ET-3 sensitive reduction of tissue blood flow in rat liver

Kurihara, Toshio; Akimoto, Masumi; Kurokawa, Kaori; Ishiguro, Hisataka; Niimi, Akiko; Maeda, Atushi; Sigemoto, Mutsuo; Yamashita, Katsuko; Yokoyama, Izumi; Hirayama, Yukio; Ihara, Masaki; Yano, Mitsuo

doi:10.1016/0024-3205(92)90492-8

Cited by 15 publications

(7 citation statements)

References 17 publications

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“…Several groups reported that both ET-1 and -3 induce the release of eicosanoids such as PGE 2 , PGF 2␣ , and TXA 2 , which potentiate the vasoconstriction in the dog and rat renal arterioles (5,24,40). Kurihara et al (20) showed that ET-3-stimulated decrease in hepatic blood flow was partially mediated by the release of TXA 2 . In contrast, NO was reported to inhibit production of PGE 2 and TXB 2 in LPS and IFN␥-activated Kupffer cells (39).…”

Section: Discussionmentioning

confidence: 99%

Role of thromboxane A₂in early BDL-induced portal hypertension

Yokoyama

Kresge

et al. 2003

American Journal of Physiology-Gastrointestinal and Liver Physi

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Although the mechanisms of cirrhosis-induced portal hypertension have been studied extensively, the role of thromboxane A2 (TXA2) in the development of portal hypertension has never been explicitly explored. In the present study, we sought to determine the role of TXA2 in bile duct ligation (BDL)-induced portal hypertension in Sprague-Dawley rats. After 1 wk of BDL or sham operation, the liver was isolated and perfused with Krebs-Henseleit bicarbonate buffer at a constant flow rate. After 30 min of nonrecirculating perfusion, the buffer was recirculated in a total volume of 100 ml. The perfusate was sampled for the enzyme immunoassay of thromboxane B2(TXB2), the stable metabolite of TXA2. Although recirculation of the buffer caused no significant change in sham-operated rats, it resulted in a marked increase in portal pressure in BDL rats. The increase in portal pressure was found concomitantly with a significant increase of TXB2 in the perfusate (sham vs. BDL after 30 min of recirculating perfusion: 1,420 ± 803 vs. 10,210 ± 2,950 pg/ml; P < 0.05). Perfusion with a buffer containing indomethacin or gadolinium chloride for inhibition of cyclooxygenase (COX) or Kupffer cells, respectively, substantially blocked the recirculation-induced increases in both portal pressure and TXB2 release in BDL group. Hepatic detection of COX gene expression by RT-PCR revealed that COX-2 but not COX-1 was upregulated following BDL, and this upregulation was confirmed at the protein level by Western blot analysis. In conclusion, these results clearly demonstrate that increased hepatic TXA2 release into the portal circulation contributes to the increased portal resistance in BDL-induced liver injury, suggesting a role of TXA2 in liver fibrosis-induced portal hypertension. Furthermore, the Kupffer cell is likely the source of increased TXA2, which is associated with upregulation of the COX-2 enzyme.

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Section: Discussionmentioning

confidence: 99%

Role of thromboxane A₂in early BDL-induced portal hypertension

Yokoyama

Kresge

et al. 2003

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…in portal venules, results in vasoconstriction and, hence, may also contribute to a reduction in hepatic blood flow (Kurihara et al, 1992;Bauer et al, 1994;Zhang et al, 1995). As endotoxaemia (this model) results in a rapid and substantial increase in the plasma levels of ET-1 (Ruetten et al, 1996), any reduction in sinusoidal blood flow is likely to be due to extra-sinusoidal as well as sinusoidal constriction.…”

Section: Inhibition Of Pre-sinusoidal Contractionsmentioning

confidence: 94%

Effect of selective blockade of endothelin ET_B receptors on the liver dysfunction and injury caused by endotoxaemia in the rat

Ruetten

Thiemermann

1996

British J Pharmacology

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1 We investigated the effects of the selective endothelin (ET)A receptor antagonist BQ-485 and the selective ETB receptor antagonist BQ-788 on circulatory failure, multiple organ dysfunction syndrome (MODS) and the alterations in acid base balance caused by endotoxaemia in the anaesthetized rat. 2 Male Wistar rats were anaesthetized (thiopentone sodium; 120 mg kg-', i.p.) and received a continuous infusion of vehicle (saline, 0.6 ml kg-'h-', i.v.), i.v.) or i.v.). Fifteen min later, animals received a bolus injection of either saline (0.9% NaCl, 1 ml kg-', i.v.) or E. coli lipopolysaccharide (LPS, 10 mg kg-', i.v.). 3 Injection of LPS resulted in a fall in blood pressure from 115 + 4 mmHg (time 0) to 82 + 4 mmHg at 360 min (n = 15) as well as a hyporeactivity to the pressor responses to noradrenaline (NA, 1 jug kg-', i.v.). Infusion of BQ-788 attenuated the delayed hypotension (at 360 min: 100 + 4 mmHg, n = 7; P < 0.05) and significantly enhanced the pressor responses elicited by NA (at 60 to 240 min). In contrast, treatment of LPS-rats with BQ-485 augmented the hypotension (at 360 min), but did not affect the vascular hyporeactivity elicited by endotoxaemia. 4 Endotoxaemia for 360 min resulted in rises in the serum levels of urea and creatinine (indicators of renal failure), glutamate-oxalate-transferase (GOT) and glutamate-pyruvate-transferase (GPT) (indicators of hepatocellular injury), and bilirubin and 'y-glutamyl transferase (yGT) (indicators of liver failure) as well as nitrite (indicator of the induction of nitric oxide synthase; iNOS). Treatment of LPS-rats with BQ-788, but not with BQ-485, attenuated the degree of liver injury and failure, while neither BQ-788 nor BQ-485 affected the acute renal failure or the induction of iNOS caused by endotoxin. 5 Endotoxaemia also caused (within 15 min) an acute metabolic acidosis (falls in pH, HCO3-and base excess) which was compensated by hyperventilation (fall in Paco2). Treatment of LPS-rats with BQ-788 or BQ-485 did not affect the metabolic acidosis caused by LPS.6 Thus, the selective ETB receptor antagonist BQ-788 attenuated (i) the delayed hypotension, (ii) the vascular hyporeactivity to NA as well as (iii) the degree of hepatocellular injury and dysfunction caused by endotoxin in the anaesthetized rat. In contrast, the selective ETA receptor antagonist did neither attenuate the circulatory failure nor the liver or renal dysfunction associated with endotoxaemia. We propose that the prevention of the hepatocellular dysfunction and injury caused BQ-788 in endotoxaemia is due to an improvement in oxygen delivery to the liver secondary to (i) inhibition of pre-sinusoidal constriction, (ii) inhibition of sinusoidal constriction, and (iii) improvement in perfusion pressure.

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“…It has been suggested that mediators of activated Kupffer cells cause severe microcirculatory disturbances in the hepatic microcirculation, e. g., after liver transplantation [12,13]. In this context, it has been suggested recently that endothelium-derived contracting factors, such as endothelin-1 or -3 [7], may contribute to liver injury [S, 151. Therefore, the aim of this study was to evaluate whether ET-3 contributes to postischemic microvascular disturbances in liver sinusoids, e. g., by contraction of sinusoids.…”

Section: Discussionmentioning

confidence: 99%

Endothelin-1 is involved in hepatic sinusoidal vasoconstriction after ischemia and reperfusion

et al. 1994

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Endothelin-1 (ET-1), a vasoactive peptide, causes a significant rise in portal vein pressure, which is most likely a result of severe vasoconstriction in the liver. In this study, the effect of ET-1 on sinusoidal vasoconstriction in the liver after ischemia and reperfusion was directly investigated using intravital microscopy. In anesthetized female Sprague Dawley rats (200-250 g) ischemia of the median and left liver lobes was induced for 90 min by temporary ligation of the left pedicle. After declamping and a 90-min reperfusion period, the livers were exposed for intravital microscopy. Using a Nikon MM-11 fluorescence microscope (545 nm, 330x), a CCD camera (Cohu FK 6990), and a SVHS video recording unit, the hepatic microcirculation was directly investigated. Besides sham groups, two ischemia groups were studied, receiving ET-1 antiserum (anti-ET-1; 0.5 ml; Peptide Inst., Osaka, Japan) or NaCl 0.9% (0.5 ml) 5 min prior to reperfusion of the liver (n = 6/group). Following a transient drop in the mean arterial blood pressure in the anti-ET-1-treated groups, comparable systemic hemodynamic conditions among the four groups were noted during intravital microscopic assessment at the end of the 90-min reperfusion period. Reduction in the sinusoidal diameters during postischemic reperfusion (7.7 +/- 0.5 microm) was prevented by anti-ET-1 treatment (9.6 +/- 0.25 microm; P < 0.01; mean + SEM) back to control values (9.6 +/- 0.32 microm), while most of other microcirculatory parameters did not show significant differences. The results supported further the role of ET-1 in dysregulation of the sinusoidal vascular tone in the liver, e.g., after ischemia and reperfusion.

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ET-3 sensitive reduction of tissue blood flow in rat liver

Cited by 15 publications

References 17 publications

Role of thromboxane A₂in early BDL-induced portal hypertension

Role of thromboxane A₂in early BDL-induced portal hypertension

Effect of selective blockade of endothelin ET_B receptors on the liver dysfunction and injury caused by endotoxaemia in the rat

Endothelin-1 is involved in hepatic sinusoidal vasoconstriction after ischemia and reperfusion

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ET-3 sensitive reduction of tissue blood flow in rat liver

Cited by 15 publications

References 17 publications

Role of thromboxane A2in early BDL-induced portal hypertension

Role of thromboxane A2in early BDL-induced portal hypertension

Effect of selective blockade of endothelin ETB receptors on the liver dysfunction and injury caused by endotoxaemia in the rat

Endothelin-1 is involved in hepatic sinusoidal vasoconstriction after ischemia and reperfusion

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Product

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Role of thromboxane A₂in early BDL-induced portal hypertension

Role of thromboxane A₂in early BDL-induced portal hypertension

Effect of selective blockade of endothelin ET_B receptors on the liver dysfunction and injury caused by endotoxaemia in the rat