The a1-adrenoceptor profile in human skeletal muscle resistance arteries in critical limb ischaemia

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

Research output: Contribution to journalArticle

Abstract

We recently reported the hyper-responsiveness of human skeletal muscle resistance arteries (SkMRAs) to noradrenaline in critical limb ischaemia (CLI). In this study we investigated the characteristics of a1-adrenoceptor subtypes and evaluated the agonist affinity and adrenoceptor reserve in the ischaemic arteries. Human SkMRAs were isolated from non-ischaemic and ischaemic areas of limbs amputated for CLI. Subcutaneous resistance arteries were isolated from inguinal biopsies from healthy subjects. Arterial segments were mounted on a small vessel wire myograph. Contractile responses to agonists, adrenaline and A-61603 (a1A-selective) were significantly increased in ischaemic arteries compared to those in non-ischaemic arteries. Receptor inactivation studies indicated an increase in the a-adrenoceptor reserve in the ischaemic arteries but the affinity of noradrenaline was unaffected. Healthy subcutaneous arteries had a similar noradrenaline affinity but a higher receptor reserve than skeletal muscle arteries. In the ischaemic arteries, the antagonists prazosin (a1-selective), 5-methyl-urapidil (a1A-selective) and BMY 7378 (a1D-selective) produced rightward shifts in the concentration response curves (CRCs) of noradrenaline giving pKBs of 9.6±0.3, 8.4±0.2 and 7.1±0.4, respectively. Pretreatment with 10 µM chloroethylclonidine decreased the contractile responses to noradrenaline and A-61603 to 57±7 and 72±4% of their respective controls. These results demonstrate that the ischaemic SkMRAs have an increased a-adrenoceptor reserve with no change in the predominant a1A-adrenoceptor profile.

Original languageEnglish
JournalCardiovascular Research
Publication statusPublished - 1 Feb 2003

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Adrenergic Receptors
Skeletal Muscle
Ischemia
Extremities
Arteries
Norepinephrine
A 61603
Groin
Prazosin
Epinephrine
Healthy Volunteers
Biopsy

Keywords

  • ischemia receptors
  • adrenergic agonists
  • arteries

Cite this

Jarajapu, Yagna P.R. ; McGrath, John C. ; Hillier, Chris ; MacDonald, Allan. / The a1-adrenoceptor profile in human skeletal muscle resistance arteries in critical limb ischaemia. In: Cardiovascular Research. 2003.
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The a1-adrenoceptor profile in human skeletal muscle resistance arteries in critical limb ischaemia. / Jarajapu, Yagna P.R.; McGrath, John C.; Hillier, Chris; MacDonald, Allan.

In: Cardiovascular Research, 01.02.2003.

Research output: Contribution to journalArticle

TY - JOUR

T1 - The a1-adrenoceptor profile in human skeletal muscle resistance arteries in critical limb ischaemia

AU - Jarajapu, Yagna P.R.

AU - McGrath, John C.

AU - Hillier, Chris

AU - MacDonald, Allan

N1 - Originally published in: Cardiovascular Research (2003), 57 (2), pp.554-562.

PY - 2003/2/1

Y1 - 2003/2/1

N2 - We recently reported the hyper-responsiveness of human skeletal muscle resistance arteries (SkMRAs) to noradrenaline in critical limb ischaemia (CLI). In this study we investigated the characteristics of a1-adrenoceptor subtypes and evaluated the agonist affinity and adrenoceptor reserve in the ischaemic arteries. Human SkMRAs were isolated from non-ischaemic and ischaemic areas of limbs amputated for CLI. Subcutaneous resistance arteries were isolated from inguinal biopsies from healthy subjects. Arterial segments were mounted on a small vessel wire myograph. Contractile responses to agonists, adrenaline and A-61603 (a1A-selective) were significantly increased in ischaemic arteries compared to those in non-ischaemic arteries. Receptor inactivation studies indicated an increase in the a-adrenoceptor reserve in the ischaemic arteries but the affinity of noradrenaline was unaffected. Healthy subcutaneous arteries had a similar noradrenaline affinity but a higher receptor reserve than skeletal muscle arteries. In the ischaemic arteries, the antagonists prazosin (a1-selective), 5-methyl-urapidil (a1A-selective) and BMY 7378 (a1D-selective) produced rightward shifts in the concentration response curves (CRCs) of noradrenaline giving pKBs of 9.6±0.3, 8.4±0.2 and 7.1±0.4, respectively. Pretreatment with 10 µM chloroethylclonidine decreased the contractile responses to noradrenaline and A-61603 to 57±7 and 72±4% of their respective controls. These results demonstrate that the ischaemic SkMRAs have an increased a-adrenoceptor reserve with no change in the predominant a1A-adrenoceptor profile.

AB - We recently reported the hyper-responsiveness of human skeletal muscle resistance arteries (SkMRAs) to noradrenaline in critical limb ischaemia (CLI). In this study we investigated the characteristics of a1-adrenoceptor subtypes and evaluated the agonist affinity and adrenoceptor reserve in the ischaemic arteries. Human SkMRAs were isolated from non-ischaemic and ischaemic areas of limbs amputated for CLI. Subcutaneous resistance arteries were isolated from inguinal biopsies from healthy subjects. Arterial segments were mounted on a small vessel wire myograph. Contractile responses to agonists, adrenaline and A-61603 (a1A-selective) were significantly increased in ischaemic arteries compared to those in non-ischaemic arteries. Receptor inactivation studies indicated an increase in the a-adrenoceptor reserve in the ischaemic arteries but the affinity of noradrenaline was unaffected. Healthy subcutaneous arteries had a similar noradrenaline affinity but a higher receptor reserve than skeletal muscle arteries. In the ischaemic arteries, the antagonists prazosin (a1-selective), 5-methyl-urapidil (a1A-selective) and BMY 7378 (a1D-selective) produced rightward shifts in the concentration response curves (CRCs) of noradrenaline giving pKBs of 9.6±0.3, 8.4±0.2 and 7.1±0.4, respectively. Pretreatment with 10 µM chloroethylclonidine decreased the contractile responses to noradrenaline and A-61603 to 57±7 and 72±4% of their respective controls. These results demonstrate that the ischaemic SkMRAs have an increased a-adrenoceptor reserve with no change in the predominant a1A-adrenoceptor profile.

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KW - adrenergic agonists

KW - arteries

M3 - Article

JO - Cardiovascular Research

JF - Cardiovascular Research

SN - 0008-6363

ER -