What is the mechanism of organic nitrates (e.g. nitroglycerin) in managing angina?

Mechanism of Organic Nitrates in Angina Management

Organic nitrates work by undergoing enzymatic denitrification by mitochondrial aldehyde dehydrogenase in the vessel wall to produce vasoactive nitric oxide, which activates guanylate cyclase and increases cyclic GMP, leading to vascular smooth muscle relaxation and reduced myocardial oxygen demand. 1

Biochemical Conversion Process

• Nitrates are biotransformed through a sulfhydryl-dependent enzymatic process involving mitochondrial aldehyde dehydrogenase, which liberates nitric oxide (NO) as the active metabolite 2, 1
• The released NO activates guanylate cyclase, converting GTP to cyclic guanosine 3',5'-monophosphate (cGMP), which causes dephosphorylation of myosin light chains in smooth muscle cells, resulting in vasodilatation 3, 4
• This bioconversion occurs in both endothelial cells and vascular myocytes, making nitrate effects independent of endothelial integrity—a theoretically important feature in patients with endothelial dysfunction, though clinical benefits in microvascular angina have been disappointing 1

Dose-Dependent Hemodynamic Effects

Low-Dose Effects (Predominantly Venodilation)

• At low doses, nitrates primarily dilate venous capacitance vessels, reducing preload and venous return to the heart 1
• This decreases left ventricular end-diastolic pressure and volume, reducing ventricular wall tension and myocardial oxygen demand 3, 1

High-Dose Effects (Arterial and Coronary Dilation)

• At higher doses, nitrates dilate epicardial coronary arteries, prevent coronary spasm, and improve subendocardial blood flow to ischemic areas 1
• They reduce systemic vascular resistance (afterload) through arteriolar relaxation, decreasing arterial blood pressure and further lowering myocardial oxygen consumption 3, 1
• Nitrates enhance collateral blood flow and can enlarge some coronary atherosclerotic stenoses 1, 5

Important Mechanistic Limitations

Microcirculatory Resistance

• Small arterioles are nitrate-resistant, explaining why nitrates have minimal action in the microcirculation 1
• This resistance accounts for less reflex tachycardia compared to direct NO donors like nitroprusside 1

Compensatory Reflex Activation

• The beneficial effects on preload and afterload are partially offset by reflex sympathetic activation, causing increased heart rate and myocardial contractility 1
• Combining nitrates with β-blockers blocks this reflex tachycardia, creating a synergistic anti-ischemic effect 1

Tolerance Development Mechanism

• Tolerance is dose and duration dependent, typically becoming clinically important after 24 hours of continuous therapy due to depletion of sulfhydryl cofactors required for enzymatic biotransformation 6, 2
• A nitrate-free interval of 10-12 hours prevents tolerance by allowing recovery of metabolic mechanisms responsible for nitrate efficacy 6, 2

Clinical Efficacy Context

Symptom Relief Without Mortality Benefit

• No data support that nitrates improve outcomes (mortality or myocardial infarction) in chronic stable angina—they are purely symptomatic therapy 1
• Meta-analyses show no differences in symptom relief or exercise parameters between nitrates and other antianginal agents 1

Specific Clinical Scenarios

• Nitrates provide clear benefit in patients with overlapping coronary spasm (microvascular or macrovascular angina with vasospastic component) 1
• Sublingual nitroglycerin achieves onset of vasodilatory effects within 1-3 minutes, reaching maximum effect by 5 minutes and persisting for at least 25 minutes 3