Effects of Propranolol on Bone Metabolism in Spontaneously Hypertensive Rats

Abstract

The effects of propranolol (PRO), a nonselective ␤-adrenergic receptor (␤-AR) antagonist with membrane-stabilizing action on bone metabolism, were examined in spontaneously hypertensive rats (SHR) showing osteoporosis with hyperactivity of the sympathetic nervous system. Treatment of SHR with PRO at 1 and 5 mg/kg p.o. for 12 weeks increased bone mass of the lumbar vertebra and proximal tibia without affecting blood pressure, but PRO at 50 and 100 mg/kg with hypotensive action did not increase bone mass. Next, the effects of PRO at 0.1, 1, and 10 mg/kg on bone status were examined in more detail. Compared with the SHR control, not only bone mass but also biomechanical parameters of strength and toughness of the lumbar vertebrae were increased in SHR treated with PRO at 0.1 and 1 mg/kg, suggesting antiosteoporotic action. PRO at 1 mg/kg statistically increased histomorphometry indices of bone formation, whereas PRO at doses of 0.1, 1, and 10 mg/kg decreased those of bone resorption. Antiosteoporotic effect of PRO is attenuated at 10 mg/kg compared with 0.1 and 1 mg/kg. In addition, treatment with timolol, a nonselective ␤-AR antagonist without membrane-stabilizing action, or butoxamine, a selective ␤2-AR antagonist, at 1 mg/kg increased bone mass in SHR. These results suggested that treatment of SHR with ␤-blockers at low dose improved bone loss and bone fragility. This antiosteoporotic effect of ␤-blockers seems to be caused by the blocking action of ␤2-AR, regardless of the membrane-stabilizing action.

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

“…The effect of the lowest dose was consistent with the early observation of Minkowitz et al [24] and subsequent studies of Bonnet et al [3,4]. There was an attenuated antiosteoporotic effect of propranolol at 10 mg/kg/day po compared to 0.1 and 1 mg/kg/day po in spontaneously hypertensive rats; however, no deleterious effect of propranolol at 50 and 100 mg/kg/day po on the trabecular microarchitecture of bones was reported [31]. Positive effects of propranolol were reported after its use in drinking water (500 mg/l) in rats with bone changes induced by mechanical unloading [22] and in other rat studies [1,42].…”

“…It was demonstrated that activation of b -adrenergic receptors in osteoblasts and stromal cells leads to the inhibition of bone formation and intensification of bone resorption [36,37]. Propranolol, a nonselective b-receptor antagonist, was reported to be effective in counteracting bone damage in different experimental models of bone disorders [1,6,22,31,34,35,42]. Results of some, but not all, human studies [5, 12, 23, 27-30, 32, 41] confirm the hypothesis that b-blockers may decrease the fracture rate.…”

Noradrenaline stimulates cell proliferation by suppressing potassium channels via Gi/o‐protein‐coupled α1B‐adrenoceptors in human osteoblasts

“…In recent years, many studies have demonstrated that the sympathetic nervous system is involved in bone metabolism (Cherruau et al, 1999;Elefteriou et al, 2005;Togari and Arai, 2008;He et al, 2011). Bone loss can be induced by continuously high sympathetic tone and this is reversed by b-adrenoceptor blockade (Bonnet et al, 2008;Sato et al, 2010). Previous studies, including ours, showed that mRNAs of both a-and b-adrenoceptors were expressed in human osteoblasts (Togari et al, 1997;Togari, 2002;Huang et al, 2009).…”

“…Both experimental and clinical studies have demonstrated that b-adrenoceptor blockade is effective against osteoporosis accompanied by a highly active sympathetic nervous system (Pasco et al, 2004;Bonnet et al, 2007;Sato et al, 2010;Yang et al, 2011). There is also a report that a1-adrenoceptor blockade increased the risk of hip/ femur fracture (Souverein et al, 2003).…”

“…Each figure shows representative data from three independent experiments. spontaneous hypertensive rats, is required to investigate the physiological role of a1B-adrenoceptor (Elefteriou et al, 2005;Sato et al, 2010).…”