Inactivation of nitric oxide (NO) by superoxide anions (O₂ ^·−) contributes to impaired endothelium-dependent vasodilation in patients with CAD. Xanthine oxidase (XO) is a major source of O₂ ⁻ and its activity is abundant in both vascular endothelium and plasma of CAD patients. Increased activity of XO in human coronary arteries has been shown to reduce vascular NO availability and increase vascular oxidative stress (OS) and endothelial dysfunction in CAD patients [37]. Conversely, XO inhibition reduced the levels of OS in the circulation and improved endothelial function and cardiac contractility in patients with CAD [38, 39]. Allopurinol, a XO inhibitor, reduces OS and improves endothelial/vascular dysfunction in patients with CAD [8, 40]. These effects of allopurinol are independent from changes induced by the agent on plasma uric acid and tend to persist when given in addition to conventional optimal antianginal therapy, including statins and ACE inhibitors [41]. These findings raise the possibility that allopurinol may be a useful agent for treatment of CSA.

The effects of high-dose allopurinol were assessed in patients with angiographically documented stable CAD and left ventricular ejection fraction (LVEF) >45 % [7]. Compared with baseline, allopurinol significantly prolonged the time to ST depression (43-s, 95 % CI 31–58), total exercise time (58-s, 95 % CI 45–77), and time to chest pain (38-s, 95 % CI 17–55). Baseline urate plasma concentration did not correlate with the effects of allopurinol on exercise variables. Diastolic blood pressure during exercise was significantly lower, while maximum tolerated rate pressure product was significantly higher on allopurinol compared with placebo. The observed absolute increase in median time to ST depression was similar to that previously described with other antianginal drugs including amlodipine, nitrates, ivabradine, atenolol and ranolazine. In another study from the same group of investigators, patients with CSA treated with conventional anti-ischemic and vasculoprotective agents were randomized to receive high-dose allopurinol (600 mg/day) or placebo [8]. Allopurinol was shown to abolish vascular OS and improved endothelial-dependent vasodilation and central augmentation index, as assessed by pulse wave velocity analysis. These findings confirm that XO is a major source of vascular OS and XO inhibitors improve vascular OS and endothelial function which results in increased coronary blood flow in patients already receiving treatment with optimal conventional CAD therapy. Of interest, as the anti-ischemic effect of allopurinol is not associated to haemodynamic changes this agent could be used safely in combination with conventional antianginal drugs or as an alternative therapy when conventional agents cannot be tolerated because of adverse hemodynamic or electrophysiological effects.

In the acute coronary setting, i.e., patients undergoing primary coronary intervention, allopurinol treatment improved ST segment recovery (reflecting improved epicardial coronary flow and perfusion at microvascular level) and reduced troponin I, CPK and CK-MB elevations [9]. In addition, allopurinol significantly reduced (13 %) major adverse cardiac events (MACE) at 1-month follow-up.

This is a more potent and selective XO inhibitor than allopurinol [46, 47]. Febuxostat is rapidly absorbed (bioavailability 49 %) after oral administration, reaching peak plasma levels within 0.5–1.3 h. It binds to plasma proteins (99 %), is extensively metabolized in the liver [by conjugation via uridine diphosphate glucuronosyl transferases (UGT1A1, 1A3, 1A9 and 2B7) and oxidation via CYP1A2, CYP2C8, and CYP2C9 and non-P450 enzymes] and is eliminated (mostly as metabolites) by both hepatic and renal pathways with a half-life of 5–8 h. The main adverse effects of febuxostat include cutaneous rashes, headache, arthralgia, abdominal pain, nausea and liver function abnormalities. A phase 2 trial designed to assess the effect of febuxostat as an add on to stable anti-anginal therapy on exercise treadmill testing in subjects with CSA and a serum urate ≥5 mg/dl (NCT01549977) was prematurely terminated and an ongoing phase 4 study assesses the effects of febuxostat on coronary artery endothelial dysfunction in patients with CSA (NCT01763996). Thus, at present, the role of febuxostat in the management of patients with CSA is uncertain.

F15845 is a new selective I_NaL blocker with anti-ischemic properties. In atrial and ventricular muscle cells and in Purkinje fibres, the rapid upstroke (phase 0) of the action potential (AP) is due to the activation-opening of Na⁺ channels generating the peak inward Na⁺ current (I_Na) which determines the initiation and propagation of the cardiac AP. Under normal conditions, most cardiac Na⁺ channels open transiently (1–3 ms) upon membrane depolarization but rapidly inactivate-close and remain closed during the plateau phase of the AP. However, a small percentage of Na⁺ channels either fail to inactivate properly, or close and then reopen during the plateau phase, generating the so-called late Na⁺ current (I_NaL) [48]. The amplitude of the I_Na,L is ~1 % of the peak I_Na, but because it persists hundreds of milliseconds, the amount of Na⁺ carried by the I_Na,L can be of the same order as that carried by the peak I_Na. The amplitude of I_NaL markedly increases during both myocardial ischemia and increased OS. The increase in I_NaL enhances Na⁺ influx and intracellular Na⁺ concentration ([Na⁺]_i) which leads to an increase in the intracellular Ca²⁺ concentration ([Ca²⁺]_i) via the reverse mode of the Na⁺-Ca²⁺ exchanger [48, 49]. This increase in cytosolic Na⁺ and Ca²⁺ concentrations during ischemia is a major contributor to the impairment of ventricular relaxation, leading to an increase in diastolic wall tension and MVO₂ and a decrease in subendocardial coronary blood flow during the diastole [48]. Moreover, the increase in cytosolic Na⁺ during ischemia and the kinetics of [Na⁺]_i recovery are key determinants of the recovery of LV function during reperfusion [50] and enhanced Na⁺ influx, directly or through Ca²⁺ overload, increases ATP consumption and decreases ATP production. Thus, an increase in I_NaL plays a key role in the contractile and metabolic disturbances observed in the ischemic myocardium.

In HEK293 cells transfected with the SCN5A gene, which encodes the α-subunit of hNa_v1.5, F15845 inhibited veratridine-induced I_NaL (IC₅₀ 5.3–9.3 μM) and shifted the I_NaL inactivation curve towards hyperpolarized potentials without interfering with activation kinetics [51, 52]. F15845 blocked the Na⁺ channel in a voltage-dependent manner, being more effective at depolarized potentials, i.e., in ischemic cardiac tissues. However, F 15845 did not affect the I_Na responsible of the upstroke, the L-type Ca²⁺ and several K⁺ channels activated during the cardiac AP, which confirmed its selectivity towards I_NaL and explain why it did not affect shape of the cardiac AP [51, 52]. In rat isolated left atria F15845 inhibited the diastolic contracture elicited by activators of the I_NaL (ischemia, veratrine or lysophosphatidylcholine) [53]. In isolated hearts from diabetic (db/db) mice no-flow ischemia produced a rapid increase in [Na⁺]_i which persisted elevated upon reperfusion. F15845 significantly inhibited the increase in [Na⁺]_i and in diastolic pressure during ischemia/reperfusion (I/R). In rats subjected to a 15-min occlusion of left coronary artery followed by 24-h reperfusion F 15845 reduced myocardial infarct size and troponin I plasma levels; in rats subjected to 14-day reperfusion, F 15845 significantly reduced the expansion of infarct size [53]. In guinea pig isolated and perfused hearts F 15845 did not modify affect coronary blood flow, heart rate and left ventricular function, but reduced the increase in LV end-diastolic pressure (diastolic contracture) induced by global ischemia [51]. In rabbits subjected to 5 min coronary artery occlusion and in dogs with coronary stenosis and subjected to left atrial pacing F15845 dose-dependently inhibited ischamia-induced ST segment elevation [51]. The myocardial protection afforded by F15845 was assessed in two pig models of I/R [54]. In the first model, the left circumflex coronary artery (LCCA) was ligated for 60-min and then reperfused for 48-h and F15845 administered i.v. before ischemia. In the second model a ligation of the LCCA was applied for 15 min 1 week before the actual 60 min occlusion. In both models, F15845 significantly reduced infarct size and lowered plasma myoglobin and troponin I levels. Of note, in both models the protective effects of F15845 were not associated with significant hemodynamic effects, confirming a direct cardiac anti-ischemic activity. However, the pharmacokinetic properties, safety and clinical development of F 15845 are unknown and require further assessment.