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.
|Publication status||Published - 1 Feb 2003|
- ischemia receptors
- adrenergic agonists