Functional characterization of a1-adrenoceptor subtypes in human skeletal muscle resistance arteries

Yagna P.R. Jarajapu, John C. McGrath, Paul Coats, Chris Hillier, Allan MacDonald

Research output: Contribution to journalArticle

Abstract

a1-adrenoceptor subtypes in human skeletal muscle resistance arteries were characterized using agonists noradrenaline (non-selective) and A61603 (a1A-selective), the antagonists prazosin (non-selective), 5-methyl-urapidil (a1A-selective) and BMY7378 (a1D-selective) and the alkylating agent chloroethylclonidine (preferential for a1B). Small arteries were obtained from the non-ischaemic skeletal muscle of limbs amputated for critical limb ischaemia and isometric tension recorded using wire myography. Prazosin antagonized responses to noradrenaline with a pA2 value of 9.18, consistent with the presence of a1-adrenoceptors, although the Schild slope (1.32) was significantly different from unity. 5-Methyl-urapidil competitively antagonized responses to noradrenaline with a pKB value of 8.48 and a Schild slope of 0.99, consistent with the presence of a1A-adrenoceptors. In the presence of 300 nM 5-methyl-urapidil, noradrenaline exhibited biphasic concentration response curves, indicating the presence of a minor population of a 5-methyl-urapidil-resistant subtype. Contractile responses to noradrenaline were not affected by 1 µM chloroethylclonidine suggesting the absence of a1B-adrenoceptors. Maximum responses to noradrenaline and A61603 were reduced to a similar extent by 10 µM chloroethylclonidine, suggesting an effect of chloroethylclonidine at a1A-adrenoceptors at the higher concentration. BMY7378 (10 and 100 nM) had no effect on responses to noradrenaline. BMY7378 (1 µM) poorly shifted the potency of noradrenaline giving a pA2 of 6.52. These results rule out the presence of the a1D-subtype. These results show that contractile responses to noradrenaline in human skeletal muscle resistance arteries are predominantly mediated by the a1A-adrenoceptor subtype with a minor population of an unknown a1-adrenoceptor subtype.

Original languageEnglish
Pages (from-to)679-686
Number of pages8
JournalBritish Journal of Pharmacology
Volume133
Issue number5
Publication statusPublished - 1 Jul 2001

Fingerprint

Adrenergic Receptors
Norepinephrine
Skeletal Muscle
Arteries
A 61603
Prazosin
Extremities
Myography
Alkylating Agents
Population
Ischemia
chlorethylclonidine
5-methylurapidil

Keywords

  • skeletal muscle resistance arteries
  • a1-adrenoceptor subtypes

Cite this

Jarajapu, Y. P. R., McGrath, J. C., Coats, P., Hillier, C., & MacDonald, A. (2001). Functional characterization of a1-adrenoceptor subtypes in human skeletal muscle resistance arteries. British Journal of Pharmacology, 133(5), 679-686.
Jarajapu, Yagna P.R. ; McGrath, John C. ; Coats, Paul ; Hillier, Chris ; MacDonald, Allan. / Functional characterization of a1-adrenoceptor subtypes in human skeletal muscle resistance arteries. In: British Journal of Pharmacology. 2001 ; Vol. 133, No. 5. pp. 679-686.
@article{f078009bdf584781b187d0451a64b9e3,
title = "Functional characterization of a1-adrenoceptor subtypes in human skeletal muscle resistance arteries",
abstract = "a1-adrenoceptor subtypes in human skeletal muscle resistance arteries were characterized using agonists noradrenaline (non-selective) and A61603 (a1A-selective), the antagonists prazosin (non-selective), 5-methyl-urapidil (a1A-selective) and BMY7378 (a1D-selective) and the alkylating agent chloroethylclonidine (preferential for a1B). Small arteries were obtained from the non-ischaemic skeletal muscle of limbs amputated for critical limb ischaemia and isometric tension recorded using wire myography. Prazosin antagonized responses to noradrenaline with a pA2 value of 9.18, consistent with the presence of a1-adrenoceptors, although the Schild slope (1.32) was significantly different from unity. 5-Methyl-urapidil competitively antagonized responses to noradrenaline with a pKB value of 8.48 and a Schild slope of 0.99, consistent with the presence of a1A-adrenoceptors. In the presence of 300 nM 5-methyl-urapidil, noradrenaline exhibited biphasic concentration response curves, indicating the presence of a minor population of a 5-methyl-urapidil-resistant subtype. Contractile responses to noradrenaline were not affected by 1 µM chloroethylclonidine suggesting the absence of a1B-adrenoceptors. Maximum responses to noradrenaline and A61603 were reduced to a similar extent by 10 µM chloroethylclonidine, suggesting an effect of chloroethylclonidine at a1A-adrenoceptors at the higher concentration. BMY7378 (10 and 100 nM) had no effect on responses to noradrenaline. BMY7378 (1 µM) poorly shifted the potency of noradrenaline giving a pA2 of 6.52. These results rule out the presence of the a1D-subtype. These results show that contractile responses to noradrenaline in human skeletal muscle resistance arteries are predominantly mediated by the a1A-adrenoceptor subtype with a minor population of an unknown a1-adrenoceptor subtype.",
keywords = "skeletal muscle resistance arteries, a1-adrenoceptor subtypes",
author = "Jarajapu, {Yagna P.R.} and McGrath, {John C.} and Paul Coats and Chris Hillier and Allan MacDonald",
note = "<p>Originally published in: British Journal of Pharmacology (2001), 133 (5), pp.679-686.</p>",
year = "2001",
month = "7",
day = "1",
language = "English",
volume = "133",
pages = "679--686",
journal = "British Journal of Pharmacology",
issn = "0007-1188",
publisher = "Wiley-Blackwell",
number = "5",

}

Jarajapu, YPR, McGrath, JC, Coats, P, Hillier, C & MacDonald, A 2001, 'Functional characterization of a1-adrenoceptor subtypes in human skeletal muscle resistance arteries', British Journal of Pharmacology, vol. 133, no. 5, pp. 679-686.

Functional characterization of a1-adrenoceptor subtypes in human skeletal muscle resistance arteries. / Jarajapu, Yagna P.R.; McGrath, John C.; Coats, Paul; Hillier, Chris; MacDonald, Allan.

In: British Journal of Pharmacology, Vol. 133, No. 5, 01.07.2001, p. 679-686.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Functional characterization of a1-adrenoceptor subtypes in human skeletal muscle resistance arteries

AU - Jarajapu, Yagna P.R.

AU - McGrath, John C.

AU - Coats, Paul

AU - Hillier, Chris

AU - MacDonald, Allan

N1 - <p>Originally published in: British Journal of Pharmacology (2001), 133 (5), pp.679-686.</p>

PY - 2001/7/1

Y1 - 2001/7/1

N2 - a1-adrenoceptor subtypes in human skeletal muscle resistance arteries were characterized using agonists noradrenaline (non-selective) and A61603 (a1A-selective), the antagonists prazosin (non-selective), 5-methyl-urapidil (a1A-selective) and BMY7378 (a1D-selective) and the alkylating agent chloroethylclonidine (preferential for a1B). Small arteries were obtained from the non-ischaemic skeletal muscle of limbs amputated for critical limb ischaemia and isometric tension recorded using wire myography. Prazosin antagonized responses to noradrenaline with a pA2 value of 9.18, consistent with the presence of a1-adrenoceptors, although the Schild slope (1.32) was significantly different from unity. 5-Methyl-urapidil competitively antagonized responses to noradrenaline with a pKB value of 8.48 and a Schild slope of 0.99, consistent with the presence of a1A-adrenoceptors. In the presence of 300 nM 5-methyl-urapidil, noradrenaline exhibited biphasic concentration response curves, indicating the presence of a minor population of a 5-methyl-urapidil-resistant subtype. Contractile responses to noradrenaline were not affected by 1 µM chloroethylclonidine suggesting the absence of a1B-adrenoceptors. Maximum responses to noradrenaline and A61603 were reduced to a similar extent by 10 µM chloroethylclonidine, suggesting an effect of chloroethylclonidine at a1A-adrenoceptors at the higher concentration. BMY7378 (10 and 100 nM) had no effect on responses to noradrenaline. BMY7378 (1 µM) poorly shifted the potency of noradrenaline giving a pA2 of 6.52. These results rule out the presence of the a1D-subtype. These results show that contractile responses to noradrenaline in human skeletal muscle resistance arteries are predominantly mediated by the a1A-adrenoceptor subtype with a minor population of an unknown a1-adrenoceptor subtype.

AB - a1-adrenoceptor subtypes in human skeletal muscle resistance arteries were characterized using agonists noradrenaline (non-selective) and A61603 (a1A-selective), the antagonists prazosin (non-selective), 5-methyl-urapidil (a1A-selective) and BMY7378 (a1D-selective) and the alkylating agent chloroethylclonidine (preferential for a1B). Small arteries were obtained from the non-ischaemic skeletal muscle of limbs amputated for critical limb ischaemia and isometric tension recorded using wire myography. Prazosin antagonized responses to noradrenaline with a pA2 value of 9.18, consistent with the presence of a1-adrenoceptors, although the Schild slope (1.32) was significantly different from unity. 5-Methyl-urapidil competitively antagonized responses to noradrenaline with a pKB value of 8.48 and a Schild slope of 0.99, consistent with the presence of a1A-adrenoceptors. In the presence of 300 nM 5-methyl-urapidil, noradrenaline exhibited biphasic concentration response curves, indicating the presence of a minor population of a 5-methyl-urapidil-resistant subtype. Contractile responses to noradrenaline were not affected by 1 µM chloroethylclonidine suggesting the absence of a1B-adrenoceptors. Maximum responses to noradrenaline and A61603 were reduced to a similar extent by 10 µM chloroethylclonidine, suggesting an effect of chloroethylclonidine at a1A-adrenoceptors at the higher concentration. BMY7378 (10 and 100 nM) had no effect on responses to noradrenaline. BMY7378 (1 µM) poorly shifted the potency of noradrenaline giving a pA2 of 6.52. These results rule out the presence of the a1D-subtype. These results show that contractile responses to noradrenaline in human skeletal muscle resistance arteries are predominantly mediated by the a1A-adrenoceptor subtype with a minor population of an unknown a1-adrenoceptor subtype.

KW - skeletal muscle resistance arteries

KW - a1-adrenoceptor subtypes

M3 - Article

VL - 133

SP - 679

EP - 686

JO - British Journal of Pharmacology

JF - British Journal of Pharmacology

SN - 0007-1188

IS - 5

ER -

Jarajapu YPR, McGrath JC, Coats P, Hillier C, MacDonald A. Functional characterization of a1-adrenoceptor subtypes in human skeletal muscle resistance arteries. British Journal of Pharmacology. 2001 Jul 1;133(5):679-686.