Canadian Journal of Anaesthesia

, Volume 45, Issue 12, pp 1186–1189 | Cite as

Systemic hypotensive response to protamine following chronic inhibition of nitric oxide synthase in rats

  • Hiroshi Komatsu
  • Keiji Enzan
  • Shin Matsuura
  • Shin Kurosawa
  • Hiromasa Mitsuhata
Laboratory Investigations



The aims of the present studies were to determine whether the systemic hypotensive response to protamine was modified in rats pre-treated for two weeks with the nitric oxide synthase inhibitor, NG-nitro-L-argi-nine-methyl ester (L-NAME), and to evaluate the inhibitory effect of heparin on the systemic hypotensive response to protaminein vivo.


Male rats were randomly assigned into four groups. Normal saline 12μl·day−1, D-NAME (an inactive enantiomer of L-NAME), 10 mg·kg−1·day−1, L-NAME, 1 or 10 mg·kg−1·day−1 ip was administered for two weeks and the haemodynamic changes were measured after protamine administration. In another experiment, male rats were assigned to two groups. In one, the heparin group, protamine was administered after heparin had been administered and in the other, protamine group, protamine alone was administered.


L-NAME inhibited the decrease in systemic arterial pressure after protamine administration (P < 0.05), but D-NAME had no effect. Also, heparin reduced the decrease in systemic arterial pressure after protamine (P < 0.05).


Nitric oxide is mainly responsible for mediation of the systemic hypotensive response to protamine which is also reduced by heparin.


Nitric Oxide Protamine Systemic Arterial Pressure Systemic Hypotension Heparin Group 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



L’objectif des présentes études était de déterminer si la réaction hypotensive généralisée à la protamine était modifiée chez les rats prétraités pendant deux semaines avec l’inhibiteur de l’oxyde nitrique synthase, NG-nitro-L-arginine-methyl ester (L-NAME), et d’évaluer l’effet inhibiteur de l’héparine sur la réaction hypotensive généralisée à la protamine,in vivo.


Des rats mâles ont été répartis au hasard en quatre groupes. Une solution salée de 12 μl·jour−1, DNAME (un énantiomère inactif de L-NAME), 10 mg·kg−1·jour−1, L-NAME, 1 ou 10 mg·kg−1·jour−1 ip a été administré pendant deux semaines et les changements hémodynamiques ont été mesurés après l’administration de protamine. Lors d’une autre expérience, les rats ont été divisés en deux groupes. Dans l’un d’eux, le groupe héparine, l’administration de la protamine a suivi celle de l’héparine et, dans l’autre groupe, le groupe protamine, seule la protamine a été administrée.


L-NAME a empêché la baisse de tension artérielle générale après l’administration de la protamine (P < 0,05), mais D-NAME n’a pas eu d’effet. De même, l’héparine a réduit la baisse de la tension artérielle générale après l’administration de protamine (P < 0,05).


Loxyde nitrique est principalement responsable de la médiation de la réaction hypotensive généralisée à la protamine, laquelle est aussi réduite par l’héparine.


  1. 1.
    Neidhart PP, Meier B, Pollo BS, Schifferli JA, Morel DR. Fatal anaphylactoid response to protamine after percutaneous transluminal coronary angioplasty. Eur Heart J 1992; 13: 856–8.PubMedGoogle Scholar
  2. 2.
    Komatsu H, Enzan K, Suzuki M. Role of nitric oxide on systemic hypotension caused by intra-arterial injection of protamine. JunkanSeigyo 1995; 15: 268–71.Google Scholar
  3. 3.
    Guyton AC. Short-term regulation of mean arterial pressure: nervous reflex and hormonal mechanisms for rapid pressure control.In: Guyton AC (Ed.). Textbook of Medical Physiology 6th ed. Philadelphia, W.B. Saunders Company, 1981: 246–58.Google Scholar
  4. 4.
    Pearson PJ, Evora PRB, Ayrancioglu K, Schaff HV. Protamine release endothelium-derived relaxing factor from systemic arteries. A possible mechanism of hypotension during heparin neutralization. Circulation 1992; 86: 289–94.PubMedGoogle Scholar
  5. 5.
    Evora PRB, Pearson PJ, Schaff HV. Protamine induces endothelium-dependent vasodilation of the pulmonary artery. Ann Thorac Surg 1995; 60: 405–10.PubMedCrossRefGoogle Scholar
  6. 6.
    Raikar GV, Hisamochi K, Raikar B-NL, Schaff HV. Cardiopulmonary bypass, myocardial management, and support techniques. J Thorac Cardiovasc Surg 1996; 111: 1240–7.PubMedCrossRefGoogle Scholar
  7. 7.
    Baylis C, Mitruka B, Deng A. Chronic blockade of nitric oxide synthesis in the rat produces systemic hypertension and glomerular damage. J Clin Invest 1992; 90: 278–81.PubMedCrossRefGoogle Scholar
  8. 8.
    Ribeiro MO, Antunes E, de Nucci G, Lovisolo SM, Zatz R. Chronic inhibition of nitric oxide synthesis. A new model of arterial hypertension. Hypertension 1992; 20: 298–303.PubMedGoogle Scholar
  9. 9.
    Montelescot G, Fischman AJ, Straus HW, et al. Imaging the ovine heparin-protamine interaction with 111 Inprotamine. J Appl Physiol 1993; 75: 963–71.Google Scholar
  10. 10.
    Komatsu H, Enzan K. Repeated administration of protamine attenuates protamin-induced systemic hypotension. Masui 1996; 45: 1319–22.PubMedGoogle Scholar
  11. 11.
    Prater RMW, Oka Y, Hong Y Tsubo T, Loubser PG, Masone R. Protamine-induced circulatory changes. J Thorac Cardiovasc Surg 1984; 87: 687–92.Google Scholar
  12. 12.
    Procaccini B, dementi G, Bersanetti L, et al. Cardiovascular effects of protamine sulphate in man: intra-aortic vs intra-right atrial rapid administration after cardiopulmonary bypass. J Cardiovasc Surg 1987; 28: 112–9.Google Scholar

Copyright information

© Canadian Anesthesiologists 1998

Authors and Affiliations

  • Hiroshi Komatsu
    • 1
  • Keiji Enzan
    • 1
    • 2
  • Shin Matsuura
    • 1
    • 3
  • Shin Kurosawa
    • 1
    • 4
  • Hiromasa Mitsuhata
    • 1
  1. 1.Department of AnesthesiologyHiraga General HospitalJapan
  2. 2.Department of Japanese Oriental Medicine, Toyama MedicalPharmaceutical University, Faculty of MedicineJapan
  3. 3.Department of AnesthesiologyTohoku University, School of MedicineJapan
  4. 4.Department of AnesthesiologyJuntcndo University School of MedicineJapan

Personalised recommendations