Pharmacological Screening of Kv7.1 and Kv7.1/KCNE1 Activators as Potential Antiarrhythmic Drugs in the Zebrafish Heart
Abstract
:1. Introduction
2. Results
2.1. AP Optical Recordings Are Stable in Control Conditions
2.2. The IKr Inhibitor E4031 Prolongs Zebrafish APD
2.3. Two Different Human IKs Inhibitors Have Different Effects on Zebrafish AP
2.4. The IKs Blocker Chromanol 293B Prolongs the APD More after IKr Inhibition
2.5. The Human IKs Inhibitor JNJ303 Does Not Prolong the APD More after IKr Inhibition
2.6. JNJ303 Is Not an Effective IKs Inhibitor of Zebrafish Kv7.1/KCNE1 Currents
2.7. PUFA Analogues Have Modest Effects on Zebrafish AP
2.8. PUFA Analogues Do Not Reverse APD in Drug-Induced LQTS Zebrafish Hearts
2.9. DHA-Gly and LIN-Gly Have Only Modest Effects on Zebrafish Kv7.1/KCNE1 and Kv7.1 Channels
2.10. DHA-Gly and LIN-Gly Did Not Reverse the Triangulation Effect of Drug-Induced LQT2
2.11. The IKs Activator ML-277 Partially Restored the APD in Drug-Induced LQT2 Zebrafish Hearts
3. Discussion
3.1. IKr and IKs Contribution to Zebrafish AP Repolarization
3.2. Small Effects of Other Human IKs Inhibitors
3.3. PUFA Analogues Slightly Shorten Zebrafish AP
4. Materials and Methods
4.1. Zebrafish Heart Isolation Procedure
4.2. Action Potential Optical Recordings and Analysis
4.3. Molecular Biology
4.4. Two-Electrode Voltage Clamp
4.5. Statistics
5. Study Limitations, Future Directions, and Clinical Relevance
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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APD80 (ms) | APD80 (ms) | (n, p) | ||
---|---|---|---|---|
CTRL | 174.9 ± 15.7 | Long CTRL | 185.2 ± 13.5 | n = 6, NS, p > 0.05 |
E4031 | 332.2 ± 19.2 | Long E4031 | 338.6 ± 17.8 | n = 3, NS, p > 0.05 |
E4031 CTRL | 217.6 ± 7.1 | E4031 | 350.5 ± 11.4 | n = 22, p < 0.001 |
C293B CTRL | 225.9 ± 33.5 | C293B | 243.0 ± 39.8 | n = 3, NS, p > 0.05 |
E4031 | 392.8 ± 14.0 | E4031/C293B | 463.5 ± 16.2 | n = 3, p < 0.05 |
JNJ303 CTRL | 180.2 ± 17.3 | JNJ303 | 204.7 ± 13.5 | n = 3, p < 0.05 |
E4031 | 325.6 ± 14.3 | E4031/JNJ303 | 369.8 ± 28.7 | n = 4, NS, p > 0.05 |
DHA-Gly CTRL | 212.3 ± 9.1 | DHA-Gly | 206.1 ± 6.7 | n = 7, NS, p > 0.05 |
LIN-Gly CTRL | 210.8 ± 14.9 | LIN-Gly | 204.8 ± 15.1 | n = 5, p < 0.05 |
E4031 | 325.3 ± 36.3 | E4031/DHA-Gly | 438.6 ± 54.7 | n = 4, NS, p > 0.05 |
E4031 | 397.9 ± 14.6 | E4031/LIN-Gly | 433.0 ± 19.7 | n = 3, NS, p > 0.05 |
ML-277 CTRL | 236.4 ± 26.6 | ML-277 CTRL | 211.1 ± 22.3 | n = 3, p < 0.05 |
E4031 | 301.5 ± 13.1 | E4031/ML-277 | 272.2 ± 8.4 | n = 3, p < 0.05 |
ΔAPD25 (%) | (n, p) | ΔAPD50 (%) | (n, p) | ΔAPD80 (%) | (n, p) | ΔAPD90 (%) | (n, p) | |
---|---|---|---|---|---|---|---|---|
E4031 | 48.3 ± 14.6 | n = 26, p < 0.001 | 49.6 ± 4.8 | n = 26, p < 0.001 | 72.8 ± 5.7 | n = 26, p < 0.001 | 71.6 ± 5.8 | n = 26, p < 0.001 |
C293B | −5.1 ± 2.0 | n = 3, p < 0.05 | 6.5 ± 3.1 | n = 3, NS, p > 0.05 | 9.6 ± 0.3 | n = 3, p < 0.05 | 9.2 ± 2.1 | n = 3, p < 0.01 |
JNJ303 | 27.1 ± 7.0 | n = 3, p < 0.05 | 17.5 ± 6.8 | n = 3, NS, p > 0.05 | 16.4 ± 3.4 | n = 3, p < 0.01 | 13.6 ± 3.5 | n = 3, p < 0.05 |
E4031/C293B | 13.2 ± 9.2 | n = 3, NS, p > 0.05 | 12.5 ± 7.6 | n = 3, NS, p > 0.05 | 20.2 ± 2.0 | n = 3, p < 0.01 | 22.0 ± 4.3 | n = 3, p < 0.05 |
E4031/JNJ303 | 27.5 ± 10.5 | n = 5, p < 0.05 | 20.2 ± 5.5 | n = 5, p < 0.05 | 14.3 ± 4.3 | n = 5, p < 0.05 | 14.0 ± 4.1 | n = 5, p < 0.05 |
ML-277 | −12.5 ± 6.0 | n = 4, NS, p > 0.05 | −13.1 ± 4.0 | n = 4, p < 0.05 | 12.1 ± 2.3 | n = 4, p < 0.05 | −13.6 ± 3.8 | n = 3, NS, p > 0.05 |
E4031/ML-277 | 3.9 ± 7.1 | n = 5, NS, p > 0.05 | −12.3 ± 1.5 | n = 5, p < 0.01 | −13.6 ± 2.2 | n = 5, p < 0.01 | −14.0 ± 3.5 | n = 5, p < 0.05 |
ΔAPD25 (%) | (n, p) | ΔAPD50 (%) | (n, p) | ΔAPD80 (%) | (n, p) | ΔAPD90 (%) | (n, p) | |
---|---|---|---|---|---|---|---|---|
DHA-Gly | −0.7 ± 10.5 | n = 9, NS, p > 0.05 | −4.5 ± 3.4 | n = 9, NS, p > 0.05 | −6.1 ± 2.3 | n = 9, p < 0.05 | −6.4 ± 3.0 | n = 9, NS, p > 0.05 |
LIN-Gly | 7.6 ± 8.4 | n = 6, NS, p > 0.05 | −6.4 ± 4.5 | n = 6, NS, p > 0.05 | −4.9 ± 0.8 | n = 6, p < 0.01 | −9.4 ± 3.3 | n = 6, NS, p > 0.05 |
E4031/DHA-Gly | −2.6 ± 9.5 | n = 4, NS, p > 0.05 | 4.4 ± 6.9 | n = 4, NS, p > 0.05 | 13.7 ± 5.8 | n = 4, NS, p > 0.05 | 14.2 ± 5.8 | n = 4, p < 0.05 |
E4031/LIN-Gly | 18.6 ± 5.8 | n = 3, p < 0.05 | 3.7 ± 2.9 | n = 3, NS, p > 0.05 | 7.5 ± 0.9 | n = 3, p < 0.05 | 0.8 ± 3.6 | n = 3, NS, p > 0.05 |
APD25/APD80 | APD25/APD80 | (n, p) | ||
---|---|---|---|---|
E4031 CTRL | 0.48 ± 0.03 | E4031 | 0.36 ± 0.02 | n = 24, p < 0.001 |
C293B CTRL | 0.47 ± 0.14 | C293B | 0.41 ± 0.06 | n = 3, p < 0.01 |
E4031 | 0.35 ± 0.01 | E4031/C293B | 0.31 ± 0.02 | n = 3, p < 0.05 |
JNJ303 CTRL | 0.51 ± 0.02 | JNJ303 | 0.55 ± 0.01 | n = 3, NS, p > 0.05 |
E4031 | 0.38 ± 0.03 | E4031/JNJ303 | 0.42 ± 0.03 | n = 5, NS, p > 0.05 |
DHA-Gly CTRL | 0.45 ± 0.02 | DHA-Gly | 0.46 ± 0.02 | n = 9, NS, p > 0.05 |
LIN-Gly CTRL | 0.41 ± 0.04 | LIN-Gly | 0.46 ± 0.01 | n = 5, NS, p > 0.05 |
E4031 | 0.38 ± 0.11 | E4031/DHA-Gly | 0.33 ± 0.1 | n = 3, NS, p > 0.05 |
E4031 | 0.34 ± 0.02 | E4031/LIN-Gly | 0.36 ± 0.04 | n = 5, NS, p > 0.05 |
ML-277 CTRL | 0.51 ± 0.03 | ML-277 CTRL | 0.51 ± 0.03 | n = 4, NS, p > 0.05 |
E4031 | 0.37 ± 0.03 | E4031/ML-277 | 0.44 ± 0.03 | n = 5, NS, p > 0.05 |
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De la Cruz, A.; Wu, X.; Rainer, Q.C.; Hiniesto-Iñigo, I.; Perez, M.E.; Edler, I.; Liin, S.I.; Larsson, H.P. Pharmacological Screening of Kv7.1 and Kv7.1/KCNE1 Activators as Potential Antiarrhythmic Drugs in the Zebrafish Heart. Int. J. Mol. Sci. 2023, 24, 12092. https://doi.org/10.3390/ijms241512092
De la Cruz A, Wu X, Rainer QC, Hiniesto-Iñigo I, Perez ME, Edler I, Liin SI, Larsson HP. Pharmacological Screening of Kv7.1 and Kv7.1/KCNE1 Activators as Potential Antiarrhythmic Drugs in the Zebrafish Heart. International Journal of Molecular Sciences. 2023; 24(15):12092. https://doi.org/10.3390/ijms241512092
Chicago/Turabian StyleDe la Cruz, Alicia, Xiaoan Wu, Quinn C. Rainer, Irene Hiniesto-Iñigo, Marta E. Perez, Isak Edler, Sara I. Liin, and H. Peter Larsson. 2023. "Pharmacological Screening of Kv7.1 and Kv7.1/KCNE1 Activators as Potential Antiarrhythmic Drugs in the Zebrafish Heart" International Journal of Molecular Sciences 24, no. 15: 12092. https://doi.org/10.3390/ijms241512092