Chronic systemic administration of salmeterol to rats promotes pulmonary beta(2)-adrenoceptor desensitization and down-regulation of G(s alpha)

1 The aim of the present study was to examine the effects of chronic infusi on of the long-acting agonist salmeterol on pulmonary beta (2)-adrenoceptor function in Sprague-Dawley rats in vivo and to elucidate the molecular bas is of any altered state. 2 Systemic administration of rats with salmeterol for 7 days compromised th e ability of salmeterol and prostaglandin E-2 (PGE(2)), given acutely by th e intravenous route, to protect against ACh-induced bronchoconstriction whe n compared to rats treated identically with vehicle. 3 beta (1)- and beta (2)-adrenoceptor density was significantly reduced in lung membranes harvested from salmeterol-treated animals, which was associa ted with impaired salmeterol- and PGE(2)-induced cyclic AMP accumulation ex vivo. 4 Three variants of G(s alpha) that migrated as 42, 44 and 52 kDa peptides on SDS polyacrylamide gels were detected in lung membranes prepared from bo th groups of rats but the intensity of each isoform was markedly reduced in rats that received salmeterol. 5 The activity of cytosolic, but not membrane-associated, G-protein recepto r-coupled kinase was elevated in the lung of salmeterol-treated rats when c ompared to vehicle-treated animals. 6 The ability of salmeterol, administered systemically, to protect the airw ays of untreated rats against ACh-induced bronchoconstriction was short-act ing (t(off) similar to 45 min), which contrasts with its long-acting nature when given to asthmatic subjects by inhalation. 7 These results indicate that chronic treatment of rats with salmeterol res ults in heterologous desensitization of pulmonary G(s)-coupled receptors. I n light of previous data obtained in rats treated chronically with salbutam ol, we propose that a primary mechanism responsible for this effect is a re duction in membrane-associated G(s alpha). The short-acting nature of salme terol, when administered systemically, and the reduction in beta -adrenocep tor number may be due to metabolism to a biologically-active, short-acting and non-selective beta -adrenoceptor agonist.