Nitroglycerin is a mainstay drug for the treatment of angina. In vascular smooth cells, nitroglycerin is metabolized to nitric oxide, which is converted to S-nitrosothiols, which in turn activate guanylate cyclase and generate cyclic guanosine monophosphate (GMP), resulting in smooth muscle relaxation and subsequent vasodilatation of venous beds, peripheral arteries, and coronary arteries. Nitroglycerin has a more pronounced effect on veins than on arteries, and thus its anti-ischemic effect is more related to venodilatation and preload reduction, which reduces myocardial wall stress that decreases myocardial oxygen demand, and indirectly improves subendocardial myocardial flow and collateral flow when present. Nitroglycerin dilates both normal and diseased coronary arteries, though this action is of uncertain clinical importance, except in patients who have vasospastic angina.

Nitroglycerin has a rapid onset and a short duration of action. It can be administered via the sublingual, intra-arterial, intravenous (IV), intracoronary, or intraventricular route. Nitroglycerin is commonly used in the catheterization laboratory during coronary angiography or percutaneous coronary interventions (PCIs) to improve coronary flow, prevent or alleviate coronary spasm, provoke myocardial bridging, relieve angina, or reduce preload in patients with elevated filling pressures. Prophylactic intracoronary nitroglycerin is commonly used before intravascular ultrasound or rotablation device activation. Nitroglycerin is also used in the pharmacological cocktail given via the radial artery to prevent or treat radial artery spasm during transradial procedures. Sublingual nitroglycerin is usually given as a 0.4-mg tablet or spray. Intracoronary, intra-arterial, or intraventricular nitroglycerine is commonly administered in 50 to 300 µg boluses. Higher doses can result in hypotension and reflex tachycardia without further augmentation in coronary blood flow. Nitroglycerin should not be administered to patients with a systolic blood pressure of <90 mm Hg or to patients who have taken phosphodiesterase inhibitors within 24 hours. Nitroglycerin should be administered very cautiously to patients with severe aortic stenosis, hypertrophic cardiomyopathy, severe left main disease, right ventricular infarctions, or volume depletion because of increased risk of causing deleterious hypotension (1, 2).

Acetylcholine is an endogenous neurotransmitter that causes endothelial-dependent vasodilatation via release of nitric oxide and other vasoactive substances in the presence of a normal endothelium, and causes vasoconstriction via direct activation of receptors on smooth muscle cells in the presence of an abnormal endothelium. Intracoronary acetylcholine administration constricts diseased coronary arteries (endothelial dysfunction or atherosclerosis) and vasodilates normal coronary arteries (normal endothelial function). Acetylcholine has been used to diagnose variant (Prinzmetal) angina, particularly in patients who have normally apparent coronary arteries on coronary angiography. Acetylcholine has also been used to assess epicardial and microvascular vasomotor responses that can lead to ischemia in patients with stable angina who have normal or minimal coronary artery disease without features of variant angina. In one study of patients with stable angina and normal or minimal coronary artery disease, two thirds of patients had an abnormal test, where 45% of patients had epicardial spasm (≥75% coronary narrowing with symptom production) and 55% of patients had microvascular spasm (symptom reproduction with ischemic ECG changes and no epicardial spasm) (21). Intracoronary incremental doses of acetylcholine of 20, 50, and 80 µg are usually injected into the RCA, and 20, 50, and 100 µg doses are injected into the LCA. Spasm is defined as total or subtotal occlusion after acetylcholine administration. Spasm caused by low doses of acetylcholine is usually more proximal and focal and is associated with more ST elevation and the clinical findings of variant angina. Spasm caused by higher acetylcholine doses is associated with more distal and diffuse spasm and is associated with less ST elevation and less characteristics of variant angina. Acetylcholine is very short acting and rapidly inactivated. Continuous infusions of 0.02 to 2.2 µg (10^-8, 10^-7, 10^-6 M) have been used to identify normal endothelial coronary artery function manifesting as vasodilatation. Marked bradycardia, heart block, and vasospasm are common with acetylcholine, and thus temporary pacing is recommended during its administration. Serious side effects such as sustained ventricular tachycardia (VT), shock, and cardiac tamponade occurred in 4 of 715 patients (0.56%) in one study, though no death or irreversible complications occurred (22, 23 and 24).

Ergonovine is an ergot derivative that causes smooth muscle cell contraction and is commonly used to induce uterine contractions to treat or prevent postpartum hemorrhage. It can also be used in the coronary tree to provoke coronary spasm and evaluate patients with angina pectoris who have normal coronaries or minimal coronary artery disease on coronary angiography. Ergonovine can be administered intracoronary as an infusion of 10 µg/min over 4 minutes for a maximal dose of 40 µg in the RCA and as 16 µg/min over 4 minutes for a total dose of 64 µg in the LCA (25). Alternatively, ergonovine can be administered by slow intracoronary injections over 1 minute each of sequential doses of 1, 5, 10, and 30 µg at 3- to 5-minute intervals, with a maximum cumulative dose of 50 µg (26). An ECG is obtained at the end of each interval or if the patient develops angina symptoms. Angiography of the RCA and LCA should be promptly performed when angina symptoms occur.
Diffuse coronary narrowing is a physiologic response to ergonovine, whereas a severe (more than 75% narrowing in some studies and subtotal to total occlusion in other studies) focal coronary narrowing is considered a response indicative of coronary spasm when associated with ischemic ECG changes or typical symptoms (25). Ergonovine-induced spasm can be reversed with the administration of intracoronary nitroglycerine. In one study, intracoronary acetylcholine-induced spasm (873 patients) was compared with intracoronary ergonovine-induced spasm (635 patients). In patients without ischemic heart disease, acetylcholine-induced spasm was significantly more common than ergonovine-induced spasm (11% vs. 6%). In addition, acetylcholine significantly provoked more spasm in patients without fixed stenosis than did ergonovine (36.2% vs. 25.5%). Major complications occurred in 1.4% of patients with the acetylcholine test and in 0.2% of patients with the ergonovine test, with no occurrence of any myocardial infarction or death with either test (25).