Protamine sulfate causes endothelium-independent vasorelaxation via inducible nitric oxide synthase pathway.

Abstract

PURPOSE:

The precise mechanism of systemic hypotension frequently observed with the use of protamine is unclear. Although it has been reported that protamine stimulates the release of nitric oxide (NO) from endothelium NO synthase (eNOS), the association with inducible NOS (iNOS) remains unknown, despite the induction of iNOS by lipopolysaccharides (LPS) and/or inflammatory cytokines during cardiopulmonary bypass (CPB). The purpose of this study was to determine whether protamine stimulates the release of NO from iNOS induced by LPS.

METHODS:

We performed prospective and controlled functional examinations with isolated endothelium-denuded thoracic aortas from 21 male Wister rats. Aortic strips were mounted in Krebs solution and treated with LPS (1 microg x mL(-1)) for six hours to induce iNOS. Changes in tension caused by L-arginine (a substrate of NOS), protamine or a heparin-protamine complex (heparin: protamine = 1 unit: 10 microg) were measured in strips pre-contracted by phenylephrine.

RESULTS:

No drug relaxed the strips before LPS-treatment, but each drug relaxed the strips in a dose-dependent manner after LPS-treatment (P < 0.05). Aminoguanidine (an iNOS inhibitor) and methylene blue (a guanylyl cyclase inhibitor) inhibited the relaxations.

CONCLUSION:

These results indicate that protamine and the heparin-protamine complex stimulated the release of NO from iNOS. As iNOS is induced during CPB, protamine or a heparin-protamine complex might cause systemic hypotension, at least in part, by stimulating iNOS.

• Authors: Ko Takakura, Maki Mizogami, Satoru Fukuda
• Journal: Canadian journal of anaesthesia = Journal canadien d'anesthesie (Can J Anaesth) Vol. 53 Issue 2 Pg. 162-7 (Feb 2006) ISSN: 0832-610X [Print] United States
• PMID: 16434757 (Publication Type: Journal Article)

Chemical References

• Enzyme Inhibitors
• Guanidines
• Heparin Antagonists
• Lipopolysaccharides
• Protamines
• protamine heparin aggregate
• Nitric Oxide
• Heparin
• Arginine
• Nitric Oxide Synthase Type II
• pimagedine
• Methylene Blue

Topics

• Animals
• Aorta, Thoracic
• Arginine (pharmacology)
• Dose-Response Relationship, Drug
• Endothelium, Vascular (metabolism, physiology)
• Enzyme Inhibitors (pharmacology)
• Guanidines (pharmacology)
• Heparin (pharmacology)
• Heparin Antagonists (pharmacology)
• In Vitro Techniques
• Lipopolysaccharides (pharmacology)
• Male
• Methylene Blue (pharmacology)
• Nitric Oxide (metabolism)
• Nitric Oxide Synthase Type II (antagonists & inhibitors, metabolism)
• Protamines (pharmacology)
• Rats
• Rats, Wistar
• Vasodilation (drug effects)