DOI: 10.1111/j.1476-5381.1993.tb13815.x. Inhibitory actions of ZENECA ZD7288 on whole‐cell hyperpolarization activated inward current (<i>I</i><sub>f</sub>) in guinea‐pig dissociated sinoatrial node cells

Inhibitory actions of ZENECA ZD7288 on whole‐cell hyperpolarization activated inward current (If) in guinea‐pig dissociated sinoatrial node cells

10.1111/j.1476-5381.1993.tb13815.x

Crossref journal-article

Wiley

British Journal of Pharmacology (311)

Abstract

ZENECA 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. Whole‐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. The 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. ZD7288 did not affect the ion selectivity of the If channel, since the tail current reversal potential was unchanged in the presence of the drug. With ZD7288 the inhibition of If was not use‐dependent, whereas UL‐FS 49 displayed use‐dependence in the block of the If current. Whereas 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. The 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.

Bibliography

BoSmith, R. E., Briggs, I., & Sturgess, N. C. (1993). Inhibitory actions of ZENECA ZD7288 on wholeâcell hyperpolarization activated inward current (If) in guineaâpig dissociated sinoatrial node cells. British Journal of Pharmacology, 110(1), 343â349. Portico.

Authors 3

Robert E. BoSmith (first)
Ian Briggs (additional)
Nicholas C. Sturgess (additional)

References 32 Referenced 261

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{'key': 'e_1_2_1_3_1', 'first-page': '382P', 'article-title': 'Actions of ICI D7288 on sinoatrial node cellular electrophysiology: action potentials', 'volume': '107', 'author': 'BRIGGS I.', 'year': '1992', 'journal-title': 'Br. J. Pharmacol.'} / Br. J. Pharmacol. / Actions of ICI D7288 on sinoatrial node cellular electrophysiology: action potentials by BRIGGS I. (1992)
10.1113/jphysiol.1990.sp018219
10.1113/jphysiol.1990.sp018264
10.1093/eurheartj/8.suppl_L.19
10.1113/jphysiol.1991.sp018457
10.1113/jphysiol.1986.sp016177
10.1113/jphysiol.1988.sp017343
10.1113/jphysiol.1988.sp017344
10.1007/BF00180659
10.1113/jphysiol.1992.sp019230
10.1161/01.CIR.75.3.661
10.1161/01.RES.60.5.738
10.1113/jphysiol.1989.sp017488
10.1007/BF00656997
HARGREAVES R.B. MILLS S.D. McLOUGHLIN B.J.&MARSHALL P.W.(1992).ICI D7288 a novel sino‐atrial node modulator: synthesis and pharmacological activity.23rd National Medicinal Chemistry Symposium. American Chemical Society. Buffalo June 1992; abstract 21. (10.1097/00005344-199306000-00008)
10.1007/BF00584963
10.1016/0014-2999(84)90363-7
10.1007/BF00507111
{'key': 'e_1_2_1_21_1', 'first-page': '791', 'article-title': 'Investigations into the bradycardic effects of UL‐FS 49 (1,3,4,5‐tetrahydro‐7,8‐dimethoxy‐3‐[3‐[[2‐[3,4‐dimethoxyphenyl)‐ethyl] methylimino]propyl]‐2H‐3‐benzazepin‐2‐on hydrochloride) in isolated guinea pig atria', 'volume': '8', 'author': 'LILLIE C.', 'year': '1986', 'journal-title': 'J. Cardiovasc. Pharmacol.'} / J. Cardiovasc. Pharmacol. / Investigations into the bradycardic effects of UL‐FS 49 (1,3,4,5‐tetrahydro‐7,8‐dimethoxy‐3‐[3‐[[2‐[3,4‐dimethoxyphenyl)‐ethyl] methylimino]propyl]‐2H‐3‐benzazepin‐2‐on hydrochloride) in isolated guinea pig atria by LILLIE C. (1986)
10.1111/j.1476-5381.1992.tb14475.x
10.1097/00005344-199306000-00008
10.1007/BF00584356
10.1016/0022-2828(89)90691-3
{'key': 'e_1_2_1_26_1', 'first-page': '383P', 'article-title': 'Haemodynamic actions of ICI D7288, a novel sino‐atrial node modulator', 'volume': '107', 'author': 'ROUSE W.', 'year': '1992', 'journal-title': 'Br. J. Pharmacol.'} / Br. J. Pharmacol. / Haemodynamic actions of ICI D7288, a novel sino‐atrial node modulator by ROUSE W. (1992)
10.1016/0014-2999(86)90492-9
10.1007/BF00581900
{'key': 'e_1_2_1_29_1', 'first-page': '19', 'article-title': 'On the mechanism of action of the bradycardic agent UL‐FS 49 on ventricular Ca channels', 'volume': '9', 'author': 'TYTGAT J.', 'year': '1990', 'journal-title': 'Pharmacodyn. Ther.'} / Pharmacodyn. Ther. / On the mechanism of action of the bradycardic agent UL‐FS 49 on ventricular Ca channels by TYTGAT J. (1990)
{'key': 'e_1_2_1_30_1', 'first-page': '342P', 'article-title': 'Kinetics of the blocking and unblocking processes of the i\n f pacemaker current by bradycardic agents injected into isolated sheep cardiac Purkinje fibres', 'volume': '446', 'author': 'BOGAERT P.‐P.', 'year': '1992', 'journal-title': 'J. Physiol.'} / J. Physiol. / Kinetics of the blocking and unblocking processes of the i f pacemaker current by bradycardic agents injected into isolated sheep cardiac Purkinje fibres by BOGAERT P.‐P. (1992)
10.1093/eurheartj/8.suppl_L.35
10.1016/0014-2999(90)90011-T
10.1113/jphysiol.1991.sp018459

Dates

Type	When
Created	13 years, 1 month ago (July 19, 2012, 8:02 p.m.)
Deposited	1 year, 10 months ago (Oct. 15, 2023, 6:41 p.m.)
Indexed	2 months, 2 weeks ago (June 11, 2025, 7:41 a.m.)
Issued	31 years, 11 months ago (Sept. 1, 1993)
Published	31 years, 11 months ago (Sept. 1, 1993)
Published Online	13 years, 1 month ago (July 19, 2012)
Published Print	31 years, 11 months ago (Sept. 1, 1993)

Funders 0

None

BibTeX

@article{BoSmith_1993, title={Inhibitory actions of ZENECA ZD7288 on whole‐cell hyperpolarization activated inward current (If) in guinea‐pig dissociated sinoatrial node cells}, volume={110}, ISSN={1476-5381}, url={http://dx.doi.org/10.1111/j.1476-5381.1993.tb13815.x}, DOI={10.1111/j.1476-5381.1993.tb13815.x}, number={1}, journal={British Journal of Pharmacology}, publisher={Wiley}, author={BoSmith, Robert E. and Briggs, Ian and Sturgess, Nicholas C.}, year={1993}, month=sep, pages={343–349} }

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