Alpha‐1 adrenoceptor up‐regulation induced by prazosin but not KMD‐3213 or reserpine in rats

Abstract

1 We have investigated the e ects of chronic administration of prazosin (a subtype-nonspeci®c alpha-1 AR antagonist), KMD-3213 (an alpha-1A AR subtype-speci®c 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). H]-KMD-3213 of alpha-1 ARs in ®ve rat tissues tested. However, it caused 52% upregulation 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 a ected by prazosin administration in any tissue tested. 3 Neither administration of KMD-3213 (2 mg kg 71 day 71 , i.p.) nor reserpine (0.5 ± 1 mg kg 71 day 71 , i.p.) for 2 weeks caused any change in either the binding a nity for [ 3 H]-prazosin or [ 3 H]-KMD-3213 or the density of the alpha-1 AR subtypes in the ®ve rat tissues. 4 Neither prazosin nor KMD-3213 treatment reduced the noradrenaline content in the ®ve rat tissues, in contrast to reserpine treatment, which markedly reduced it. 5 The ®ndings 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.

Alpha‐1D adrenoceptors are involved in reserpine‐induced supersensitivity of rat tail artery

“…However, in contrast with the aorta but like the tail artery, the endogenous noradrenaline level in the spleen was high and was markedly reduced by reserpine treatment. Present and previous functional or binding studies have clearly demonstrated the exclusive presence of alpha-1B AR subtype in rat spleen, irrespective of reserpine treatment (Kenakin & Novak, 1988;Yang et al, 1997;Buckner et al, 2002;Zhang et al, 2002). Thus, it does not appear that noradrenaline depletion and/or lack of adrenergic input necessarily cause the changes of alpha-1 AR expression and supersensitivity in sympathetically innervated tissues all.…”

Pharmacological Characterization and Cross Talk of α1A- and α1B-Adrenoceptors Coexpressed in Human Embryonic Kidney 293 Cells

“…The ␣ 1A, 1B -AR cell lines used in this study, which demonstrated a coexpression of these receptor populations, both exhibited ␣ 1A -AR Ͻ ␣ 1B -AR densities. This kind of subpopulation ratio has been seen in many tissues (Minneman et al, 1988;Lazou et al, 1994;Michel et al, 1994a;Zhang et al, 2002), but a distinct opposite population ratio has been observed in other tissues (Zhang et al, 2002;Tanaka et al, 2004). At first, we examined the ␣ 1A, 1B -AR cell line by a ligand binding approach and compared its properties with those of cells expressing ␣ 1A -or ␣ 1B -AR alone.…”

“…For example, ␣ 1A -and ␣ 1B -ARs are found in different proportions to be coexpressed in brain, heart, kidney, and artery of various mammalian species (Price et al, 1994). In the rat myocardium, ␣ 1A -and ␣ 1B -ARs coexist in a 20 to 30%:70 to 80% ratio and mediate divergent effects on cardiac inotropy, rhythmicity, and cell growth (Michel et al, 1994a;Zhang et al, 2002). In rat tail artery, ␣ 1A -and ␣ 1B -ARs occur in a ratio of approximately 60%:40%, mediating adrenergic contractions (Tanaka et al, 2004).…”

Effects of the inverse alpha‐agonist doxazosin in allergic rhinitis

“…The difference between single and repeated dosing is most likely explained by adaptive up regulation of alpha-1 receptors in the nasal vasculature [7] ,although we did not measure nasal alpha receptor density in the present study. The same disconnect between single and chronic dosing was also seen with cardiovascular responses.…”

“…In healthy volunteers the dorsal hand vein vasoconstrictor DRC to the alpha-1 agonist phenylephrine was shifted by seven fold to the right after the first dose of the alpha-1 antagonist terazosin compared to baseline, but after 4 weeks of terazosin the dose response to phenylephrine returned back to baseline, in turn indicating that alpha-1 receptor up regulation occurs during chronic dosing [6,7].…”