This Article Résumé de cet Article Full Text Full Text (PDF) Submit a scholarly reply Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Takakura, K. Articles by Fukuda, S. Search for Related Content PubMed PubMed Citation Articles by Takakura, K. Articles by Fukuda, S.

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

[Le sulfate de protamine cause un vasorelâchement indépendant de l’endothélium par la voie de l’oxyde nitrique synthase inductible]

Ko Takakura, MD PhD^*, Maki Mizogami, MD PhD^* and Satoru Fukuda, MD, PhD

^* From the Department of Anesthesiology, Asahi University, Hozumi, Mizuho, Gifu, Japan; and the
Department of Anesthesiology, Fukui Medical University, Matsuoka, Fukui, Japan.

Address correspondence to: Dr. Ko Takakura, Department of Anesthesiology, Asahi University, 1851-1 Hozumi, Mizuho, Gifu 501-0296, Japan. Phone: +81-058-329-1111; Fax: +81-058-329-1479; E-mail: takakura{at}dent.asahi-u.ac.jp

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 µg·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 µg) 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.