Elsevier

Journal of Hepatology

Volume 32, Issue 1, January 2000, Pages 32-37
Journal of Hepatology

Pressor and renal effects of cross-linked hemoglobin in anesthetized cirrhotic rats

https://doi.org/10.1016/S0168-8278(00)80186-5Get rights and content

Abstract

Background/Aims: Cross-linked hemoglobin (XL-Hb), a hemoglobin-based oxygen carrier, is currently under investigation as a blood substitute. In the present study we have evaluated its pressor and renal effects in a rat model of liver cirrhosis by bile duct ligation.

Methods: Experiments were performed 3 weeks after surgery in anesthetized rats. In the first protocol, the ability of XL-Hb to recover blood pressure after a hypotensive hemorrhage (0.5 ml/min, 10 min) was analyzed. In the second protocol, the pressor and renal effects produced by the administration of XL-Hb were evaluated during a period of 3 h.

Results: After a hypotensive hemorrhage (0.5 ml/min, 10 min), resuscitation with XL-Hb resulted in greater and faster recovery of blood pressure than with the administration of blood. In non-hemorrhaged rats, administration of XL-Hb (5% of blood volume) reversibly increased blood pressure in bile duct ligation and in control rats, but this effect was oflonger duration in the control animals. XL-Hb also induced brisk increases in water and sodium excretion in both groups of animals, but the response of the control animals was more intense and sustained than that of the bile duct ligation rats. Glomerular filtration rate and renal blood flow showed slight decreases, but they were well maintained around the baseline levels. All the parameters studied were normalized 3 h later. In additional experiments, the effect of a bolus of L-NAME (10 mg/kg), an inhibitor of nitric oxide synthase, 1 h after the administration of XL-Hb was partially reduced, suggesting that the effect of XL-Hb may be secondary to the disappearance of circulating nitric oxide.

Conclusions: XL-Hb seems to be effective as a resuscitative solution in case of hemorrhage in cirrhotic rats. Moreover, this blood substitute only moderately and reversibly elevates blood pressure and does not adversely affects renal function.

Section snippets

Materials and Methods

All the experiments were conducted following the European Union guidelines for the ethical treatment of animals. Male Sprague-Dawley rats, born and raised in the Animalario of the Universidad de Murcia, were used in the present study. Bile duct ligation (BDL) was performed in rats weighing 225–275 g, following a method previously described 19., 20., 21.. In brief, the animals were anesthetized with ethylic ether and, under aseptic techniques, subjected to BDL and excision or simulated operation

Protocol 1. Comparison of pressor effects of XL-Hb and blood

Fig. 1 shows the MAP response to the reinfusion of blood or XL-Hb in control and cirrhotic rats. MAP was always lower in the BDL animals (96.1±2.5 mmHg) than in the controls (116.5±3.6). In the control animals, the hemorrhage decreased MAP to 59.3±2.9 and the reinfusion of blood slowly returned it to the control values, reaching a maximum of 121.3±5.0 8 min later. In contrast, the infusion of XL-Hb elevated MAP faster and to higher values, reaching a maximum of 138.0±9.4 at the third minute.

Discussion

In the present study, we have evaluated the effects of a blood substitute, the cross-linked hemoglobin, in a rat model of liver cirrhosis to assess its efficacy in restoring blood pressure after a hypotensive hemorrhage. Replacing lost blood with hemoglobin has the advantage of simultaneous scavenging of nitric oxide (22), which is implicated in the induction of endotoxic shock. In the first series of experiments, XL-Hb proved useful as a tool to recover blood pressure after an important acute

Acknowledgements

This study was supported by Spanish Government grants SAF95-1549-C02-02 and SAF97-0176 from the Comisión Interministerial de Ciencia y Tecnología. During the period of this study, M.C.O. (FP94-29000129) and L.A.F. (PN95-42849602) were recipients of a predoctoral fellowship from the Ministerio de Educación y Cultura of Spain.

References (26)

  • RW Schrier et al.

    Peripheral arteriolar vasodilation hypothesis: a proposal for the initiation of renal sodium and water retention in cirrhosis

    Hepatology

    (1988)
  • LJ Ignarro

    Biosynthesis and metabolism of endothelium-derived nitric oxide

    Annu Rev Pharmacol Toxicol

    (1990)
  • SC Schultz et al.

    A role for endothelin and nitric oxide in the pressor response to diaspirin cross-linked hemoglobin

    J Lab Clin Med

    (1993)
  • Cited by (3)

    • Hepatically-metabolized and -excreted artificial oxygen carrier, hemoglobin vesicles, can be safely used under conditions of hepatic impairment

      2010, Toxicology and Applied Pharmacology
      Citation Excerpt :

      Recently, Zapletal et al. showed that acellular type hemoglobin-based oxygen carrier (HBOC-201) attenuated the microvascular dysfunction and improved the tissue oxygenation following the ischemic reperfusion injury in liver (Zapletal et al., 2009). Furthermore, it was reported that acellular type HBOC was useful for prehospital resuscitation with uncontrolled hemorrhage due to liver injury and hepatic cirrhosis (Ortiz et al., 2000; Arnaud et al., 2008). These results suggest that HbV and acellular type HBOC are potential candidates for alternative treatment of RBCs during liver transplantation, hepatic injury and bleeding induced by hepatic cirrhosis.

    • Vitamin E prevents renal dysfunction induced by experimental chronic bile duct ligation

      2003, Kidney International
      Citation Excerpt :

      While this degree of renal vasoconstriction is well known to occur during cirrhosis (even before renal dysfunction becomes apparent) [2,56-58], it is more variable in the CBDL rats. Some studies have found decreases in RVR [32,34,44], while others have found either no change or an increase in RVR, both of which suggest renal vasoconstriction or impaired autoregulatory vasodilation [6-10,45,59,60]. The reasons for these discrepancies are not clear but may be related to subtle differences in the rat (e.g., strain, breeder, etc.), anesthesia, or the severity of the disease.

    View full text