Alpha-1 adrenoceptor up-regulation induced by prazosin but not KMD-3213 or reserpine in rats.
1. We have investigated the effects of chronic administration of prazosin (a subtype-nonspecific alpha-1 AR antagonist), KMD-3213 (an alpha-1A AR subtype-specific antagonist) and reserpine (a catecholamine depletor) on the density of alpha-1 AR subtypes in various rat tissues (liver, kidney, submaxillary gland, heart and spleen). 2. Administration of prazosin (2 mg kg(-1) day(-1), i.p.) for 2 weeks did not affect K(D) values for [(3)H]-prazosin or [(3)H]-KMD-3213 of alpha-1 ARs in five rat tissues tested. However, it caused 52% up-regulation of alpha-1B AR in the spleen, and 84% and 107% up-regulation of alpha-1A- and alpha-1B ARs, respectively, in the heart. Although major subtypes of alpha-1 AR are alpha-1A AR in the submaxillary gland, alpha-1B AR in the liver, and alpha-1A and alpha-1B ARs in the kidney, these tissues showed no up-regulation. The mRNA levels of alpha-1 AR subtypes were not affected by prazosin administration in any tissue tested. 3. Neither administration of KMD-3213 (2 mg kg(-1) day(-1), i.p.) nor reserpine (0.5 - 1 mg kg(-1) day(-1), i.p.) for 2 weeks caused any change in either the binding affinity for [(3)H]-prazosin or [(3)H]-KMD-3213 or the density of the alpha-1 AR subtypes in the five rat tissues. 4. Neither prazosin nor KMD-3213 treatment reduced the noradrenaline content in the five rat tissues, in contrast to reserpine treatment, which markedly reduced it. 5. The findings of the present study demonstrated that up-regulation of alpha-1 AR is selectively caused by prazosin treatment in some tissues but neither by KMD-3213 treatment nor by chemical denervation with reserpine. These results suggest that up-regulation of alpha-1 ARs is not caused by a simple blockade of sympathetic tone.
Zhang
Li
L
Department of Pharmacology, School of Medicine, Fukui Medical University, Matsuoka, Fukui 910-1193, Japan.
Taniguchi
Takanobu
T
Tanaka
Takashi
T
Shinozuka
Kazumasa
K
Kunitomo
Masaru
M
Nishiyama
Masahiko
M
Kamata
Koji
K
Muramatsu
Ikunobu
I
D018759:Adrenergic Uptake Inhibitors / Q000494:pharmacology; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology*; D000818:Animals; D001667:Binding, Competitive; D007211:Indoles / Q000494:pharmacology*; D008297:Male; D009638:Norepinephrine / Q000378:metabolism; D016133:Polymerase Chain Reaction; D011224:Prazosin / Q000494:pharmacology*; D011869:Radioligand Assay; D051381:Rats; D017208:Rats, Wistar; D018340:Receptors, Adrenergic, alpha-1 / Q000145:classification / Q000187:drug effects / Q000378:metabolism*; D012110:Reserpine / Q000494:pharmacology; D014018:Tissue Distribution; D014316:Tritium; D015854:Up-Regulation
D018759:Adrenergic Uptake Inhibitors; D000317:Adrenergic alpha-Antagonists; D007211:Indoles; D018340:Receptors, Adrenergic, alpha-1; D014316:Tritium; D012110:Reserpine; C095285:silodosin; D009638:Norepinephrine; D011224:Prazosin