Nitrendipine block of calcium channels in cardiac and vascular muscle

Bruce P. Bean, Michael Sturek, Aurita Puga, Kent Hermsmeyer

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

The patch clamp technique was used to study the nitrendipine block of calcium channels in single cells isolated from cardiac or vascular muscle. Both cardiac cells and vascular muscle cells were found to contain two distinct types of calcium channels. One of these channels, marked by a relatively high threshold for activation and relatively slow inactivation kinetics, and called the "slow" channel, is sensitive to block by low concentrations of nitrendipine. The other channel has a lower threshold for activation and inactivates relatively quickly; it is called the "fast'' channel and is relatively insensitive to block by nitrendipine. Nitrendipine block of the slow type of channels was found to be profoundly modulated by the membrane potential of the cell. When calcium currents were elicited by depolarizations from well polarized membrane potentials of - 80 mV or so, concentrations of 100-700 nM nitrendipine were required for half-block of the currents. In contrast, when the membrane potential was held at depolarized potentials of - 10 mV or so, nitrendipine was much more potent as a blocker, with half-block being achieved by concentrations of ∼0.3 nM. The results can be understood by hypothesizing that nitrendipine binds very tightly to the inactivated state of the calcium channel (which predominates at depolarized potentials) and much more weakly to the normal resting state of the channel (which predominates at negative holding potentials). The Kd estimated for binding to inactivated channels is very similar to the dissociation constants found for high-affinity nitrendipine binding to sites in cardiac and smooth muscle. The results suggest that the high-affinity binding site is the inactivated state of the slow type of calcium channel. The results also show that the potency of nitrendipine block can be dramatically altered by resting membrane potential, which may help explain why nitrendipine is so much more potent in inhibiting contraction of smooth muscle (with typically low resting potentials) than contraction of cardiac muscle (with typically high resting potentials).

Original languageEnglish (US)
Pages (from-to)S17-S24
JournalJournal of Cardiovascular Pharmacology
Volume9
StatePublished - 1987
Externally publishedYes

Fingerprint

Nitrendipine
Calcium Channels
Blood Vessels
Myocardium
Membrane Potentials
Smooth Muscle
Binding Sites
Patch-Clamp Techniques
Muscle Cells
Calcium

Keywords

  • Calcium channels
  • Cardiac muscle
  • Dihydropyridines
  • Nitrendipine
  • Smooth muscle
  • Vascular muscle

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Pharmacology

Cite this

Nitrendipine block of calcium channels in cardiac and vascular muscle. / Bean, Bruce P.; Sturek, Michael; Puga, Aurita; Hermsmeyer, Kent.

In: Journal of Cardiovascular Pharmacology, Vol. 9, 1987, p. S17-S24.

Research output: Contribution to journalArticle

Bean, Bruce P. ; Sturek, Michael ; Puga, Aurita ; Hermsmeyer, Kent. / Nitrendipine block of calcium channels in cardiac and vascular muscle. In: Journal of Cardiovascular Pharmacology. 1987 ; Vol. 9. pp. S17-S24.
@article{271c9dddce3849f2ae80223eef4f16a5,
title = "Nitrendipine block of calcium channels in cardiac and vascular muscle",
abstract = "The patch clamp technique was used to study the nitrendipine block of calcium channels in single cells isolated from cardiac or vascular muscle. Both cardiac cells and vascular muscle cells were found to contain two distinct types of calcium channels. One of these channels, marked by a relatively high threshold for activation and relatively slow inactivation kinetics, and called the {"}slow{"} channel, is sensitive to block by low concentrations of nitrendipine. The other channel has a lower threshold for activation and inactivates relatively quickly; it is called the {"}fast'' channel and is relatively insensitive to block by nitrendipine. Nitrendipine block of the slow type of channels was found to be profoundly modulated by the membrane potential of the cell. When calcium currents were elicited by depolarizations from well polarized membrane potentials of - 80 mV or so, concentrations of 100-700 nM nitrendipine were required for half-block of the currents. In contrast, when the membrane potential was held at depolarized potentials of - 10 mV or so, nitrendipine was much more potent as a blocker, with half-block being achieved by concentrations of ∼0.3 nM. The results can be understood by hypothesizing that nitrendipine binds very tightly to the inactivated state of the calcium channel (which predominates at depolarized potentials) and much more weakly to the normal resting state of the channel (which predominates at negative holding potentials). The Kd estimated for binding to inactivated channels is very similar to the dissociation constants found for high-affinity nitrendipine binding to sites in cardiac and smooth muscle. The results suggest that the high-affinity binding site is the inactivated state of the slow type of calcium channel. The results also show that the potency of nitrendipine block can be dramatically altered by resting membrane potential, which may help explain why nitrendipine is so much more potent in inhibiting contraction of smooth muscle (with typically low resting potentials) than contraction of cardiac muscle (with typically high resting potentials).",
keywords = "Calcium channels, Cardiac muscle, Dihydropyridines, Nitrendipine, Smooth muscle, Vascular muscle",
author = "Bean, {Bruce P.} and Michael Sturek and Aurita Puga and Kent Hermsmeyer",
year = "1987",
language = "English (US)",
volume = "9",
pages = "S17--S24",
journal = "Journal of Cardiovascular Pharmacology",
issn = "0160-2446",
publisher = "Lippincott Williams and Wilkins",

}

TY - JOUR

T1 - Nitrendipine block of calcium channels in cardiac and vascular muscle

AU - Bean, Bruce P.

AU - Sturek, Michael

AU - Puga, Aurita

AU - Hermsmeyer, Kent

PY - 1987

Y1 - 1987

N2 - The patch clamp technique was used to study the nitrendipine block of calcium channels in single cells isolated from cardiac or vascular muscle. Both cardiac cells and vascular muscle cells were found to contain two distinct types of calcium channels. One of these channels, marked by a relatively high threshold for activation and relatively slow inactivation kinetics, and called the "slow" channel, is sensitive to block by low concentrations of nitrendipine. The other channel has a lower threshold for activation and inactivates relatively quickly; it is called the "fast'' channel and is relatively insensitive to block by nitrendipine. Nitrendipine block of the slow type of channels was found to be profoundly modulated by the membrane potential of the cell. When calcium currents were elicited by depolarizations from well polarized membrane potentials of - 80 mV or so, concentrations of 100-700 nM nitrendipine were required for half-block of the currents. In contrast, when the membrane potential was held at depolarized potentials of - 10 mV or so, nitrendipine was much more potent as a blocker, with half-block being achieved by concentrations of ∼0.3 nM. The results can be understood by hypothesizing that nitrendipine binds very tightly to the inactivated state of the calcium channel (which predominates at depolarized potentials) and much more weakly to the normal resting state of the channel (which predominates at negative holding potentials). The Kd estimated for binding to inactivated channels is very similar to the dissociation constants found for high-affinity nitrendipine binding to sites in cardiac and smooth muscle. The results suggest that the high-affinity binding site is the inactivated state of the slow type of calcium channel. The results also show that the potency of nitrendipine block can be dramatically altered by resting membrane potential, which may help explain why nitrendipine is so much more potent in inhibiting contraction of smooth muscle (with typically low resting potentials) than contraction of cardiac muscle (with typically high resting potentials).

AB - The patch clamp technique was used to study the nitrendipine block of calcium channels in single cells isolated from cardiac or vascular muscle. Both cardiac cells and vascular muscle cells were found to contain two distinct types of calcium channels. One of these channels, marked by a relatively high threshold for activation and relatively slow inactivation kinetics, and called the "slow" channel, is sensitive to block by low concentrations of nitrendipine. The other channel has a lower threshold for activation and inactivates relatively quickly; it is called the "fast'' channel and is relatively insensitive to block by nitrendipine. Nitrendipine block of the slow type of channels was found to be profoundly modulated by the membrane potential of the cell. When calcium currents were elicited by depolarizations from well polarized membrane potentials of - 80 mV or so, concentrations of 100-700 nM nitrendipine were required for half-block of the currents. In contrast, when the membrane potential was held at depolarized potentials of - 10 mV or so, nitrendipine was much more potent as a blocker, with half-block being achieved by concentrations of ∼0.3 nM. The results can be understood by hypothesizing that nitrendipine binds very tightly to the inactivated state of the calcium channel (which predominates at depolarized potentials) and much more weakly to the normal resting state of the channel (which predominates at negative holding potentials). The Kd estimated for binding to inactivated channels is very similar to the dissociation constants found for high-affinity nitrendipine binding to sites in cardiac and smooth muscle. The results suggest that the high-affinity binding site is the inactivated state of the slow type of calcium channel. The results also show that the potency of nitrendipine block can be dramatically altered by resting membrane potential, which may help explain why nitrendipine is so much more potent in inhibiting contraction of smooth muscle (with typically low resting potentials) than contraction of cardiac muscle (with typically high resting potentials).

KW - Calcium channels

KW - Cardiac muscle

KW - Dihydropyridines

KW - Nitrendipine

KW - Smooth muscle

KW - Vascular muscle

UR - http://www.scopus.com/inward/record.url?scp=2442532431&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=2442532431&partnerID=8YFLogxK

M3 - Article

AN - SCOPUS:2442532431

VL - 9

SP - S17-S24

JO - Journal of Cardiovascular Pharmacology

JF - Journal of Cardiovascular Pharmacology

SN - 0160-2446

ER -