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PMID: 2549176 Published · ppublish English Journal Article Research Support, U.S. Gov't, P.H.S.

Influence of pHo on calcium channel block by amlodipine, a charged dihydropyridine compound. Implications for location of the dihydropyridine receptor.

The Journal of general physiology ·Vol. 93 ·No. 6 ·1989-06-00 ·Pages 1109-27

Kass RS, Arena JP

Abstract

We have investigated the modulation of L-type calcium channel currents in isolated ventricular cells by the dihydropyridine derivative amlodipine, a weak base with a pKa of 8.6. Under conditions that favor neutral drug molecules, amlodipine block resembles other, previously described, neutral dihydropyridine derivatives: block is more pronounced at depolarized voltages, repetitive pulsing is not needed to promote block, and recovery is complete at hyperpolarized voltages. When the drug is ionized, depolarized voltages still enhance block, however, the time course is slow and speeded by repetitive pulses that open channels. Recovery from block by ionized drug molecules is very slow and incomplete, but can be rapidly modified by changes in external hydrogen ion concentration. We conclude from these observations that the degree of ionization of the drug molecule can affect access to the dihydropyridine receptor and that external protons can interact with the drug-receptor complex even if channels are blocked and closed. These observations place limitations on the location of this receptor in the ventricular cell membrane.

MeSH Terms
Amlodipine Animals Calcium Channel Blockers/pharmacology Calcium Channels Guinea Pigs Hydrogen-Ion Concentration In Vitro Techniques Myocardium/cytology Nifedipine/analogs & derivatives,pharmacology Receptors, Nicotinic/drug effects
Chemicals
Calcium Channel Blockers Calcium Channels Receptors, Nicotinic Amlodipine Nifedipine
Authors & Affiliations
2 authors, click to expand affiliations / ORCID
Kass R S
Department of Physiology, University of Rochester Medical Center, New York 14642.
Arena J P
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Article Info
Journal
The Journal of general physiology
Abbr.
J Gen Physiol
ISSN
0022-1295
DOI
10.1085/jgp.93.6.1109
Published
1989-06-00
Pages
1109-27
Language
English
Region
United States
NLM ID
2985110R
PMCID
PMC2216251
Subset
IM
Grants
NHLBI NIH HHS · HL-07678 · United States
NHLBI NIH HHS · HL-21922 · United States
External Links
PubMed source DOI: 10.1085/jgp.93.6.1109 PMC Full Text View journal details
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