Inhibitory actions of ZENECA ZD7288 on whole-cell hyperpolarization activated inward current (If) in guinea-pig dissociated sinoatrial node cells
Version of Record online: 19 JUL 2012
1993 British Pharmacological Society
British Journal of Pharmacology
Volume 110, Issue 1, pages 343–349, September 1993
How to Cite
BoSmith, R. E., Briggs, I. and Sturgess, N. C. (1993), Inhibitory actions of ZENECA ZD7288 on whole-cell hyperpolarization activated inward current (If) in guinea-pig dissociated sinoatrial node cells. British Journal of Pharmacology, 110: 343–349. doi: 10.1111/j.1476-5381.1993.tb13815.x
- Issue online: 19 JUL 2012
- Version of Record online: 19 JUL 2012
- Received February 3, 1993; Revised April 4, 1993; Accepted April 21, 1993
- Sinoatrial node;
- hyperpolarization activated current;
- specific bradycardic agent;
- patch clamp;
- UL-FS 49
- 1ZENECA ZD7288 (4-(N-ethyl-N-phenylamino)-1,2-dimethyl-6-(methylamino) pyrimidinium chloride) is a sinoatrial node (SAN) modulating agent which produces a selective slowing of the heart rate. Its effects have been studied in single, freshly dissociated guinea-pig SAN cells, by standard patch clamp procedures.
- 2Whole-cell inward currents were evoked by hyperpolarizing voltage clamp steps from a holding potential of −40 mV. ZD7288 inhibited the hyperpolarization activated cationic current (If) in a concentration-dependent manner. The ‘selective bradycardic agents' alinidine and UL-FS 49 (zatebradine) both also inhibited If.
- 3The activation of If was investigated by measuring tail current amplitudes at +20 mV after hyperpolarizing steps to different potentials to activate the current. The reduction in If resulted from both a shift in the If current activation curve in the negative direction on the voltage axis, and also a reduction in the activation curve amplitude.
- 4ZD7288 did not affect the ion selectivity of the If channel, since the tail current reversal potential was unchanged in the presence of the drug.
- 5With ZD7288 the inhibition of If was not use-dependent, whereas UL-FS 49 displayed use-dependence in the block of the If current.
- 6Whereas ZD7288 had no significant effect on the delayed rectifier current (Ik) in these cells, both alinidine and UL-FS 49 significantly reduced Ik at the same concentrations which reduced If.
- 7The data show that ZD7288 reduces If by affecting the activation characteristics of the If current; this inhibition may account for this agent's selective bradycardic properties.