| dc.contributor.author | Jones, Stephen Edward. | en_US |
| dc.date.accessioned | 2014-10-21T12:36:07Z | |
| dc.date.available | 2001 | |
| dc.date.issued | 2001 | en_US |
| dc.identifier.other | AAINQ66661 | en_US |
| dc.identifier.uri | http://hdl.handle.net/10222/55791 | |
| dc.description | The objective of this electrophysiological study on guinea pig and rabbit ventricular myocytes was to investigate the effects of three urinary-dysfunction drugs (terodiline, oxybutynin, and S-oxybutynin) on ionic currents that govern repolarization of the cardiac action potential. Terodiline is presently restricted due to its adverse effects on cardiac function, oxybutynin has replaced terodiline as the drug of choice for management of bladder dysfunction, and S-oxybutynin is currently in Phase 3 trials. | en_US |
| dc.description | Membrane currents were recorded from myocytes in the whole-cell patch clamp configuration. The currents included L-type Ca2+ current (ICa,L), the inwardly-rectifying K+ current (IK1), and three delayed-rectifier K+ currents (rapidly-activating inactivating IKr, slowly-activating noninactivating IKs, and transient outward current Ito). | en_US |
| dc.description | Terodiline inhibited ICa,L with an IC50 of 12--15 muM; inhibition was use-dependent, with block increasing with pulsing rate and more positive holding potential. The drug accelerated the decay of I Ca,L, and slowed its recovery from inactivation. | en_US |
| dc.description | Terodiline preferentially inhibited IKr over the two other delayed-rectifier K+ currents. The IC50 for I Kr was 0.5 muM, versus 6 muM for Ito, 7 muM for I K1, and 26 muM for IKs. Inhibition of IK1 was independent of current direction, and persisted after removal of the drug. Block of IKs appeared to be voltage-dependent, and was fully attained on the first pulse following a rest period. | en_US |
| dc.description | Membrane currents were unaffected by ≤1 muM oxybutynins, and inhibited by higher concentrations. Compared to terodiline, IC50 values were up to 2.6-fold higher for ICa,L, IKs and IK1, and >10-fold higher for Ito and IKr. | en_US |
| dc.description | The results obtained with clinically relevant concentrations (<10 muM) of terodiline help explain its cardiotoxic profile (bradycardia; nodal conduction disturbance; QT prolongation; ventricular tachyarrhythmia); whereas the results obtained with clinically relevant concentrations (<<1 muM) of the oxybutynins indicate that clinical use of these drugs is highly unlikely to result in terodiline-like cardiotoxicity. | en_US |
| dc.description | Thesis (Ph.D.)--Dalhousie University (Canada), 2001. | en_US |
| dc.language | eng | en_US |
| dc.publisher | Dalhousie University | en_US |
| dc.publisher | | en_US |
| dc.subject | Health Sciences, Pharmacology. | en_US |
| dc.subject | Biology, Animal Physiology. | en_US |
| dc.title | The effects of terodiline and oxybutynins on cardiac membrane currents. | en_US |
| dc.type | text | en_US |
| dc.contributor.degree | Ph.D. | en_US |
