Functional characterization of alpha1-adrenoceptor subtypes in human subcutaneous resistance arteries.
The functional characteristics of the alpha1-adrenoceptor subtypes in human resistance arteries are still not clear. We recently reported that the alpha1A-adrenoceptor predominantly mediates contraction to norepinephrine in human skeletal muscle resistance arteries. In this study we extended these investigations to human subcutaneous resistance arteries. Arterial segments were isolated from the inguinal subcutaneous fat and mounted on a small vessel wire myograph. Potencies of agonists and antagonists were examined. N-[5-(4,5-dihydro-1H-imidazol-2yl)-2-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl]methanesulphonamide (A-61603) was found to be 10- and 54-fold more potent than norepinephrine and phenylephrine, respectively. Brimonidine (UK 14304) evoked significantly smaller contractile responses than norepinephrine and phenylephrine, showing the presence of a small population of alpha2-adrenoceptors in these arteries, and this was confirmed by the studies with selective alpha1- and alpha2-adrenoceptor antagonists prazosin and (8aR,12aS,13aS)-5,8,8a,9,10,11,12,12a,13a-decahydro-3-methoxyl-12-(ethylsulphonyl)-6H-isoquino[2,1-g][1,6]-naphthyridine (RS 79948). Prazosin, 5-methyl-urapidil, and 2-[2,6-dimethoxyphenoxyethyl]aminomethyl)-1,4-benzodioxane (WB 4101) shifted the potency of norepinephrine concentration dependently giving pA2 values of 9.4, 8.9, and 10.1, respectively, showing the presence of the alpha1A-subtype in these arteries. Pretreatment with 1 and 10 microM chloroethylclonidine did not affect the potency of and maximum responses to norepinephrine, ruling out the presence of the alpha1B-subtype in these arteries. 8-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-8-azaspiro[4.5]decane-7,9-dione (BMY 7378, 10 and 100 nM) did not affect the potency of norepinephrine but a small shift was observed by 1 microM BMY 7378, giving a pK(B) value of 7.1, much less than that reported for the alpha1D-subtype. These results suggest the predominant involvement of alpha1A-adrenoceptor in the contractile responses to norepinephrine in these arteries. The physiological role of this subtype in the maintenance of peripheral arterial resistance is yet to be confirmed.
Jarajapu
Y P
YP
Vascular Assessment Unit, School of Biological and Biomedical Sciences, Glasgow Caledonian University, Glasgow, Scotland, United Kingdom.
Johnston
F
F
Berry
C
C
Renwick
A
A
McGrath
J C
JC
MacDonald
A
A
Hillier
C
C
D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000477:Alkylating Agents / Q000494:pharmacology; D001158:Arteries / Q000187:drug effects*; D006801:Humans; D066298:In Vitro Techniques; D009119:Muscle Contraction / Q000502:physiology; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D009213:Myography; D018340:Receptors, Adrenergic, alpha-1 / Q000187:drug effects*; D012039:Regional Blood Flow / Q000187:drug effects / Q000502:physiology; D012867:Skin / Q000098:blood supply; D014655:Vascular Resistance / Q000502:physiology*
D000316:Adrenergic alpha-Agonists; D000319:Adrenergic beta-Antagonists; D000477:Alkylating Agents; D018340:Receptors, Adrenergic, alpha-1