Mediation of noradrenaline-induced contractions of rat aorta by the alpha 1B-adrenoceptor subtype.
1. The subtypes of alpha 1-adrenoceptor mediating contractions to exogenous noradrenaline (NA) in rat aorta have been examined in both biochemical and functional studies. 2. Incubation of rat aortic membranes with the irreversible alpha 1B-adrenoceptor antagonist, chloroethylclonidine (CEC: 10 microM) did not change the KD of [3H]-prazosin binding in comparison to untreated membranes, but reduced by 88% the total number of binding sites (Bmax). 3. Contractions of rat aortic strips to NA after CEC (50 microM for 30 min) incubation followed by repetitive washing, showed a marked shift in the potency of NA and a partial reduction in the maximum response. The residual contractions to NA after CEC incubation were not affected by prazosin (10 nM). 4. The competitive antagonists prazosin, terazosin, (R)-YM-12617, phentolamine, 5-methylurapidil and spiperone inhibited contractions to NA with estimated pA2 values of 9.85, 8.54, 9.34, 7.71, 7.64 and 8.41, respectively. 5. The affinity of the same antagonists for the alpha 1A- and alpha 1B- adrenoceptors was evaluated by utilizing membranes from rat hippocampus pretreated with CEC, and rat liver, respectively. 5-Methylurapidil and phentolamine were confirmed as selective for the alpha 1A-adrenoceptors, whereas spiperone was alpha 1B-selective. 6. A significant correlation was found between the pA2 values of the alpha 1-adrenoceptor antagonists tested and their affinity for the alpha 1B-adrenoceptor subtype, but not for the alpha 1A-subtype. 7. In conclusion, these findings indicate that in rat aorta most of the contraction is mediated by alpha 1B-adrenoceptors, and that the potency (pA2) of an antagonist in this tissue should be related to its antagonistic effect on this subtype of the alpha 1-adrenoceptor population.
Testa
R
R
Research and Development Division, Recordati S.p.A., Milan, Italy.
Guarneri
L
L
Poggesi
E
E
Simonazzi
I
I
Taddei
C
C
Leonardi
A
A
D000317:Adrenergic alpha-Antagonists / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects* / Q000378:metabolism; D001667:Binding, Competitive; D003000:Clonidine / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D003198:Computer Simulation; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D066298:In Vitro Techniques; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D009638:Norepinephrine / Q000008:administration & dosage / Q000494:pharmacology*; D010646:Phentolamine / Q000378:metabolism / Q000494:pharmacology; D010879:Piperazines / Q000378:metabolism / Q000494:pharmacology; D011224:Prazosin / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018340:Receptors, Adrenergic, alpha-1 / Q000187:drug effects / Q000378:metabolism*; D012044:Regression Analysis; D013134:Spiperone / Q000378:metabolism / Q000494:pharmacology; D013237:Stereoisomerism; D013449:Sulfonamides / Q000378:metabolism / Q000494:pharmacology; D000096926:Benzenesulfonamides
D000317:Adrenergic alpha-Antagonists; D003000:Clonidine; D009638:Norepinephrine; D010646:Phentolamine; D010879:Piperazines; D011224:Prazosin; D018340:Receptors, Adrenergic, alpha-1; D013134:Spiperone; D013449:Sulfonamides; C057446:5-methylurapidil; C051731:chlorethylclonidine; C044648:YM 12617; D000096926:Benzenesulfonamides