Journal of Cardiovascular Pharmacology

1994

DOI: 10.1097/00005344-199412001-00012

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Experimental Vasoprotection by Calcium Antagonists Against Calcium-Mediated Arteriosclerotic Alterations

G. Fleckenstein-Grün

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How Is Ca Sensed By Vsmcs?1

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Cited by 8 publications

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“…Moreover, the increased NO release of the endothelium may contribute to the beneficial effects of DHP calcium antagonists that were found by others, such as antiarteriosclerotic (35,36), antiproliferative (37,38), and antiaggregatory (23,39,40) properties.…”

Section: I80mentioning

confidence: 82%

Nifedipine and Bay K 8644 Induce an Increase of [Ca2+] i and Nitric Oxide in Endothelial Cells

et al. 1999

J Cardiovasc Pharmacol Ther

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BACKGROUND: The dihydropyridine-induced vasorelaxation is partly dependent on the endothelium, which does not express L-type calcium channels. Because nitric oxide (NO) is one of the most important endothelium-derived vasorelaxing factors, we investigated how the calcium antagonist nifedipine and the calcium agonist Bay K 8644 modulate intracellular calcium and NO formation in porcine endothelial cells. METHODS AND RESULTS: NO formation of porcine aortic endothelial cell cultures and of native endothelium of intact porcine coronary arteries was measured with an electrochemical electrode, and the intracellular concentration of Ca(2+) [Ca(2+)](i) was evaluated using the Fura-2 technique. Nifedipine induced a concentration-dependent [0,01-1 µmol/L] increase in [Ca(2+)](i) and NO formation in cultured porcine aortic endothelial cells, and moreover a dose-dependent NO formation in native endothelial cells from intact porcine coronary arteires, which was higher than in cultured cells. This effect was inhibited by N-nitro-l-arginine, a specific NO synthase inhibitor. Bay K 8644 caused a [Ca(2+)](i) increase and NO release in cultured cells, too, although to a lesser extent. Nifedipine-induced and Bay K 8644-induced [Ca(2+)](i) rise could be blocked by removal of extracellular calcium, indicating that a calcium influx may be involved. CONCLUSIONS: The calcium antagonist nifedipine as well as the calcium agonist Bay K 8644 cause an increase of [Ca(2+)](i) and NO in porcine endothelium. Therefore, these effects seem to be related to the dihydropyridines as a substance class, which may explain the endothelial component in dihydropyridine-induced vasorelaxation.

“…Moreover, the increased NO release of the endothelium may contribute to the beneficial effects of DHP calcium antagonists that were found by others, such as antiarteriosclerotic (35,36), antiproliferative (37,38), and antiaggregatory (23,39,40) properties.…”

Section: I80mentioning

confidence: 82%

Nifedipine and Bay K 8644 Induce an Increase of [Ca2+] i and Nitric Oxide in Endothelial Cells

et al. 1999

J Cardiovasc Pharmacol Ther

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BACKGROUND: The dihydropyridine-induced vasorelaxation is partly dependent on the endothelium, which does not express L-type calcium channels. Because nitric oxide (NO) is one of the most important endothelium-derived vasorelaxing factors, we investigated how the calcium antagonist nifedipine and the calcium agonist Bay K 8644 modulate intracellular calcium and NO formation in porcine endothelial cells. METHODS AND RESULTS: NO formation of porcine aortic endothelial cell cultures and of native endothelium of intact porcine coronary arteries was measured with an electrochemical electrode, and the intracellular concentration of Ca(2+) [Ca(2+)](i) was evaluated using the Fura-2 technique. Nifedipine induced a concentration-dependent [0,01-1 µmol/L] increase in [Ca(2+)](i) and NO formation in cultured porcine aortic endothelial cells, and moreover a dose-dependent NO formation in native endothelial cells from intact porcine coronary arteires, which was higher than in cultured cells. This effect was inhibited by N-nitro-l-arginine, a specific NO synthase inhibitor. Bay K 8644 caused a [Ca(2+)](i) increase and NO release in cultured cells, too, although to a lesser extent. Nifedipine-induced and Bay K 8644-induced [Ca(2+)](i) rise could be blocked by removal of extracellular calcium, indicating that a calcium influx may be involved. CONCLUSIONS: The calcium antagonist nifedipine as well as the calcium agonist Bay K 8644 cause an increase of [Ca(2+)](i) and NO in porcine endothelium. Therefore, these effects seem to be related to the dihydropyridines as a substance class, which may explain the endothelial component in dihydropyridine-induced vasorelaxation.

“…Calcium channels are the main entry mechanism for calcium into VSMCs as well as into matrix vesicles and play an important role in calcification of VSMCs [44]. Despite not being true for all blockers tested, inhibition of calcium channels have been shown to inhibit calcification [45, 46]. Futhermore, there are several in vitro studies showing inhibitory action of elevated magnesium concentration on different types of calcium channels in VSMCs as well as other cell types of the cardiovascular system [47–49].…”

Section: Discussionmentioning

confidence: 99%

Magnesium reduces calcification in bovine vascular smooth muscle cells in a dose-dependent manner

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et al. 2011

Nephrology Dialysis Transplantation

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Background.Vascular calcification (VC), mainly due to elevated phosphate levels, is one major problem in patients suffering from chronic kidney disease. In clinical studies, an inverse relationship between serum magnesium and VC has been reported. However, there is only few information about the influence of magnesium on calcification on a cellular level available. Therefore, we investigated the effect of magnesium on calcification induced by β-glycerophosphate (BGP) in bovine vascular smooth muscle cells (BVSMCs).Methods.BVSMCs were incubated with calcification media for 14 days while simultaneously increasing the magnesium concentration. Calcium deposition, transdifferentiation of cells and apoptosis were measured applying quantification of calcium, von Kossa and Alizarin red staining, real-time reverse transcription–polymerase chain reaction and annexin V staining, respectively.Results.Calcium deposition in the cells dramatically increased with addition of BGP and could be mostly prevented by co-incubation with magnesium. Higher magnesium levels led to inhibition of BGP-induced alkaline phosphatase activity as well as to a decreased expression of genes associated with the process of transdifferentiation of BVSMCs into osteoblast-like cells. Furthermore, estimated calcium entry into the cells decreased with increasing magnesium concentrations in the media. In addition, higher magnesium concentrations prevented cell damage (apoptosis) induced by BGP as well as progression of already established calcification.Conclusions.Higher magnesium levels prevented BVSMC calcification, inhibited expression of osteogenic proteins, apoptosis and further progression of already established calcification. Thus, magnesium is influencing molecular processes associated with VC and may have the potential to play a role for VC also in clinical situations.

“…Pioneering studies by Fleckenstein 119 showed that in response to Vitamin D overload in rats vascular calcification could be prevented by treatment with the CCBs verapamil or nifedipine. Although it was assumed that the mechanism of action was via prevention of Ca uptake in the hypercalcemic environment induced in the rats in response to vitamin D, other direct VSMC effects have not been excluded.…”

Section: How Is Ca Sensed By Vsmcs?mentioning

confidence: 99%

Arterial Calcification in Chronic Kidney Disease: Key Roles for Calcium and Phosphate

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Circulation Research

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Vascular calcification contributes to the high risk of cardiovascular mortality in chronic kidney disease (CKD) patients. Dysregulation of calcium (Ca) and phosphate (P) metabolism is common in CKD patients, and drives vascular calcification. In this article, we review the physiological regulatory mechanisms for Ca and P homeostasis and the basis for their dysregulation in CKD. In addition, we highlight recent findings indicating that elevated Ca and P have direct effects on vascular smooth muscle cells (VSMCs) that promote vascular calcification, including stimulation of osteo/chondrogenic differentiation, vesicle release, apoptosis, loss of inhibitors, and ECM matrix degradation. These studies suggest a major role for elevated P in promoting osteo/chondrogenic differentiation of VSMC, whereas elevated Ca has a predominant role in promoting VSMC apoptosis and vesicle release. Furthermore, the effects of elevated Ca and P are synergistic providing a major stimulus for vascular calcification in CKD. Unravelling the complex regulatory pathways that mediate the effects of both Ca and P on VSMCs will ultimately provide novel targets and therapies to limit the destructive effects of vascular calcification in CKD patients.

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