A patient, with known left ventricular failure presented with severe pulmonary edema, an ejection fraction of 10% to 15%, knee mottling, and lactates of 7 mM L⁻¹. He was treated with unusually high-dose nitroglycerin (NTG) intravenously (IV; NTG ≈ 70 mg for 1 hour). To suppress dyspnea, systolic blood pressure had to be lowered from ≈ 150-160 to ≈ 100-120 mm Hg. To lower NTG requirement, an α-2 agonist, clonidine, was administered (300 μg IV for 2 hours). Dyspnea, tachypnea, and tachycardia subsided for 1 to 2 hours, allowing to reduce NTG infusion to 2 to 4 mg h⁻¹. State-of the-art treatment was superimposed: sitting position with leg down, noninvasive ventilation, positive end-expiratory pressure, bolus of furosemide 250 mg, and administration of 1000 mL of crystalloid for 1 hour under echocardiographic guidance. We ascribed the resistance to NTG to the activation of the sympathetic, vasopressin, and renin-angiotensin systems ("neurohormonal activation"). α-2 agonists reduce the sympathetic activation observed during severe left ventricular failure and overall oxygen consumption, evoke systemic and pulmonary arterial dilation, increase diastolic time, and improve diastolic function and diuresis. Because the α-2 agonist, dexmedetomidine, is available as an IV drug on the North American market, a niche may exist in the setting of emergency medicine/coronary care. This awaits evidence-based documentation.