Investigation of alpha1-adrenoceptor subtypes mediating vasoconstriction in rabbit cutaneous resistance arteries.
1. Cutaneous resistance arteries (c.r.a.) (internal diameter=240.94+/-5.42 microm, n=67/25 (number arteries/number animals)) from New Zealand white rabbits were mounted in wire myographs and a normalization procedure followed. 2. Cumulative concentration-response curves (CCRCs) were constructed for the alpha-adrenoceptor agonists noradrenaline (NA), (R)A61603 and phenylephrine (PE) in the presence of cocaine (3 microM), propranolol (1 microM) and corticosterone (10 microM). The effects of competitive alpha1-adrenoceptor antagonists, prazosin, WB4101, 5-methyl-urapidil, HV723, BMY7378 and the irreversible alpha1B selective compound chloroethylclonidine (CEC) were examined versus the potency and maximum response of the c.r.a.s to noradrenaline. 3. The high potency of A-61603 relative to PE has been shown to differentiate both functional and binding site alpha1A- or alpha1B-adrenoceptors from alpha1D-adrenoceptors: A-61603 was 944 times more potent than phenylephrine (at EC50) suggesting the presence of a functional alpha1A or alpha1B as opposed to an alpha1D-subtype. 4. Exposure to chloroethylclonidine (CEC; 100 microM) decreased the maximum response to noradrenaline but did not significantly change noradrenaline sensitivity indicating that a substantial part of noradrenaline-induced vasoconstriction in rabbit cutaneous arteries is CEC-insensitive. 5. The potencies of prazosin (pA2=9.14) and WB4101 (pA2=9.30) indicate the involvement of prazosin-sensitive functional alpha1-adrenoceptors. The slopes of corresponding Schild plots for prazosin and WB4101 did not include negative unity which implies the possible involvement of more than one functional alpha1-adrenoceptor subtype in noradrenaline-induced vasoconstriction in rabbit cutaneous resistance arteries. In contrast to this, in the case of 5-methyl-urapidil and HV723, the Schild plot slope parameters were not significantly different from negative unity over the range of concentrations used; the low pA2 value for 5-methylurapidil (7.27) suggests the non-involvement of an alpha1A- or an alpha1D-adrenoceptor; the low pA2 value for HV723 (8.47) was similar to that against responses postulated as alpha1L. 6. We conclude that rabbit cutaneous resistance arteries express a prazosin-sensitive functional alpha1-adrenoceptor resembling the alpha1B and another low affinity site for prazosin which on the basis of the functional antagonism produced by HV723 most closely resembles the alpha1L-adrenoceptor; the low pA2 value for HV723 (8.47) is similar to that against responses postulated as alpha1L.
Smith
K M
KM
Clinical Research Initiative in Heart Failure, Neuroscience and Biomedical Systems, University of Glasgow, Scotland.
Macmillan
J B
JB
McGrath
J C
JC
D000097:Acetonitriles / Q000494:pharmacology; D000316:Adrenergic alpha-Agonists / Q000494:pharmacology*; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology*; D000818:Animals; D001158:Arteries / Q000187:drug effects; D003000:Clonidine / Q000031:analogs & derivatives / Q000494:pharmacology; D004146:Dioxanes / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D007093:Imidazoles / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D009638:Norepinephrine / Q000494:pharmacology; D010656:Phenylephrine / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D011224:Prazosin / Q000494:pharmacology; D011817:Rabbits; D018340:Receptors, Adrenergic, alpha-1 / Q000187:drug effects* / Q000378:metabolism; D012867:Skin / Q000098:blood supply*; D013764:Tetrahydronaphthalenes / Q000494:pharmacology; D014655:Vascular Resistance / Q000187:drug effects*; D014661:Vasoconstriction / Q000187:drug effects*
C094643:A 61603; D000097:Acetonitriles; D000316:Adrenergic alpha-Agonists; D000317:Adrenergic alpha-Antagonists; D004146:Dioxanes; D007093:Imidazoles; D010879:Piperazines; D018340:Receptors, Adrenergic, alpha-1; D013764:Tetrahydronaphthalenes; C058562:HV 723; D010656:Phenylephrine; C051731:chlorethylclonidine; C010654:(2-(2',6'-dimethoxy)phenoxyethylamino)methylbenzo-1,4-dioxane; C053428:BMY 7378; D003000:Clonidine; D009638:Norepinephrine; D011224:Prazosin