Table 1.

Summary of medications that have been studied in patients with coronary microvascular disease

Agent	Mechanism of action	Evidence base
Vasodilatory beta blockers (for example, nebivolol, carvedilol and celiprolol)	Vasodilatory properties can be due to activation of the eNOS pathway (nebivolol) or preservation of NO bioactivity (carvedilol)	Nebivolol augmented hyperaemic CBF and attenuated resting CBF in patients with idiopathic dilated cardiomyopathy with unobstructed coronary arteries and coronary microvascular dysfunction [46] and improved exercise time in patients with CSX [47]. Four months’ therapy of carvedilol improved flow-mediated dilatation, a marker of endothelium-dependent function, in patients with epicardial coronary artery disease [48].
Calcium channel blockers: amlodipine or diltiazem	Reduces influx of calcium in the VSMCs; therefore, leading to vasodilation (Fig. 1)	Treatment with calcium channel blockers improved symptom control in patients with endothelium-dependent CMD over 48 months [49]
Ranolazine	#1: Inhibits the sodium–calcium co-transporter and reduces influx of calcium in cardiomyocytes	Bairey-Merz et al. [50] and Rambarat et al. [51] have shown that ranolazine improves myocardial perfusion and angina frequency in patients with angina, NOCAD and CFR < 2.5. Tagliamonte et al. reported an improvement in SAQ domains and CFR in patients with angina, NOCAD and myocardial ischaemia after 8 weeks of ranolazine [52]
	#2: shifts ATP metabolism from inefficient fatty-acid oxidation to oxygen-sparing glucose oxidation
Endothelin receptor antagonists (ERA)	ERAs antagonise endothelin-1 (ET-1). ET-1 increases peripheral and coronary vascular tone by activating the ETA receptor on VSMCs (Fig. 1)	Oral atrasentan (ERA) improved endothelial function in patients with angina and NOCAD with impaired endothelium-dependent microvascular function [53]
Rho-kinase inhibitors	Rho-kinase inhibitors prevent the inactivation of MLCP, therefore, lead to VSM vasodilatation (Fig. 1)	Intracoronary fasudil (rho-kinase inhibitor) ameliorated myocardial ischaemia (defined as ischaemic ECG changes, increased myocardial lactate or both) in patients with endothelium-dependent microvascular dysfunction [54]
Angiotensin-converting enzyme (ACE) inhibitors	Angiotensin II is a potent coronary vasoconstrictor; therefore, ACE inhibitors, by inhibiting the action of Angiotensin II, may promote coronary microvascular vasodilation	Treatment with 16 weeks of quinapril improved CFR in women with angina, NOCAD and CMD. There was also improvement in angina frequency, although the study was not adequately powered for the latter outcome [57]

ATP, adenosine triphosphate; CMD, coronary microvascular disease; CBF, coronary blood flow; CSX, coronary syndrome X; CFR, coronary flow reserve; eNOS, endothelial nitric oxide synthase; MLCP, myosin light chain phosphatase; NOCAD, nonobstructive coronary artery disease; SAQ, Seattle Angina Questionnaire; VSMC, vascular smooth muscle cell.