

Gilbert DL and Ehrenstein G (1969) Effect of divalent cations on potassium conductance of squid axons: determination of surface charge. Biophys J 9: 447– 463.

Hamill OP, Marty A, Neher E, Sakmann B, and Sigworth FJ (1981) Improved patch-clamp techniques for high-resolution current recording from cells and cellfree membrane patches. Pfluegers Arch 391: 85–100.[CrossRef][Medline]

Handelsman H (1990) Diagnosis and treatment of impotence. Health Technol Assess Rep 1–23.

Hondeghem LM and Snyders DJ (1990) Class III antiarrhythmic agents have a lot of potential but a long way to go. Reduced effectiveness and dangers of reverse use dependence. Circulation 81: 686 – 690.[Abstract/Free Full Text]

Huddart H, Langton PD, and Saad KH (1984) Inhibition by papaverine of calcium movements and tension in the smooth muscles of rat vas deferens and urinary bladder. J Physiol (Lond) 349: 183–194.[Abstract/Free Full Text]

Inoue T, Asahi S, Takayanagi K, Morooka S, and Takabatake Y (1994) QT prolongation and possibility of ventricular arrhythmias after intracoronary papaverine. Cardiology 84: 9 –13.[Medline]

Jeck CD and Boyden PA (1992) Age-related appearance of outward currents may contribute to developmental differences in ventricular repolarization. Circ Res 71: 1390 –1403.[Abstract/Free Full Text]

Jonsson PE, Olsson AM, Petersson BA, and Johansson K (1987) Intravenous indomethacin and oxycone-papaverine in the treatment of acute renal colic. A double-blind study. Br J Urol 59: 396 – 400.[Medline]

Konarzewska H, Peeters GA, and Sanguinetti MC (1995) Repolarizing K⁺ currents in nonfailing human hearts. Similarities between right septal subendocardial and left subepicardial ventricular myocytes. Circulation 92: 1179 –1187.[Abstract/Free Full Text]

Li GR, Feng J, Wang Z, Fermini B, and Nattel S (1996) Adrenergic modulation of ultrarapid delayed rectifier K⁺ current in human atrial myocytes. Circ Res 78: 903–915.[Abstract/Free Full Text]

Mays DJ, Foose JM, Philipson LH, and Tamkun MM (1995) Localization of the Kv1.5 K⁺ channel protein in explanted cardiac tissue. J Clin Invest 96: 282–292.

Newell DW, Elliott JP, Eskridge JM, and Winn HR (1999) Endovascular therapy for aneurysmal vasospasm. Crit Care Clin 15: 685– 699.[CrossRef][Medline]

Overturf KE, Russell SN, Carl A, Vogalis F, Hart PJ, Hume JR, Sanders KM, and Horowitz B (1994) Cloning and characterization of a Kv1.5 delayed rectifier K⁺ channel from vascular and visceral smooth muscles. Am J Physiol 267: C1231– C1238.

Rampe D, Wible B, Brown AM, and Dage RC (1993a) Effects of terfenadine and its metabolites on a delayed rectifier K⁺ channel cloned from human heart. Mol Pharmacol 44: 1240 –1245.[Abstract]

Rampe D, Wible B, Fedida D, Dage RC, and Brown AM (1993b) Verapamil blocks a rapidly activating delayed rectifier K⁺ channel cloned from human heart. Mol Pharmacol 44: 642– 648.[Abstract]

Roden DM (1993) Current status of class III antiarrhythmic drug therapy. Am J Cardiol 72: 44B– 49B.[CrossRef][Medline]

Snyders DJ, Tamkun MM, and Bennett PB (1993) A rapidly activating and slowly inactivating potassium channel cloned from human heart. Functional analysis after stable mammalian cell culture expression. J Gen Physiol 101: 513–543.[Abstract/Free Full Text]

Snyders J, Knoth KM, Roberds SL, and Tamkun MM (1992) Time-, voltage- and state-dependent block by quinidine of a cloned human cardiac potassium channel. Mol Pharmacol 41: 322–330.[Abstract]

Tamkun MM, Knoth KM, Walbridge JA, Kroemer H, Roden DM, and Glover DM (1991) Molecular cloning and characterization of two voltage-gated K⁺ channel cDNAs from human ventricle. FASEB J 5: 331–337.[Abstract]

Tashiro N and Tomita T (1970) The effects of papaverine on the electrical and mechanical activity of the guinea-pig taenia coli. Br J Pharmacol 39: 608 – 618.[Medline]

Tsurushima H, Hyodo A, and Yoshii Y (2000) Papaverine and vasospasm. J Neurosurg 92: 509 –511.

Uebele VN, England SK, Chaudhary A, Tamkun MM, and Snyders DJ (1996) Functional differences in Kv1.5 currents expressed in mammalian cell lines are due to the presence of endogenous Kv 2.1 subunits. J Biol Chem 271: 2406 –2412.[Abstract/Free Full Text]

Valenzuela C, Delpon E, Franqueza L, Gay P, Perez O, Tamargo J, and Snyders DJ (1996) Class III antiarrhythmic effects of zatebradine. Time-, state-, use- and voltage-dependent block of hKv1.5 channels. Circulation 94: 562–570.[Abstract/Free Full Text]

Valenzuela C, Delpon E, Franqueza L, Gay P, Snyders DJ, and Tamargo J (1997) Effects of ropivacaine on a potassium channel (hKv1.5) cloned from human ventricle. Anesthesiology 86: 718 –728.[Medline]

Valenzuela C, Snyders DJ, Bennett PB, Tamargo J, and Hondeghem LM (1995) Stereoselective block of cardiac sodium channels by bupivacaine in guinea pig ventricular myocytes. Circulation 92: 3014 –3024.[Abstract/Free Full Text]

Wang Z, Fermini B, and Nattel S (1993) Sustained depolarization-induced outward current in human atrial myocytes. Evidence for a novel delayed rectifier K⁺ current similar to Kv1.5 cloned channel currents. Circ Res 73: 1061–1076.[Abstract/Free Full Text]

Wilson RF and White CW (1986) Intracoronary papaverine: an ideal coronary vasodilator for studies of the coronary circulation in conscious humans. Circulation 73: 444 – 451.[Abstract/Free Full Text]

Woodhull AM (1973) Ionic blockage of sodium channels in nerve. J Gen Physiol 61: 687–708.[Abstract/Free Full Text]

Yang T, Prakash C, Roden DM, and Snyders DJ (1995) Mechanism of block of a human cardiac potassium channel by terfenadine racemate and enantiomers. Br J Pharmacol 115: 267–274.[Medline]

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