Decreased monocarboxylate transporter 1 in rat soleus and EDL muscles exposed to clenbuterol.
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We hypothesized that a shift in muscle fiber type induced by clenbuterol would change monocarboxylate transporter 1 (MCT1) content and activity of lactate dehydrogenase (LDH) and isoform pattern and shift myosin heavy chain (MHC) pattern in soleus (Sol) and extensor digitorum longus (EDL) of male rats. In the clenbuterol-administered rats (2.0 mg x kg(-1) x day(-1) subcutaneously for 4 wk), the ratio of muscle weight to body weight increased in the Sol (P < 0.05) and the EDL (P < 0.01). Clenbuterol induced the appearance of fast MHC(2D) and decreased slow MHC(1) in Sol (13%) but had no effect on EDL. The MHC pattern of Sol changed from slow to fast type. Clenbuterol increased LDH-specific activity (P < 0.01) and the ratio of the muscle-type isozyme of LDH to the heart type (P < 0.05) in Sol. The LDH total activity of the EDL muscle was also increased (P < 0.05). Furthermore, MCT1 content significantly (P < 0.05) decreased in both Sol and EDL (27 and 52%, respectively). This study suggests that clenbuterol might mediate the shift of MHC from slow to fast type and the changes in the regulation of lactate metabolism. Novel to this study is the observation that clenbuterol decreases MCT1 content in the hindlimb muscles and that the decrease in MCT1 is not muscle-type specific. It may suggest that the genetic expressions of individual factors involving slow-type MHC, heart-type isozyme of LDH, and MCT1 are associated with one another but are regulated independently. (+info)
Biomechanical hearts: muscular blood pumps, performed in a 1-step operation, and trained under support of clenbuterol.
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BACKGROUND: As shown previously in goats, clenbuterol increased the power of electrically conditioned skeletal muscle ventricles (SMVs) of clinically relevant size (150 mL), which were constructed around a mock system. They pumped against a pressure of 60 to 70 mm Hg immediately during surgery and up to several months after, finally at >1 L/min. SMVs without clenbuterol administration failed. Thus, we expected that clenbuterol-supported SMVs might become integrated into the circulation by a 1-step operation instead of the 2-step procedure required up to now. METHODS AND RESULTS: In adult Boer goats (n=5), latissimus dorsi muscle was wrapped around a polyurethane chamber of 150 mL that was connected to the descending aorta. This muscular flow-through pumping chamber containing a stabilizing inner layer (called a biomechanical heart [BMH]) was formed and immediately made to work against a systemic load with the support of clenbuterol (5x150 microg/wk). During surgery, the mean stroke volume of BMHs was 53.8+/-22.4 mL. One month after surgery, in peripheral arterial pressure, the mean diastolic (P(MD)) and minimal diastolic (P(min)) pressures of BMH-supported heart cycles differed significantly from unsupported ones (P(MD)=+2.9+/-1.1 mm Hg [P<0.04], P(min)=-2.4+/-0.9 mm Hg [P<0.04]). After BMH-supported heart contractions, the subsequent maximal rate of pressure generation, dP/dt(max), increased by 20.5+/-8.1% (P<0.02). One BMH, catheterized 132 days after surgery, shifted a volume of 34.8 mL per beat and 1.4 L/min with a latissimus dorsi muscle of 330 g. Depending on duration of training, the percentage of myosin heavy chain type 1 ranged between 31% and 100%. CONCLUSIONS: Under support of clenbuterol, BMHs of a clinically relevant size can be trained effectively in the systemic circulation after a 1-step operation and offer the prospect of a sufficient volume shift and probably unloading of the left ventricle. (+info)
Catecholamines inhibit Ca(2+)-dependent proteolysis in rat skeletal muscle through beta(2)-adrenoceptors and cAMP.
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Overall proteolysis and the activity of skeletal muscle proteolytic systems were investigated in rats 1, 2, or 4 days after adrenodemedullation. Adrenodemedullation reduced plasma epinephrine by 95% and norepinephrine by 35% but did not affect muscle norepinephrine content. In soleus and extensor digitorum longus (EDL) muscles, rates of overall proteolysis increased by 15-20% by 2 days after surgery but returned to normal levels after 4 days. The rise in rates of protein degradation was accompanied by an increased activity of Ca(2+)-dependent proteolysis in both muscles, with no significant change in the activity of lysosomal and ATP-dependent proteolytic systems. In vitro rates of Ca(2+)-dependent proteolysis in soleus and EDL from normal rats decreased by ~35% in the presence of either 10(-5) M clenbuterol, a beta(2)-adrenergic agonist, or epinephrine or norepinephrine. In the presence of dibutyryl cAMP, proteolysis was reduced by 62% in soleus and 34% in EDL. The data suggest that catecholamines secreted by the adrenal medulla exert an inhibitory control of Ca(2+)-dependent proteolysis in rat skeletal muscle, mediated by beta(2)-adrenoceptors, with the participation of a cAMP-dependent pathway. (+info)
Elevated IGF-II mRNA and phosphorylation of 4E-BP1 and p70(S6k) in muscle showing clenbuterol-induced anabolism.
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Muscle wasting affects large numbers of people, but few therapeutic approaches exist to treat and/or reverse this condition. The beta(2)-adrenoceptor agonist clenbuterol produces a muscle-specific protein anabolism in both normal and catabolic muscle and has been used to limit muscle wasting in humans. Because clenbuterol appears to interact with or mimic innervation, its effect on the expression of the neurotrophic agents insulin-like growth factor (IGF)-II and H19 and their putative pathways was examined in normal rat plantaris muscle. The results showed that the well-documented early effects of clenbuterol on protein metabolism were preceded by elevated levels of IGF-II and H19 transcripts together with increased phosphorylation of eukaryotic initiation factor (eIF)4E binding protein-1 (4E-BP1) and p70(S6k). By 3 days, transcript levels for IGF-II and H19 and 4E-BP1 and p70(S6k) phosphorylation had returned to control values. These novel findings indicate that clenbuterol-induced muscle anabolism is potentially mediated, at least in part, by an IGF-II-induced activation of 4E-BP1 and p70(S6k). (+info)
Aging alters neuronal nitric oxide release from rat mesenteric arteries: role of presynaptic beta-adrenoceptors.
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This study examines the influence of aging on the neuronal nitric oxide (NO) and noradrenaline (NA) release elicited by electrical field stimulation (EFS; 200 mA, 0.3 ms, 1-16 Hz, 30 s) in endothelium-denuded mesenteric arteries from young and old rats, as well as the influence of the presynaptic beta-adrenoceptors in that release. EFS induced frequency-dependent contractions. N(G)-nitro-l-arginine methyl ester (l-NAME) only enhanced EFS-elicited contractions in arteries from young rats. Capsaicin did not alter the EFS-induced contractions in either age group. Clenbuterol did not modify the contraction elicited by EFS in arteries from young or old rats either. A subsequent addition of l-NAME also induced an increase in the EFS-induced response in arteries from both age groups. In old rats, the presence of propranolol did not alter the response induced by EFS, and the subsequent addition of clenbuterol or clenbuterol plus l-NAME did not affect this response. In precontracted segments, sodium nitroprusside or clenbuterol induced similar relaxation in both age groups. None of the drugs used altered the response to exogenous NA or basal tone. In arteries preincubated with [(3)H]NA, EFS induced (3)H release, which remained unmodified in the presence of clenbuterol or propranolol in young rats, whereas clenbuterol increased the (3)H overflow in old rats, and this effect was abolished by propranolol. These drugs did not alter the basal (3)H efflux and indicate that in rat mesenteric arteries EFS induces NA release in both age groups, and only NO release in young animals. Activation of presynaptic beta-adrenoceptors increased NA and probably NO release in aged rats. (+info)
Chronic administration of therapeutic levels of clenbuterol acts as a repartitioning agent.
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The purpose of this study was to examine the effect of therapeutic levels of clenbuterol, with and without exercise training, on body composition. Twenty-three unfit Standardbred mares were divided into four experimental groups: clenbuterol (2.4 microg/kg body wt twice daily) plus exercise (ClenEx; 20 min at 50% maximal oxygen consumption 3 days/wk; n = 6), clenbuterol only (Clen; n = 6), exercise only (Ex; n = 5), and control (Con; n = 6). Rump fat thickness was measured at 2-wk intervals by using B-mode ultrasound, and percent body fat (%fat) was calculated by using previously published methods. For Ex, body fat decreased (P < 0.05) at week 4 (-9.3%), %fat at week 6 (-6.9%), and fat-free mass (FFM) increased (P < 0.05) at week 8 (+3.2%). On the other hand, Clen had significant changes in %fat (-15.4%), fat mass (-14.7%), and FFM (+4.3%) at week 2. ClenEx had significant decreases in %fat (-17.6%) and fat mass (-19.5%) at week 2, which was similar to Clen; however, this group had a different FFM response, which significantly increased (+4.4%) at week 6. Con showed no changes (P > 0.05) in any variable at any time. These results suggest that exercise training and clenbuterol have additive effects with respect to %fat and fat mass but antagonistic effects in terms of FFM. Furthermore, chronic clenbuterol administration causes significant repartitioning in the horse, even when administered in therapeutic doses. (+info)
Role of IGF-I and IGFBPs in the changes of mass and phenotype induced in rat soleus muscle by clenbuterol.
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Clenbuterol induces hypertrophy and a slow-to-fast phenotype change in skeletal muscle, but the signaling mechanisms remain unclear. We hypothesized that clenbuterol could act via local expression of insulin-like growth factor I (IGF-I). Administration of clenbuterol to 3-mo-old female Wistar rats resulted in a 10 and 13% increase of soleus muscle mass after 3 and 9 days, respectively, reaching 16% after 4 wk. When associated with triiodothyronine, clenbuterol induced a dramatic slow-to-fast phenotype change. In parallel, clenbuterol administration induced in soleus muscle a fivefold increase in IGF-I mRNA levels associated with an eightfold increase in IGF-binding protein (IGFBP)-4 and a fivefold increase of IGFBP-5 mRNA levels on day 3. This increased IGF-I gene expression was associated with an increase in muscle IGF-I content, already detected on day 1 and persisting until day 5 without increase in serum IGF-I concentrations. These data show that muscle hypertrophy induced by clenbuterol is associated with a local increase in muscle IGF-I content. They suggest that clenbuterol-induced muscle hypertrophy could be mediated by local production of IGF-I. (+info)
Involvement of constitutive (COX-1) and inducible cyclooxygenase (COX-2) in the adrenergic-induced ACTH and corticosterone secretion.
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The involvement of prostaglandins synthesized by constitutive (COX-1) and inducible cyclooxygenase (COX-2) in central stimulation of the hypothalamic-pituitary-adrenal (HPA) axis by adrenergic receptor agonists was investigated in conscious rats. COX-1 and COX-2 inhibitor, piroxicam (0.02 and 0.2 microg) and compound NS-398 (0.01 and 0.1 microg), respectively, were given intracerebroventricularly (i.c.v.) 15 min prior to i.c.v. adrenergic receptor agonists: phenylephrine (30 microg) and clonidine (10 microg), an alpha1- and alpha2-adrenergic agonist, and isoprenaline (20 microg) a non-selective beta-adrenergic agonist and clenbuterol (10 microg) a selective beta2-adrenergic agonist. Piroxicam and NS-398 considerably and dose-dependently reduced the phenylephrine-induced increase in ACTH and corticosterone secretion. Pretreatment with piroxicam and NS-398 markedly impaired the clonidine-evoked ACTH and corticosterone secretion. Piroxicam moderately diminished the isoprenaline-elicited increase in ACTH and corticosterone, while NS-398 did not markedly alter ACTH secretion. The clenbuterol-induced ACTH and corticosterone responses were considerably impaired by pretreatment with piroxicam, and slightly less potently by NS-398. These results indicate that in central structures involved in regulation of the HPA axis both constitutive and inducible cyclooxygenase are present under normal conditions in rats. These isoenzymes are significantly involved in the stimulatory signaling transduced by postsynaptic alpha1-adrenergic receptors and, to a lesser extent, by alpha2-adrenergic receptors. Both isoenzymes affect moderately the stimulatory action of a non-selective beta-adrenergic agonist on ACTH and corticosterone secretion. COX-1 participates considerably and COX-2 markedly in the potent stimulatory action of selective beta2-adrenergic receptors on HPA axis. (+info)