Pulmonary injury and prostaglandin production during endotoxemia in conscious sheep

Rh, Demling; Smith, Michael E.; Gunther, Robert A.; Flynn, John T.; Gee, Marlys H.

doi:10.1152/ajpheart.1981.240.3.h348

Cited by 90 publications

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“…It is well known that even brief periods of endotoxaemia in the pig are associated with a substantial, biphasic rise in MPAP and PVR ), which in turn accounts for the observed fall in CO. This biphasic rise in MPAP and PVR is due to the formation of the vasoconstrictor thromboxane A2 (first phase) (Hardie & Olson, 1987;Leeper-Woodford et al, 1981;Weitzberg et al, 1993), as well as the development of a pulmonary oedema (second phase) (Demling et al, 1981). These pathophysiological alterations in MPAP and PVR during the acute phase of endotoxaemia are peculiar to this species and have not been described in man (Parillo et al, 1990).…”

Section: Mortalitymentioning

confidence: 96%

See 1 more Smart Citation

Effects of nitric oxide synthase inhibition combined with nitric oxide inhalation in a porcine model of endotoxin shock

Klemm¹,

Thiemermann

Winklmaier³

et al. 1995

British J Pharmacology

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1 The present investigation compares the effects of intravenous infusion of the NO synthase inhibitor NG-monomethyl-L-argiine (L-NMMA) with that of an inhalation with NO gas in a porcine model of endotoxin (lipopolysaccharide, LPS) shock. In addition, the effects of the combination of these two treatments were also investigated. 2 Male pigs were anaesthetized and instrumented for the measurement of haemodynamic parameters. Blood samples were withdrawn at different time intervals for determination of blood gases, pH, and plasma levels of nitrite/nitrate and tumour necrosis factor. 3 Endotoxin infusion (15 tLg kg-' h-' for 3 h) caused a progressive fall in mean arterial blood pressure (MABP) and cardiac output (CO) and a biphasic increase in mean pulmonary arterial pressure (MPAP) and pulmonary vascular resistence (PVR). A continuous infusion of L-NMMA (0.1 mg kg' min-') significantly attenuated the fall in MABP, but did not affect MPAP, CO and PVR. NO-inhalation (50 p.p.m.) did not affect MABP, but significantly blunted the biphasic increase in MPAP and PVR and significantly delayed the fall in CO. The combination of L-NMMA infusion (0.1 mg kg-' min-') with NO-inhalation (50 p.p.m.) completely prevented the fall in MABP, significantly improved CO, and attenuated the biphasic increase in MPAP and PVR. 4 %Endotoxin also caused a decline in Pao2 and a rise of Paco2. Infusion of L-NMMA neither affected the fall in Pao2 nor the increase in Paco2. In contrast, inhalation with NO gas alone as well as the combined administration of L-NMMA infusion and NO-inhalation completely prevented the fall in Pao2 and significantly protected against the increase in Paco2. 5 Infusion of endotoxin for 180 min resulted in a mortality of 58%, which was not affected by L-NMMA (63%). In contrast, treatment of LPS-animals with either NO-inhalation alone or NOinhalation plus L-NMMA completely prevented mortality. 6 This investigation demonstrates that treatment with NO-inhalation, in order to prevent the dramatic increase in MPAP, PVR and the alterations in peripheral blood gases combined with systemic L-NMMA to improve systemic MABP and thus organ perfusion, may be a new therapeutic regimen in the treatment of septic shock.

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Section: Mortalitymentioning

confidence: 96%

“…In contrast to the systemic vasodilatation, pulmonary hypertension often occurs in the acute phase of endotoxaemia. This may lead to rightsided heart failure, pulmonary oedema, hypoxia and death (Zapol et al, 1977;Demling et al, 1981).…”

Section: Introductionmentioning

confidence: 99%

Effects of nitric oxide synthase inhibition combined with nitric oxide inhalation in a porcine model of endotoxin shock

Klemm¹,

Thiemermann

Winklmaier³

et al. 1995

British J Pharmacology

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“…Previous studies have demonstrated increased plasma thromboxane B2 (TXB2) levels in response to endotoxin (Cook et al, 1980;Frolich et al, 1980;Harris et al, 1980;Demling et al, 1981). TXB2 is the stable metabolite of TXA2, a potent vasoconstrictor and proaggregatory substance synthesized by a variety of cells (Moncada & Vane, 1979) including platelets and macrophages (Cook et al, 1981a), which are target cells for endotoxin.…”

Section: Introductionmentioning

confidence: 99%

Beneficial effects of UK 37248, a thromboxane synthetase inhibitor, in experimental endotoxic shock in the rat.

Halushka¹,

Cook²,

Wise³

1983

Brit J Clinical Pharma

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1 The effects of pretreatment with the thromboxane synthetase inhibitor UK 37248 (dazoxiben) administered 30 min before intravenous endotoxin (S. enteriditis) in the rat was investigated. 2 Plasma prostaglandins and thromboxanes were determined via radioimmunoassay. Endotoxaemia was associated with significant elevations above control values (<200pg/ml) in plasma thromboxane B2 (TXB2), prostaglandin E (PGE) and 6-keto-prostaglandin Fla (6-keto-PGFia). Within 30 min after endotoxin administration plasma immunoreactive (i) iTXB2 was 875±90pg/ml (n=9), iPGE was 1670±271 (n=9) and i6-keto-PGFia was 1191±209 pg/ml (n= 10). By 4 h plasma iTXB2 was 1743±328 pg/ml (n=5), iPGE was 2589±494pg/ml (n=9) and i6-keto-PGFia was 4251±984pg/ml (n=10). UK 37248 pretreatment resulted in a significant (P<0.001) decrease in plasma iTXB2 at 30min and 4h to 193±28pg/ml (n=5) and 421±57pg/ml (n=5), respectively. Unexpectedly UK 37248 also significantly decreased plasma i6-keto PGFia at 30 min and 4 h to 360±75 pg/ml (n= 10) (P<0.005) and 1920±513 pg/ml (n= 10) (P<0.05), respectively. iPGE plasma levels were not significantly changed in the UK 37248-pretreated rats 30 min (2210±370 pg/ml (n=9) or 4 h 3529± 1093 pg/ml (n= 13) after endotoxin compared to the vehicle-treated rats. 3 UK 37248 significantly (P<0.05) reduced the endotoxin mortality rate at 24 h from 69% (n= 13) to 30% (n= 13). UK 37248 also reduced splanchnic infarction from 90% (n = 20) to 6% (n = 16). 4 UK 37248 significantly improved the endotoxin-induced thrombocytopaenia, disseminated intravascular coagulation, hypoglycaemia and lysosomal labilization. 5 We conclude that UK 37248 provides significant beneficial effects in experimental endotoxic shock in the rat.

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“…Recent studies have demonstrated increased plasma thromboxane (Tx)B2, the stable metabolite of TxA2, in response to endotoxin (Cook, Wise & Halushka 1980;Frolich Ogletree, Peskar & Brigham 1980;Harris, Zmudka, Maddox, Ramwell & Fletcher 1980;Demling, Smith, Gunther, Flynn & Gee 1981;Coker, Hughes, Parratt, Rodgers & Zeilin 1981). TxA2 is a potent vasoconstrictor and proaggregatory substance synthesized by a variety of cells including platelets (Moncada & Vane, 1979) and macrophages (Cook, Wise, Knapp & Halushka, 1981a;Feuerstein, Foegh & Ramwell, 1981), which are target cells for endotoxin.…”

Section: Introductionmentioning

confidence: 99%

Effects of a pyridine derivative thromboxane synthetase inhibitor and its inactive isomer in endotoxic shock in the rat

Anderegg

Anzeveno²,

Cook

et al. 1983

British J Pharmacology

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1We investigated the effects of a pyridine derivative thromboxane synthetase inhibitor and its inactive ortho isomer on arachidonic acid metabolism and pathophysiological sequelae of endotoxic shock. In vehicle-treated rats, 30 min after intravenous S. enteritidis endotoxin (15 mg/kg), plasma iTxB2 (the stable metabolite of thromboxane A2) increased from non-detectable levels (< 100 pg/ml) to 763 ± 250 pg/ml (n = 10). Plasma i6-keto-PGF1,, (the stable metabolite of prostacyclin, PGI2) increased to 1850 ± 426 pg/ml, (n = 9) and plasma iPGE increased to 2350 = 560 (n = 5). Pretreatment with the pyridine active (PA) meta isomer (30 mg/kg i.p.) significantly (P<0.05) suppressed iTxB2 to 390±31 pg/ml (n= 10) although 6-keto-PGF1,l levels (1294 ± 358 pg/ml, n = 5) and plasma iPGE (2847 ± 1103 pg/ml, n = 5) were not significantly different from the shocked control values. In contrast, pretreatment with, the pyridine inactive (PI) ortho isomer did not significantly affect endotoxin-induced iTxB2 (1431±194 pg/ml, n =5) or i6-keto-PGF1,, synthesis (628 ± 266 pg/ml, n = 5).2 Pretreatment of rats with the Tx synthetase inhibitor, PA, significantly enhanced (P <0.05) survival and prevented splanchnic infarction relative to both endotoxin shocked control rats and those pretreated with the PI isomer. 3 Significantly reduced lysosomal labilization, hepatocellular dysfunction and elevations in serum fibrin/fibrinogen degradation products were seen only in groups pretreated with the PA isomer. 4 The beneficial effects of the latter compound in tndotoxic shock thus appear to be due to inhibition of Tx synthesis, since its ortho isomer did not inhibit TxA2 synthesis nor did it protect against endotoxic shock.

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Pulmonary injury and prostaglandin production during endotoxemia in conscious sheep

Cited by 90 publications

References 0 publications

Effects of nitric oxide synthase inhibition combined with nitric oxide inhalation in a porcine model of endotoxin shock

Effects of nitric oxide synthase inhibition combined with nitric oxide inhalation in a porcine model of endotoxin shock

Beneficial effects of UK 37248, a thromboxane synthetase inhibitor, in experimental endotoxic shock in the rat.

Effects of a pyridine derivative thromboxane synthetase inhibitor and its inactive isomer in endotoxic shock in the rat

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