Category Archives: Beta Blockers

Beta Blockers May Blunt Exercise Benefits

Abstract

β-Adrenergic receptor blockade blunts postexercise skeletal muscle mitochondrial protein synthesis rates in humans.

β-Adrenergic receptor (AR) signaling is a regulator of skeletal muscle protein synthesis and mitochondrial biogenesis in mice. We hypothesized that β-AR blockade blunts postexercise skeletal muscle mitochondrial protein synthesis rates in adult humans. Six healthy men (mean ± SD: 26 ± 6 yr old, 39.9 ± 4.9 ml·kg(-1)·min(-1) peak O(2) uptake, 26.7 ± 2.0 kg/m(2) body mass index) performed 1 h of stationary cycle ergometer exercise (60% peak O(2) uptake) during 1) β-AR blockade (intravenous propranolol) and 2) administration of saline (control). Skeletal muscle mitochondrial, myofibrillar, and sarcoplasmic protein synthesis rates were assessed using [(2)H(5)]phenylalanine incorporation into skeletal muscle proteins after exercise. The mRNA content of signals for mitochondrial biogenesis was determined using real-time PCR. β-AR blockade decreased mitochondrial (from 0.217 ± 0.076 to 0.135 ± 0.031%/h, P < 0.05), but not myofibrillar or sarcoplasmic, protein synthesis rates. Peroxisome proliferator-activated receptor-γ coactivator-1α mRNA was increased ∼2.5-fold (P < 0.05) at 5 h compared with 1 h postexercise but was not influenced by β-AR blockade. We conclude that decreased β-AR signaling during cycling can blunt the postexercise increase in mitochondrial protein synthesis rates without affecting mRNA content.

Robinson MM, Bell C, Peelor FF, Miller BF
Am. J. Physiol. Regul. Integr. Comp. Physiol. Aug 2011
PMID: 21613574 | Free Full Text

Given that increased muscle tends to increase bone, this is somewhat negative, even though there is some evidence that beta blockers plus exercise is additive for bone.

Beta Blockers Increase Bone Loss from Steroids in Rats

Abstract

Effects of propranolol on the development of glucocorticoid-induced osteoporosis in male rats.

Glucocorticoid-induced osteoporosis is the most frequently occurring type of secondary osteoporosis. Antagonists of β-adrenergic receptors are now considered to be potential drugs under investigation for osteoporosis. The aim of the present study was to investigate the effects of propranolol, a nonselective β-receptor antagonist, on the skeletal system of mature male rats and on the development of bone changes induced by glucocorticoid (prednisolone) administration. The experiments were performed on 24-week-old male Wistar rats. The effects of prednisolone 21-hemisuccinate sodium salt (7 mg/kg, sc daily) or/and propranolol hydrochloride (10 mg/kg, ip daily) administered for 4 weeks on the skeletal system were studied. Bone and bone mineral mass in the tibia, femur and L-4 vertebra, length and diameter of the long bones, mechanical properties of tibial metaphysis, femoral diaphysis and femoral neck, bone histomorphometric parameters and turnover markers in serum were determined. Prednisolone-induced unfavorable skeletal changes led to disorders in bone mechanical properties. Propranolol not only did not improve bone parameters, but even caused deleterious effects on the skeletal system. Concurrent administration of propranolol with prednisolone did not counteract the changes induced by prednisolone. The results of this study may help to understand the equivocal results of human studies on the effects of β-blockers on the skeletal system. It is possible that the drugs exert biphasic effects on the skeletal system, both favorable and deleterious, depending on the dose or individual susceptibility.

Folwarczna J, Pytlik M, Sliwiński L, Cegieła U…
Pharmacol Rep 2011
PMID: 22001992 | Free Full Text

Beta Blockers or Exercise Improve Bone in Rats

Abstract

Combined effects of exercise and propranolol on bone tissue in ovariectomized rats.

The bone response to physical exercise may be under control of the SNS. Using a running session in rats, we confirmed that exercise improved trabecular and cortical properties. SNS blockade by propranolol did not affect this response on cortical bone but surprisingly inhibited the trabecular response. This suggests that the SNS is involved in the trabecular response to exercise but not in the cortical response.
Animal studies have suggested that bone remodeling is under beta-adrenergic control through the sympathetic nervous system (SNS). However, the SNS contribution to bone response under mechanical loading remains unclear. The purpose of this study was to examine the preventive effect of exercise coupled with propranolol on cancellous and cortical bone compartments in ovariectomized rats.
Six-month-old female Wistar rats were ovariectomized (OVX, n = 44) or sham-operated (n = 24). OVX rats received subcutaneous injections of propranolol 0.1 mg/kg/day or vehicle and were submitted or not submitted to treadmill exercise (13 m/minute, 60 minutes/day, 5 days/week) for 10 weeks. Tibial and femoral BMD was analyzed longitudinally by DXA. At death, the left tibial metaphysis and L(4) vertebrae were removed, and microCT was performed to study trabecular and cortical bone structure. Histomorphometric analysis was performed on the right proximal tibia.
After 10 weeks, BMD and trabecular strength decreased in OVX rats, whereas bone turnover rate and cortical porosity increased compared with the Sham group (p < 0.001). Either propranolol or exercise allowed preservation of bone architecture by increasing trabecular number (+50.35% versus OVX; p < 0.001) and thickness (+16.8% versus OVX; p < 0.001). An additive effect of propranolol and exercise was observed on cortical porosity but not on trabecular microarchitecture or cortical width. Biomechanical properties indicated a higher ultimate force in the OVX-propranolol-exercise group compared with the OVX group (+9.9%; p < 0.05), whereas propranolol and exercise alone did not have any significant effect on bone strength.
Our data confirm a contribution of the SNS to the determinants of bone mass and quality and show a antagonistic effect of exercise and a beta-antagonist on trabecular bone structure.

Bonnet N, Beaupied H, Vico L, Dolleans E…
J. Bone Miner. Res. Apr 2007
PMID: 17243867

Nervous System Does Not Induce Bone Growth – Only Resorption?

Abstract

Sympathetic nervous system does not mediate the load-induced cortical new bone formation.

The contribution of the SNS to bone’s response to mechanical loading is unclear. Using a noninvasive model of axial loading of the murine tibia, we found that sciatic neurectomy enhances load-induced new cortical bone formation and that pharmacological blockade of the SNS does not affect such responses, indicating that the SNS does not mediate the osteogenic effects of loading in cortical bone.
There is increasing evidence that the sympathetic nervous system (SNS) contributes to the regulation of bone mass and may influence remodeling by modulating bones’ response to mechanical load-bearing. The aim of this study was to examine the effect of sciatic neurectomy (SN) on the changes in cortical bone formation induced in response to mechanical loading and to investigate whether the SNS is directly involved in such load-induced responses.
Accordingly, load-induced responses were compared in tibias of growing and adult control C57Bl/J6 mice and in mice submitted to unilateral SN; noninvasive axial loading that induced 2,000 microstrain on the tibia lateral midshaft cortex was applied cyclically, 5 or 100 days after surgery, for 7 minutes, 3 days/week for 2 weeks, and mice received calcein on the third and last days of loading. Tibias were processed for histomorphometry, and transverse confocal images from diaphyseal sites were analyzed to quantify new cortical bone formation. Chemical SNS inactivation was achieved by prolonged daily treatment with guanethidine sulfate (GS) or by the introduction of propranolol in drinking water.
Our results show that new cortical bone formation is enhanced by loading in all tibial sites examined and that load-induced periosteal and endosteal new bone formation was greater in the SN groups compared with sham-operated controls. This SN-related enhancement in load-induced cortical bone formation in tibias was more pronounced 100 days after neurectomy than after 5 days, suggesting that longer periods of immobilization promote a greater sensitivity to loading. In contrast, the increases in new bone formation induced in response to mechanical loading were similar in mice treated with either GS or propranolol compared with controls, indicating that inactivation of the SNS has no effect on load-induced cortical new bone formation.
This study shows that SN, or the absence of loading function it entails, enhances loading-related new cortical bone formation in the tibia independently of the SNS.

de Souza RL, Pitsillides AA, Lanyon LE, Skerry TM…
J. Bone Miner. Res. Dec 2005
PMID: 16294269

Lipoic Acid Inhibits Resorption from Adrenaline

Abstract

β-Adrenergic signaling stimulates osteoclastogenesis via reactive oxygen species.

Sympathetic signaling regulates bone resorption through receptor activator of nuclear factor-κB ligand (RANKL) expression via the β-adrenergic receptor (β-AR) on osteoblasts. Reactive oxygen species (ROS) are known as one type of osteoclast regulatory molecule. Here we show that an antioxidant, α-lipoic acid (α-LA), treatment prevent the β-adrenergic signaling-induced bone loss by suppressing osteoclastogenesis, and sympathetic signaling directly regulates osteoclastogenesis through β2-AR expressed on osteoclasts via intracellular ROS generation. In an in vitro study, the β-AR agonist isoprenaline increased intracellular ROS generation in osteoclasts prepared from bone marrow macrophages (BBMs) and RAW 264.7 cells. Isoprenaline enhanced osteoclastogenesis through β2-AR expressed on BMMs and RAW 264.7 cells. The antioxidant α-LA inhibited isoprenaline-enhanced osteoclastogenesis. Isoprenaline increased the expression of osteoclast-related genes such as nuclear factor of activated T cells, cytoplasmic, calcineurin-dependent 1, tartrate-resistant acid phosphatase, and cathepsin K on osteoclasts. α-LA also inhibited isoprenaline-induced increases of these gene expressions. These in vitro results led to the hypothesis that β-adrenergic signaling directly stimulates osteoclastogenesis via ROS generation. In an in vivo study, isoprenaline treatment alone caused oxidative damage in local bone and reduced bone mass because of an increase in bone resorption, and, in α-LA-treated mice, isoprenaline did not increase tibial osteoclast number even though the RANKL-to-osteoprotegerin ratio increased. These in vitro and in vivo results indicate that β-adrenergic signaling, at least in part, directly stimulates osteoclastogenesis through β2-AR on osteoclasts via ROS generation.

Kondo H, Takeuchi S, Togari A
Am. J. Physiol. Endocrinol. Metab. Mar 2013
PMID: 23169789