a-61603 and Ischemia

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 alpha(1)-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 (alpha(1A)-selective) were significantly increased in ischaemic arteries compared to those in non-ischaemic arteries. Receptor inactivation studies indicated an increase in the alpha-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 (alpha(1)-selective), 5-methyl-urapidil (alpha(1A)-selective) and BMY 7378 (alpha(1D)-selective) produced rightward shifts in the concentration response curves (CRCs) of noradrenaline giving pK(B)s of 9.6+/-0.3, 8.4+/-0.2 and 7.1+/-0.4, respectively. Pretreatment with 10 microM 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 alpha-adrenoceptor reserve with no change in the predominant alpha(1A)-adrenoceptor profile.

Topics: Adrenergic alpha-Agonists; Adrenergic alpha-Antagonists; Aged; Arteries; Dose-Response Relationship, Drug; Endothelium, Vascular; Epinephrine; Female; Humans; Imidazoles; Ischemia; Leg; Male; Middle Aged; Muscle Contraction; Muscle, Skeletal; Norepinephrine; Receptors, Adrenergic, alpha-1; Tetrahydronaphthalenes; Vasoconstriction