BACKGROUND: Protamine sulfate has been found to produce systemic hypotension secondary to acute pulmonary vasoconstriction and subsequent right heart failure in pigs and sheep. Nitric oxide (NO) is a potent pulmonary vasodilator. The present study was aimed to determine whether NO inhalation prevents hypotension in an open-chest canine model. METHODS: With IRB approval, 29 mongrel dogs were acutely instrumented during 1.5% enflurane anesthesia. All animals then received protamine 3 mg/kg over 30 s given through right atrium, 5 min after heparin (300 IU/kg, iv). NO inhalation was done for 20 min beginning 10 min before protamine infusion (NO group, n = 10). Control group was without NO inhalation (n = 19), which was retrospectively divided into two groups according to the magnitude of pulmonary arterial pressure (PAP) increase: normal PAP group (increase in PAP less than 6 mmHg, n = 9) and pulmonary hypertensive group (increase in PAP more than 6 mmHg, n = 10). Mean arterial pressure (MAP), PAP, left ventricular end-diastolic pressure (LVEDP), heart rate (HR), and cardiac output and left circumflex (LCX) coronary flow via a Doppler flowmeter were continuously monitored. Calculated parameters included cardiac index (CI), and systemic and pulmonary vascular resistance indices (SVRI and PVRI). RESULTS: Protamine increased PAP (66 vs 7%) and PVRI (5.1- vs 3.0- fold) more pronouncedly in pulmonary hypertensive than in normal group. However, protamine caused similar reductions of MAP (-40 vs -46%), CI (-60 vs -59%), and LVEDP (-47 vs -53%) in pulmonary hypertensive and normal groups. SVRI showed a biphasic response in both groups, an initial decrease (-15 vs -14%), followed by an increase (48 vs 25%, P<0.05). Continuous inhalation of NO at 80 ppm did not affect the protamine-induced reductions in MAP (-40%), CI (-55%), and LVEDP (-46%) and increases in PAP (45%) and PVRI (4.1-fold). LCX flow increased immediately after the protamine treatment in all groups to a similar magnitude (83-130%), indicating a rapid release of potent vasodilators. CONCLUSIONS: Protamine produces profound hypotension, which may not be causally related to an acute pulmonary vasoconstriction in the dog. It is unlikely that exogenous NO treatment affects hypotension.