Abstract
1. The frequency-dependent electrophysiological effects of UK-68,798 in concentrations of 1, 3, 10 and 30 nM were examined in isolated cardiac Purkinje fibres of the dog at both a number of constant rates of stimulation and following abrupt changes in pacing cycle length. 2. In all concentrations evaluated, UK-68,798 lengthened action potential duration in a concentration- and rate-dependent manner (e.g., at a cycle length = 500 ms, control APD90 = 234.0 +/- 3.3 ms, while after 10 nM UK-68,798, APD90 = 315.0 +/- 5.9 ms). 3. The duration of action potentials evoked following abrupt changes in pacing rate were also increased in a concentration-dependent manner at all diastolic intervals tested. 4. The fast and slow time constants for restitution of APD were not altered by UK-68,798. However, the amplitude terms for this relation were increased. 5. In addition, the maximum upstroke velocity (Vmax) was not significantly affected by exposure to UK-68,798 at any concentration or diastolic interval. The kinetics for recovery of Vmax were thus unaffected. 6. These findings are similar to those previously reported for recognized class III antiarrhythmic agents (e.g., bretylium, clofilium, and sotalol); however, UK-68,798 was 1,000 to 10,000 times more potent. 7. The combined potency and selectivity of this agent seem to make it an ideal tool for the investigation of cardiac potassium channels believed responsible for controlling the duration of the action potential. 8. This potent and highly selective compound may prove extremely useful in the control of cardiac arrhythmias.
Full text
PDF
Selected References
These references are in PubMed. This may not be the complete list of references from this article.
- DeLean A., Munson P. J., Rodbard D. Simultaneous analysis of families of sigmoidal curves: application to bioassay, radioligand assay, and physiological dose-response curves. Am J Physiol. 1978 Aug;235(2):E97–102. doi: 10.1152/ajpendo.1978.235.2.E97. [DOI] [PubMed] [Google Scholar]
- Elharrar V., Surawicz B. Cycle length effect on restitution of action potential duration in dog cardiac fibers. Am J Physiol. 1983 Jun;244(6):H782–H792. doi: 10.1152/ajpheart.1983.244.6.H782. [DOI] [PubMed] [Google Scholar]
- Lathrop D. A. Electromechanical characterization of the effects of racemic sotalol and its optical isomers on isolated canine ventricular trabecular muscles and Purkinje strands. Can J Physiol Pharmacol. 1985 Dec;63(12):1506–1512. doi: 10.1139/y85-248. [DOI] [PubMed] [Google Scholar]
- Nattel S., Zeng F. D. Frequency-dependent effects of antiarrhythmic drugs on action potential duration and refractoriness of canine cardiac Purkinje fibers. J Pharmacol Exp Ther. 1984 Apr;229(1):283–291. [PubMed] [Google Scholar]
- Singh B. N., Nademanee K. Control of cardiac arrhythmias by selective lengthening of repolarization: theoretic considerations and clinical observations. Am Heart J. 1985 Feb;109(2):421–430. doi: 10.1016/0002-8703(85)90629-5. [DOI] [PubMed] [Google Scholar]
- Steinberg M. I., Sullivan M. E., Wiest S. A., Rockhold F. W., Molloy B. B. Cellular electrophysiology of clofilium, a new antifibrillatory agent, in normal and ischemic canine Purkinje fibers. J Cardiovasc Pharmacol. 1981 Jul-Aug;3(4):881–895. doi: 10.1097/00005344-198107000-00022. [DOI] [PubMed] [Google Scholar]
- Strauss H. C., Bigger J. T., Jr, Hoffman B. F. Electrophysiologial and beta-receptor blocking effects of MJ 1999 on dog and rabbit cardiac tissue. Circ Res. 1970 Jun;26(6):661–678. doi: 10.1161/01.res.26.6.661. [DOI] [PubMed] [Google Scholar]
- Varro A., Nakaya Y., Elharrar V., Surawicz B. Effect of antiarrhythmic drugs on the cycle length-dependent action potential duration in dog Purkinje and ventricular muscle fibers. J Cardiovasc Pharmacol. 1986 Jan-Feb;8(1):178–185. doi: 10.1097/00005344-198601000-00026. [DOI] [PubMed] [Google Scholar]
- Vaughan Williams E. M. Classification of antidysrhythmic drugs. Pharmacol Ther B. 1975;1(1):115–138. doi: 10.1016/0306-039x(75)90019-7. [DOI] [PubMed] [Google Scholar]