Review
Calcium channel regulation in vascular smooth muscle cells: Synergistic effects of statins and calcium channel blockers

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Abstract

In the Anglo-Scandinavian Cardiac Outcomes Trial—Lipid Lowering Arm (ASCOT-LLA) we have reported a positive interaction between atorvastatin and amlodipine-based antihypertensive strategy in terms of the prevention of coronary events. In cellular and molecular studies on human vascular smooth muscle cells (VSMC) we have reported that transformation from a differentiated to a synthetic or dedifferentiated phenotype is associated with loss of function of L-type calcium channels and hence loss of potential responsiveness to calcium channel blockers (CCB). Statins directly inhibit cell cycle progression and dedifferentiation of VSMC due to their ability to inhibit the synthesis of isoprenoid cholesterol intermediates. We hypothesize that statins promote a more differentiated VSMC phenotype that results in upregulation of L-type calcium channels and restoration of a CCB-sensitive calcium influx pathway in VSMC, favourably affecting the balance that exists between VSMC proliferation, apoptosis and matrix metalloproteinase production with an associated increase in stability of atheromatous plaques.

Section snippets

Introduction and background

The Anglo-Scandinavian Cardiac Outcomes Trial—Lipid Lowering Arm (ASCOT-LLA) recently demonstrated the large beneficial effects of adding a lipid lowering agent (atorvastatin) to blood pressure (BP) lowering therapy in hypertensive patients not deemed dyslipidaemic [1]. The study showed a 35% reduction in the primary endpoint of fatal coronary heart disease (CHD) and non-fatal myocardial infarction for the atorvastatin versus placebo treated groups. Two BP lowering regimens were used in

Actions of statins

Statins are the first line of treatment in the therapy of dyslipidaemia and have well documented favourable effects on the stability of established plaques [7]. These vasculoprotective actions are thought to be due to a number of mechanisms, some LDL-dependent and some LDL-independent. Many of the ‘pleiotropic’ actions of statins have been attributed to beneficial effects on endothelial function (reviewed in [8]), while possible actions on VSMC have been relatively neglected. Although the

Calcium channel blockers: Mode of action

Calcium channel blockers (CCB) are a chemically heterogeneous class of drugs consisting of dihydropyridines (DHPs), phenylalkylamines and benzothiazepines. All CCB share a common mechanism of action—the inhibition of Ca2+ influx through L-type calcium channels. This channel constitutes the dominant Ca2+ influx route in contractile VSMC and inhibition of L-type calcium channels accounts for the antihypertensive and vasodilator properties of CCB. Other Ca2+ influx routes exist in VSMC which are

Clinical trials involving calcium channel blockers

Observations in man are even more inconsistent than in animal models. In three studies using coronary angiography, the Montreal Heart Institute trial [35], the International Nifedipine Trial on Antiatherosclerotic Therapy (INTACT) [36] and The Prospective Randomized Evaluation of the Vascular Effects of Norvasc Trial (PREVENT) [37] treatment with CCB did not influence the overall rate of coronary lesion progression or minimal coronary artery diameter, although CCB-treated patients had less

Molecular mechanisms

Recently we proposed a molecular mechanism to account for these observations [50]. We showed that transition of human VSMC from a relatively differentiated (growth arrested or contractile phenotype) to a less differentiated state (synthetic phenotype) following serum stimulation was associated with loss of effect of CCB on both intracellular Ca2+ signalling and chemotaxis in response to platelet-derived growth factor (an important chemotactic agent and mitogen for VSMC). These observations

The hypothesis

Together these observations suggest a hypothesis that incorporates the loss of efficacy of CCBs on advanced plaques and provides a basis for the co-operative action of CCBs with statins. As VSMCs dedifferentiate, CCB-sensitive L-type calcium channels are functionally downregulated. The effect is independent of context and may occur in response to vascular injury, development, remodelling, plaque formation, or in cell culture. This in turn imposes a ceiling on CCB efficacy such that efficacy

Acknowledgement

This work was supported by grants from the British Heart Foundation and the Foundation for Circulatory Health. The authors acknowledge support from the NIHR Biomedical Research Centre Funding Scheme.

The authors of this manuscript have certified that they comply with the Principles of Ethical Publishing in the International Journal of Cardiology [57].

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