Inhibition of vascular smooth muscle cell proliferation by the calcium antagonist clentiazem: role of protein kinase C

Alam, Rita; Kataoka, Satoshi; Alam, Syed Sartaj; Yatsu, Frank M.

doi:10.1016/0021-9150(96)05908-4

Cited by 13 publications

(6 citation statements)

References 55 publications

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“…17,18 These findings were confirmed and extended by the same methods in normal renal artery from a human kidney donor and in the epigastric artery from a recipient CKD patient. [22][23][24] In addition to VSMC, the CaR was also detected in endothelial and perivascular cells. [22][23][24] The receptor in VSMC is functional as shown by the increase in intracellular calcium and activation of the extracellular signal-regulated kinases (ERK1/2) signaling pathway after treatment with calcium or neomycin.…”

Section: Calcimimetics and Cardiovascular Calcifications Direct Effecmentioning

confidence: 99%

“…[22][23][24] In addition to VSMC, the CaR was also detected in endothelial and perivascular cells. [22][23][24] The receptor in VSMC is functional as shown by the increase in intracellular calcium and activation of the extracellular signal-regulated kinases (ERK1/2) signaling pathway after treatment with calcium or neomycin. Physiologically, the systemic activation of the CaR by pharmacological doses of type II calcimimetics increases vascular resistance in carotid, mesenteric, and hind limb arteries, leading to a significant elevation of arterial blood pressure in uremic and non-uremic animals.…”

Section: Calcimimetics and Cardiovascular Calcifications Direct Effecmentioning

confidence: 99%

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Calcium-sensing receptor, calcimimetics, and cardiovascular calcifications in chronic kidney disease

Torres¹,

Broe

2012

Kidney International

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Renal function impairment goes along with a disturbed calcium, phosphate, and vitamin D metabolism, resulting in secondary hyperparathyroidism (sHPT). These mineral metabolism disturbances are associated with soft tissue calcifications, particularly arteries, cardiac valves, and myocardium, ultimately associated with increased risk of mortality in patients with chronic kidney disease (CKD). sHPT may lead to cardiovascular calcifications by other mechanisms including an impaired effect of parathyroid hormone (PTH), and a decreased calcium-sensing receptor (CaR) expression on cardiovascular structures. PTH may play a direct role on vascular calcifications through activation of a receptor, the type-1 PTH/PTHrP receptor, normally attributed to PTH-related peptide (PTHrP). The CaR in vascular cells may also play a role on vascular mineralization as suggested by its extremely reduced expression in atherosclerotic calcified human arteries. Calcimimetic compounds increasing the CaR sensitivity to extracellular calcium efficiently reduce serum PTH, calcium, and phosphate in dialysis patients with sHPT. They upregulate the CaR in vascular cells and attenuate vascular mineralization in uremic states. In this article, the pathophysiological mechanisms associated with cardiovascular calcifications in case of sHPT, the impact of medical and surgical correction of sHPT, the biology of the CaR in vascular structures and its function in CKD state, and finally the role played by the CaR and its modulation by the calcimimetics on uremic-related cardiovascular calcifications are reviewed.

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Section: Calcimimetics and Cardiovascular Calcifications Direct Effecmentioning

confidence: 99%

Section: Calcimimetics and Cardiovascular Calcifications Direct Effecmentioning

confidence: 99%

Calcium-sensing receptor, calcimimetics, and cardiovascular calcifications in chronic kidney disease

Torres¹,

Broe

2012

Kidney International

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“…In vascular smooth muscle cells, PKC may participate in the cellular response evoked by CCBs [38]. Clentiazem, a CCB of the benzothiazepin family, inhibits cell proliferation by regulating cytosolic PKC and preventing its membrane translocation and activation.…”

Section: Discussionmentioning

confidence: 99%

Calcium Channel Blockers Inhibit Proliferation and Matrix Production in Rat Mesangial Cells: Possible Mechanism of Suppression of AP-1 and CREB Activities

Sugiura

Imai

Moriyama

et al. 2000

Nephron

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Background: Calcium channel blockers (CCBs) are reported to attenuate the loss of renal function in various glomerulonephritides. Methods: To determine the mechanism of action of these drugs, we investigated the effects of CCBs on cell proliferation and extracellular matrix (ECM) production in cultured rat mesangial cells. Results: While stimulation with 5% fetal calf serum (FCS) increased [³H]thymidine and [³H]proline incorporation into quiescent mesangial cells, incubation with nifedipine and cilnidipine inhibited the increase in a dose-dependent manner. Northern blot analysis demonstrated that 5% FCS increased the expression of transforming growth factor beta (TGF-β) and fibronectin (FN) mRNA and that CCBs significantly reduced this induction, indicating that CCBs may reduce ECM production through inhibiting TGF-β and FN. Since activator protein 1 (AP-1) regulates cell proliferation and TGF-β expression, we evaluated the AP-1 activity by gel mobility shift analysis. Nuclear extracts of FCS-treated cells showed a strong binding to AP-1-specific oligonucleotides which was suppressed by CCBs, suggesting that these agents may inhibit cell proliferation by suppressing AP-1. CCBs also inhibited the binding activity of cyclic adenosine monophosphate responsive element binding protein which regulates FN gene expression. However, neither CCBs nor FCS affected the NFĸB activity. Conclusion: These results suggest that CCBs may, in part, inhibit the progression of glomerulonephritis through non-hemodynamic actions that include the suppression of mesangial cell proliferation and the production of ECM.

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“…The action of mibefradil on the T-type calcium channel may be involved [30,31], since an electrically responsive, voltage-operable current that resembles the T-type calcium current in its characteristics has been proposed recently as the pathway by which calcium enters lymphocytes following activation [22]. Furthermore, mibefradil and clentiazem may also inhibit intracellular mechanisms such as protein kinase C activation [32,33]. Indeed, protein kinase C activity has been shown to be an important modulator of T-cell proliferation [34].…”

Section: Discussionmentioning

confidence: 99%

Immunomodulating Effects of Second-Generation Calcium Channel Blockers on Experimental Heart Transplantation

Lapointe

Chen²,

Qi³

et al. 1999

Eur Surg Res

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The administration of second-generation calcium channel blockers (CCBs) to counteract the adverse effects of conventional immunosuppression gains more and more acceptance. Since these newly developed molecules differ in their chemical structure and possess specific pharmacokinetic profiles, we hypothesized that exposure to clinically relevant concentrations may have a significant immunomodulatory potential. The effects of various second-generation CCBs, felodipine, amlodipine, mibefradil and clentiazem, on cardiac allograft survival were therefore evaluated. Inbred male Lewis rats were used as recipients and Brown-Norway rats as donors. After abdominal implantation of the donor heart, allograft recipients were exposed to felodipine (31 μg/kg/day), amlodipine (25 μg/kg/day), mibefradil (3 mg/kg/day) or clentiazem (2.5 mg/kg/day). Other allograft recipients were treated with low-dose cyclosporine (CsA) alone (2 mg/kg/day) or with low-dose CsA combined with amlodipine (25 μg/kg/day), mibefradil (3 mg/kg/day) or clentiazem (2.5 mg/kg/day). All drugs were given daily by gavage. Median survival time of untreated cardiac allografts was 6.5 days. When given alone, not all the second-generation CCBs elicited a positive effect: the dihydropyridines felodipine and amlodipine were ineffective (median survival time was 6.5 and 7.0 days, respectively), the T- and L-type CCB mibefradil had a significant but minor impact (median survival time = 9.0 days, p <0.0015) while the benzothiazepine clentiazem produced the most significant result (median survival time = 16.0 days, p <0.0033). Neither amlodipine nor mibefradil modified the extent of survival provided by low-dose CsA (median survival time = 9.0 days), while clentiazem had a significant positive effect. These data indicate that second-generation CCBs differ in their immunomodulatory potential. These observations of pharmacodynamic specificity appear to be related to differences in their chemical structure as well as their interaction with other sites than the calcium channel.

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Inhibition of vascular smooth muscle cell proliferation by the calcium antagonist clentiazem: role of protein kinase C

Cited by 13 publications

References 55 publications

Calcium-sensing receptor, calcimimetics, and cardiovascular calcifications in chronic kidney disease

Calcium-sensing receptor, calcimimetics, and cardiovascular calcifications in chronic kidney disease

Calcium Channel Blockers Inhibit Proliferation and Matrix Production in Rat Mesangial Cells: Possible Mechanism of Suppression of AP-1 and CREB Activities

Immunomodulating Effects of Second-Generation Calcium Channel Blockers on Experimental Heart Transplantation

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