Mechanism of the Hypotension Produced Protamine Sulfate in Dogs

Yoo, Kyung Yeon; Rim, Sung Jin; Shim, Seung Jin; Chung, Sung Su; Im, Woong Mo

Abstract

INTRODUCTION
Protamine reversal of heparin anticoagulation often produces profound hypotension. However, the precise mechanisms of its hypotensive effect have not been fully elucidated. Using a canine model, we explored the effects of cyclo-oxygenase inhibitor, indomethacin (INDO), and nitric oxide synthetase inhibitor, NG-nitro-L-arginine methyl ester (L-NAME) either alone or both on the cardiopulmonary responses to protamine.
METHODS
Fifty-four mongrel dogs in five groups were studied during 1.5% halothane anesthesia. GroupI (n=17) received heparin (300 IU/kg iv) followed by protamine (3 mg/kg iv over 30 s) 5 min after the heparin. The same protocol were used in groups II (n=11), III (n=12), and IV (n=7), except that L-NAME (20 mg/kg), INDO (10 mg/kg), and INDO (10 mg/kg) plus L-NAME (10 mg/kg) were infused over 10 min beginning 30 min before the protamine injection, respectively. Animals in group V (n=7) were given protamine (3 mg/kg) alone. Mean arterial pressure (MAP), mean pulmonary arterial pressure (MPAP), left ventricular end-diastolic pressure (LVEDP), LVdP/dt and cardiac output and left circumflex coronary flow (LCX flow) via Doppler flowmeter and heart rate were continuously recorded in baseline conditions and up to 15 min. Plasma NOx (NO2-, NO3-) levels were also measured before (baseline) and 3, 5, 10, and 15 min after protamine injection.
RESULTS
In group I, protamine caused immediate but transient decreases of MAP (41%), cardiac index (CI, 58%), dP/dt (28%), and LVEDP (62%) and increases of MPAP (38%) and systemic and pulmonary vascular resistance indices (SVRI, 30%; PVRI, 316%). INDO significantly attenuated the hemodynamic responses to protamine, whereas L-NAME did not affect them at all. INDO plus L-NAME prevented protamine-induced hypotension, but CI (-24%) and LVEDP (-30%) showed similar changes as those in group II. Protamine increased MPAP but inconsistently, meanwhile no correlation was found between the magnitude of increase of MPAP and decrease of MAP at peak responses in groups I-IV. LCX flow increased significantly (124~188%) immediately after protamine infusion without any changes in plasma NOx levels in groups I-IV. Neither significant hemodynamic effects nor NOx release was found in animals given protamine alone.
CONCLUSION
Protamine in the presence of heparin induces profound hypotension which may be mediated by a prostanoid and other potent vasodilators. In addition, increase of PAP and NO release may not play a significant role in the protamine-induced hypotension.