Ion Channel Therapy of Ischemic Heart Disease: From Calcium Channel Blockers to Late Sodium Current Inhibition

Abstract

What is summarized below relates to the clinical usefulness of various ion channel antagonists reviewed by a clinical cardiologist, not a basic scientist working on ion channel biology. Copyright © 2011 Wiley Periodicals, Inc.

L Channel and L Channel Calcium Blockers

Calcium channel blockers (CCBs) bind to L‐type calcium channels located on the vascular smooth muscle, cardiac myocytes, and cardiac nodal tissue (sinoatrial and atrioventricular nodes). In 1964, Fleckenstein found that the L channels were responsible for regulating the influx of calcium into muscle cells, which in turn stimulates smooth muscle contraction and cardiac myocyte contraction. In cardiac nodal tissue, L‐type calcium channels play an important role in pacemaker currents.1 By blocking calcium entry into the cell, CCBs cause vascular smooth muscle relaxation (vasodilation), decreased myocardial force generation (negative inotropy), decreased heart rate (negative chronotropy), and decreased conduction velocity within the heart (negative dromotropy), particularly at the atrioventricular node. The L channel CCBs have found many uses in cardiovascular medicine including arrhythmias (eg, atrial fibrillation with rapid heart rate), vascular spasm (eg, coronary spasm) systemic hypertension (particularly long‐acting preparations) diastolic dysfunction [due to their negative inotropic and chronotropic effects], stable angina, unstable angina, ischemia suppression), and myocardial infarction (reserved for those with a clear indication, eg, atrial fibrillation, NSTEMI). Other uses include patients with Raynaud's disease, esophageal spasm, cerebral vasospasm, migraine headaches, idiopathic pulmonary hypertension, cardioplegia, slowing down of atherosclerosis, retardation of transplant vasculopathy, and treatment of post‐transplant hypertension.2

T Channel and T Channel CCB Mibefradil

The T‐type calcium channel is a type of voltage‐gated calcium channel. T stands for transient, referring to the length of activation. The opening of T‐type channels allows a Ca²⁺ influx that provokes membrane depolarization and an increase in the intracellular Ca²⁺ concentration. T‐type (transient) channels are blocked uniquely by mibefradil, activated at lower voltages, present in vascular smooth muscle and myocardial conduction system, and absent in ventricular myocardium. This CCB blocked calcium influx at 2 types of calcium channels, the L type and T type (transient channels).3 Mibefradil was withdrawn from the market by its manufacturer after drug interactions resulted in increased plasma concentrations of coadministered drugs including other calcium channel blockers, β‐blockers, digoxin, cyclosporine, simvastatin, and tacrolimus.

Adenosine Triphosphate‐Sensitive Potassium Channel and Nicorandil

This channel is activated by nicorandil, which then relaxes the smooth muscle of the blood vessels, especially those of the venous system.4 In addition to activating adenosine triphosphate‐sensitive potassium channels, it also donates nitric oxide to activate the enzyme guanylate cyclase, which causes activation of cyclic guanosine monophosphate (cGMP), leading to both arterial and venous vasodilation. As it is selective for vascular potassium channels, it has no significant action on cardiac contractility and conduction.

If (funny) Current and If Channel Blocker Ivabradine

The “funny” current is a mixed sodium‐potassium current, inward and slowly activating on hyperpolarization at voltages in the diastolic range. The “funny,” or pacemaker current, is highly expressed in spontaneously active cardiac regions such as the sinoatrial node, the atrioventricular node, and the Purkinje fibers of conduction tissue, and controls heart rate by electrical pacemaker activity in the sinus node. The If‐channels are natural targets of drugs aimed at pharmacologically controlling heart rate. The first selective sinus node If channel inhibitor was ivabradine.5 Ivabradine lowers heart rate, which reduces myocardial oxygen demand, and it has no negative inotropic or lusitropic effect, thus preserving ventricular contraction. Ivabradine is used to treat chronic stable angina in patients with normal sinus rhythm who have a contraindication or intolerance to β‐blockers. Two clinical trials have been performed titled “Beautiful” for chronic angina and a “Shift” for chronic heart failure.6

Late Na⁺ Current, Late Na⁺ Channel, and Ranolazine

Late sodium current in cardiac cells is very small compared with the fast component, but as it flows throughout the action potential it may make a substantial contribution to sodium loading during each cardiac cycle. The current hypothesis of ischemia at the cellular level is related to the impairment of cardiomyocyte sodium channel function.7 Impaired sodium channel function contributes to pathologic increase of the late sodium current, sodium overload, and sodium‐induced calcium overload by way of the sodium‐calcium exchanger. Calcium overload causes impaired diastolic relaxation, which increases diastolic wall tension, increases myocardial oxygen demand, reduces myocardial blood flow and oxygen supply, microvascular perfusion, and worsens ischemia and angina. The drug ranolazine was approved for use in the United States in February 2006 for chronic stable angina. Theoretically, this drug works by blocking the increase in the late sodium current. Reduction of late sodium current would therefore be expected to have therapeutic benefits, particularly in disease states such as myocardial ischemia, in which sodium‐calcium overload is a major feature. This drug has a negligible effect on coronary blood flow, heart rate, arterial pressure, venous return, and myocardial contractility. It can be used with all of the usual therapies for myocardial ischemia including β‐blockers, dihydropyridine calcium channel blockers, nonhydropyridine calcium channel blockers, and nitrates.

Summary

L channel Ca⁺⁺ antagonists are here to stay and are safe and effective for multiple conditions not just cardiovascular disease. T‐channel Ca⁺⁺ antagonists were effective therapy for ischemic heart disease (IHD) but are not available in the United States because of multiple drug interactions related to inhibition of the cytochrome enzyme system. Nicorandil activates potassium channels and donates nitric oxide to activate the enzyme guanylate cyclase, which causes activation of cGMP, leading to both arterial and venous vasodilatation. Nicorandil is not available in the United States. If (funny current) channel blockers may be useful in IHD patients with chronic stable angina and heart failure patients, but are not available in the United States at this time. Late Na⁺ channel blockers are safe in acute coronary syndrome patients, and safe and effective in patients with stable IHD, and may be useful to treat some arrhythmias.