Cilnidipine, but not amlodipine, ameliorates osteoporosis in ovariectomized hypertensive rats through inhibition of the N-type calcium channel

Abstract

Both osteoporosis and high blood pressure are major diseases in aging populations. Recent studies demonstrated that some antihypertensive drugs reduced the risk of bone fracture in elderly patients. Although calcium channel blockers (CCB) are widely used as first-line antihypertensive agents, there is no evidence that they prevent osteoporosis. In this study, we investigated the effects of two types of CCB on bone metabolism: cilnidipine (L-/N-type CCB), which suppresses norepinephrine release from the sympathetic nerve, and amlodipine (L-type CCB). In ovariectomized female spontaneous hypertensive rats, administration of cilnidipine, but not amlodipine, resulted in a significant increase in the ratio of alkaline phosphatase to tartrate-resistant acid phosphatase (TRAP) and a decrease in the number of osteoclasts, as assessed by TRAP staining in the proximal tibia. Bone mineral density, moreover, was significantly higher in the cilnidipine group as compared with the amlodipine group and was associated with a significant decrease in a urinary collagen degradation product (deoxypyridinoline). The degree of prevention of osteoporosis by cilnidipine was similar to that of carvedilol (a b-blocker) because b-blockers reduce fracture risks though the inhibition of osteoclast activation. Interestingly, these effects cannot be attributed to the reduction of blood pressure because all three drugs significantly decreased blood pressure. In contrast, both cilnidipine and carvedilol, but not amlodipine, significantly decreased heart rate, indicating that both cilnidipine and carvedilol suppressed sympathetic nervous activity. Overall, our present data showed that cilnidipine (L-/N-type CCB) ameliorated osteoporosis in ovariectomized hypertensive rats. These pleiotropic effects of antihypertensive drugs such as cilnidipine and carvedilol might provide additional benefits in the treatment of hypertensive postmenopausal women.

Involvement of N-type Ca2+channels in the fibrotic process of the kidney in rats

“…In the present study, UUO rats were treated with cilnidipine or amlodipine at the dose of 3 mg·kg Ϫ1 ·day Ϫ1 for 14 days. Several previous reports demonstrated that cilnidipine and amlodipine had a lowering effect of blood pressure to a similar extent at the dose used in this study (3 mg·kg Ϫ1 ·day Ϫ1 ) in hypertensive rats (12,25,26). Previous pharmacological study also demonstrated that cilnidipine and amlodipine inhibited L-type Ca channel current to a similar extent using a whole cell patch-clamp technique (29).…”

Influences of Treatment with Amlodipine and Valsartan on Bone Turnover Markers and OPG/RANKL/RANK System in Newly Diagnosed Hypertensive Adults; Which is more Beneficial?

“…Moreover, amlodipine alleviated the reduction in femur bone density in stroke-prone spontaneously hypertensive rats (20). However, in another study, amlodipine showed no action on bone metabolism in ovariectomized hypertensive rats (21). Despite the convincing evidence given above, there are hardly enough data about the effects of CCB use on bone physiology in humans.…”

Effects of Amlodipine on Bone Metabolism in Orchidectomised Spontaneously Hypertensive Rats

“…Some authors in the literature have described the effect of AML, whose effect on bone tissue we considered. The anti-osteoporotic effect of AML may result from the blocking of L-type calcium channels, by stimulating inositol triphosphate receptors, by releasing intracellular calcium, or by stopping the activation and maturation of osteoclasts [18]. Shimizu et al [18] demonstrated the positive effect of another CCB cilnidipine, mediated not only by the ­L-type but also by the N-type calcium channel.…”

“…The ­N-type calcium channel is thought to be involved in catecholamine release. Accordingly, the N/L-type CCB has a probability of less activation of the renin-angiotensin system [18]. Moreover, the administration of AML suppresses an inflammatory response by reducing the production of TNF-alpha, IL-1beta, and IL-6 [19], all of which are osteoclastogenic [20, 21].…”