Chronic b-blockade increases skeletal muscle b-adrenergic- receptor density and enhances contractile force RENE ´ J. L. MURPHY, 1,3 PHILLIP F. GARDINER, 1 GUY ROUSSEAU, 2,3 MICHEL BOUVIER, 2,3 AND LOUISE BE ´ LIVEAU 1,3 1 De ´partement d’E ´ ducation Physique, 2 De ´partement de Biochimie, and 3 Groupe de Recherche sur le Syste `me Nerveux Autonome, Universite ´ de Montre ´al, Montreal, Quebec, Canada H3C 3J7 Murphy, Rene ´ J. L., Phillip F. Gardiner, Guy Rous- seau, Michel Bouvier, and Louise Be ´ liveau. Chronic b-blockade increases skeletal muscle b-adrenergic-receptor density and enhances contractile force. J. Appl. Physiol. 83(2): 459–465, 1997.—The effects of a chronic 14-day admin- istration of a selective b 2 -adrenergic-receptor antagonist (ICI- 118551) on skeletal muscle were evaluated in female Sprague- Dawley rats. Chronic ICI-118551 treatment did not modify muscle mass, oxidative potential, or protein concentration of the medial gastrocnemius muscle, suggesting that mainte- nance of these skeletal muscle characteristics is not depen- dent on b 2 -adrenergic-receptor stimulation. However, the drug treatment increased b-adrenergic-receptor density of the lateral gastrocnemius (42%) and caused an increase in specific (g/g) isometric in situ contractile forces of the medial gastrocnemius [twitch, 56%; tetanic (200 Hz), 28%]. The elevated contractile forces observed after a chronic treatment with ICI-118551 were completely abolished when the b 2 - adrenergic antagonist was also administered acutely before measurement of contractile forces, suggesting that this re- sponse is b 2 -adrenergic-receptor dependent. Possible mecha- nisms for the increased forces were studied. Caffeine adminis- tration potentiated twitch forces but had little effect on tetanic force in control animals. Administration of dibutyryl adenosine 38,58-cyclic monophosphate in control animals also resulted in small increases of twitch force but did not modify tetanic forces. We conclude that increases in b-adrenergic- receptor density and the stimulation of the receptors by endogenous catecholamines appear to be responsible for increased contractile forces but that the mechanism remains to be demonstrated. contractile properties; ICI-118551 DIFFERENT SKELETAL MUSCLE fiber types have been shown to express different densities and types of b-adrenergic receptors (14). For instance, higher densities of b-adren- ergic receptors are present in slow skeletal muscles (10), and atypical b-adrenergic receptors are probably the most important type, representing up to 80% of b-adrenergic receptors of the soleus muscle (20, 23). However, b 2 -adrenergic receptors are believed to be the main type of adrenergic receptors in fast skeletal muscle (10). Recent work has focused on characterizing skeletal muscle b-adrenergic receptors, but their func- tional roles have not been completely elucidated. These receptors could be involved in several aspects of muscle function, including stimulation of glycogenolysis (28), triglyceride lipolysis (27), muscle oxygen consumption (26), ion exchange (19), and increasing muscle force generation (28). These effects could differ in various muscles because of the number and/or type of b-adren- ergic receptors present. For instance, b 2 -adrenergic- agonist stimulation of Na 1 extrusion and K 1 uptake has been reported to be much greater in slow than in fast skeletal muscles (19). Conversely, the inotropic effects of b-agonists are observed solely in fast skeletal muscles (28), but the mechanism underlying this effect is not well understood. b-Adrenergic-receptor stimula- tion causes a cascade of events leading to the intracellu- lar accumulation of the second messenger adenosine 38,58-cyclic monophosphate (cAMP). However, the intra- cellular site of cAMP action in the potentiation of fast skeletal muscle force is unknown. Other observations suggest that b-adrenergic recep- tors may be involved in skeletal muscle adaptations to changes in activity level. For example, skeletal muscle b-adrenergic-receptor density has been shown to be correlated with both the oxidative potential (29) and the percentage of type I fibers in skeletal muscle (14). Furthermore, chronic b 2 -adrenergic-receptor stimula- tion causes increased skeletal muscle mass in several animal species (10, 30). Finally, the widely used clini- cally nonspecific b-adrenergic blockers are usually asso- ciated with reduced exercise capacity (25). In previous attempts to determine the roles of skeletal muscle b 2 -adrenergic receptors, nonspecific b-adrenergic block- ers or a combination of nonspecific and b 1 -selective blockers have been used (9). However, the effects of chronic selective b 2 -adrenergic-receptor blockade on skeletal muscle properties have not been studied in detail. The purpose of this study was to determine the effects of chronic blockade of b 2 -adrenergic receptors on skeletal muscle properties. Muscle isometric contrac- tile properties, mass, protein concentration, fiber types, cytochrome oxidase activity, as well as b-adrenergic- receptor density were measured in selected muscles after chronic treatment with a selective b 2 -adrenergic- receptor antagonist. METHODS Animals. All experiments were performed in accordance with the guidelines of the Canadian Council on Animal Care (4) and the University’s Ethics and Research Committee. A total of 34 female Sprague-Dawley rats (Charles River; St-Constant, PQ) with an initial body weight of ,150 g were studied. The animals received a standard rat diet (ProLab RMH 4018) and water ad libitum. They were housed individu- ally in an environmentally controlled facility (12:12-h light- dark cycle, ,21°C) and weighed daily. Drug treatment. After a 3- to 4-day acclimatization period in the animal care facility, rats were randomly assigned to one of the following treatment groups: control (n 5 7) or antago- nist-treated (n 5 10). Rats of the antagonist group received ICI-118551 (ICI), a selective b 2 -adrenergic antagonist, at a 0161-7567/97 $5.00 Copyright r 1997 the American Physiological Society 459 http://www.jap.org