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

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). Administration of prazosin (2 mg kg−1 day−1, i.p.) for 2 weeks did not affect KD values for [3H]‐prazosin or [3H]‐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. 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 [3H]‐prazosin or [3H]‐KMD‐3213 or the density of the alpha‐1 AR subtypes in the five rat tissues. Neither prazosin nor KMD‐3213 treatment reduced the noradrenaline content in the five rat tissues, in contrast to reserpine treatment, which markedly reduced it. 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. British Journal of Pharmacology (2002) 135, 1757–1764; doi:10.1038/sj.bjp.0704639