Investigational calcium channel blockers for the treatment of hypertension

ABSTRACT

Introduction: Voltage-gated Ca²⁺ channels are the primary route of Ca²⁺ entry in vascular smooth muscle cells, playing a key role in the regulation of arterial tone and blood pressure. Since the 60´s, L-type Ca²⁺ channel blockers (CCBs) have been widely used for the treatment of hypertension.

Areas covered: T-type Ca²⁺ channels regulate vascular tone in small-resistance vessels and aldosterone secretion, and N-type channels expressed in sympathetic nerve terminals regulate the release of neurotransmitters. We performed a literature search in MEDLINE, PubMed and ClinicalTrials.gov to identify eligible studies published between January 2001 and March 2016 and reviewed the antihypertensive and renoprotective effects of four CCBs with different pharmacological profiles: azelnidipine (L-type), cilnidipine (L-/N-type) and benidipine and efonidipine (L-/T-type CCBs). Despite similar blood pressure lowering effects, L/N- and L/T-type CCBs, compared with L-type CCBs, decreased intraglomerular pressure, improved renal hemodynamics and provided a greater decrease in proteinuria even in patients already treated with renin-angiotensin-aldosterone inhibitors.

Expert opinion: Dual L/N- and L/T-type CCBs may exhibit therapeutic advantages over L-type blockers in hypertensive patients with chronic kidney disease. Because clinical trials supporting these advantages present important biases, further large-scale, long-term comparative trials are needed to confirm that these differences translate into improved clinical outcomes.

KEYWORDS:

• Voltage-gated calcium channels
• azelnidipine
• benidipine
• cilnidipine
• efonidipine
• antihypertensive drugs

Article highlights

• Voltage-gated Ca²⁺ channels are the primary route of Ca²⁺ entry in vascular smooth muscle cells, a key process for the regulation of arterial tone and blood pressure.

• L-type CCBs are widely used for the treatment of arterial hypertension. However, in the last 15 years the development of new CCBs with higher vascular selectivity and long-lasting antihypertensive effects was halted in Western countries for commercial reasons.

• New dual L-/T- (benidipine and efonidipine) and L-/N-type CCBs (cilnidipine) CCBs have been approved as antihypertensive agents in Far East countries. They produce similar antihypertensive effects than L-type CCBs, but L/N- and L/T-type CCBs decrease intraglomerular pressure, improve renal hemodynamics and provide a greater decrease in proteinuria even in patients treated with renin-angiotensin-aldosterone inhibitors.

• However, clinical trials supporting the putative advantages of L/T- and L/N-type CCBs over the conventional L-type CCBs in hypertensive patients with chronic kidney disease present important biases and their safety profile was underreported.

• Future large-scale, long-term comparative trials are needed to confirm that these differences translate into an improvement in clinical outcomes in hypertensive patients with chronic kidney disease.

• A better understanding of the role of T- and N-channels in vascular smooth muscle and endothelial cells as well as in other target organs under pathophysiological conditions is the basis for the rational development of new safer and more effective antihypertensive drugs blocking L/T-, T/N- or L/T-/N-type Ca²⁺ channels.

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Declaration of interest

J Tamargo is the principal investigator on both grants from the Instituto de Salud Carlos III (PI16/00398 and CB16/11/00303). We thank Paloma Vaquero for her invaluable technical assistance. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

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Funding

This work was supported by the Instituto de Salud Carlos III [PI11/01030, Red Española de Investigación Cardiovascular CB16/11/00303] and BBVA Foundation.