Alpha 1-adrenoceptor-mediated Ca(2+)-entry from the extracellular fluid and Ca(2+)-release from intracellular stores: no role for alpha 1A,B-adrenoceptor subtypes in the pithed rat.
1. In the present study, we tested the hypothesis that in the pithed rat preparation two subtypes of the alpha 1-adrenoceptor are linked to two different signal transduction mechanisms, both of which contribute to vasoconstriction, one facilitating Ca(2+)-entry from the extracellular fluid (alpha 1A) and one promoting the release of Ca2+ from intracellular sources (alpha 1B). 2. The selective alpha 1A-adrenoceptor antagonist, 5-methyl-urapidil, and the selective alpha 1B-adrenoceptor antagonist, chloroethylclonidine, were unable to discriminate between alpha 1-adrenoceptor-mediated pressor responses, which relied on an entry of extracellular Ca2+ sensitive to nifedipine and an intracellular release of Ca2+ insensitive to nifedipine, respectively. 3. Chloroethylclonidine, 12.5 and 25 mg kg-1 i.v., were equieffective, and had only minor effects on alpha 1-adrenoceptor-mediated increases in diastolic blood pressure. This could be associated with a small decrease in the receptor-reserve of the pithed rat preparation due to irreversible receptor blockade by this antagonist. These data indicate that chloroethylclonidine-sensitive alpha 1-adrenoceptors constitute only a minor fraction of the total alpha 1-adrenoceptor population on rat arterial resistance vessels. 4. Chloroethylclonidine behaved as a partial agonist eliciting a small increase in baseline diastolic blood pressure which could be inhibited by Ca(2+)-entry blockade with nifedipine. 5. Chloroethylclonidine potentiated the pressor responses elicited by the alpha 2-adrenoceptor agonists UK-14,304 and azepexole (B-HT 933). 6. No evidence was found in the pithed rat that alpha 1-adrenoceptor-mediated Ca(2+)-entry from the extracellular fluid and Ca(2+)-release from intracellular stores are mediated by alpha 1A and alpha 1B-adrenoceptors, respectively.
Department of Pharmacotherapy, Faculty of Medicine, University of Amsterdam, Academic Medical Centre, The Netherlands.
H R
HR
Schwietert
M J
MJ
Mathy
D
D
Wilhelm
B
B
Wilffert
M
M
Pfaffendorf
P A
PA
van Zwieten
D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002118:Calcium / Q000378:metabolism*; D003655:Decerebrate State; D004305:Dose-Response Relationship, Drug; D005110:Extracellular Space / Q000378:metabolism; D007424:Intracellular Fluid / Q000378:metabolism; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D011942:Receptors, Adrenergic, alpha / Q000502:physiology*; D014661:Vasoconstriction / Q000187:drug effects
D000317:Adrenergic alpha-Antagonists; D011942:Receptors, Adrenergic, alpha; D002118:Calcium