Serum levels of tumor necrosis factor determine the fatal or non-fatal course of endotoxic shock

Abstract The role of tumor necrosis factor alpha (TNFα) in endotoxin-induced shock was investigated in pigs receiving 5 μg kg− of Escherichia coli endotoxin (LPS) during 60 min of continuous infusion into the superior mesenteric artery. LPS concentration in aortic plasma, as determined by a chromogenic Limulus amoebocyte lysate (LAL) test, reached a peak of approximately 1000 ng 1−1 during LPS infusion, and declined rapidly after discontinuation of the infusion. Serum TNF levels were determined by a bioassay using the L929 murine transformed fibroblast line. Eight of the 17 animals infused with LPS died within 30 min after beginning LPS administration, while the other 9 pigs survived beyond the experimental observation period of 3 h, although they were in a state of shock. No difference in LPS concentration was found between the survivors and the non-survivors. However, the serum TNF levels in non-survivors were significantly higher than in survivors when measured at 30 min after beginning LPS administration. In survivors, the peak increase in serum TNF levels was measured at 60 min after the beginning of LPS injection and returned rapidly to the baseline values. Although the role of TNF inducing rapid death seems to be dominant, the hemodynamic, hematology and blood chemistry disturbances seen during shock continued in survivors long after the return of TNF to baseline levels. These findings indicate that besides TNF other mediators are also involved in the LPS infusion-induced shock

Pharmacological evidence that α1- and α2-adrenoceptors mediate vasoconstriction of carotid arteriovenous anastomoses in anaesthetized pigs

1. Vasoconstriction of carotid arteriovenous anastomoses may be involved in the therapeutic action of acutely acting antimigraine agents, including the triptans and ergot alkaloids. While 5-HT(1B/1D) receptors mediate the effect of triptans, ergotamine and dihydroergotamine also interact with α-adrenoceptors. In the present study, we investigated the potential role of α1- and α2-adrenoceptors in mediating vasoconstriction of carotid arteriovenous anastomoses in anaesthetized pigs. 2. Ten minute intracarotid infusions of phenylephrine (1, 3 and 10 μg kg-1 min-1) or BHT 933 (3, 10 and 30 μg kg-1 min-1) produced dose-dependent decreases in total carotid and arteriovenous anastomotic conductances; no changes were observed in the capillary fraction. 3. The carotid vascular effects of phenylephrine and BHT 933 were selectively abolished by prazosin (100 μg kg-1, i.v.) and rauwolscine (300 μg kg-1, i.v.), respectively. The responses to phenylephrine and BHT 933 were not affected by the selective 5-HT(1B/1D) receptor antagonist GR127935 (500 μg kg-1, i.v.). 4. These results show that both α1- and α2-adrenoceptors can mediate vasoconstriction of carotid arteriovenous anastomoses in anaesthetized pigs. Since vasoconstrictor activity in this in vivo model is predictive of anti-migraine activity, an agonist activity at particularly the α2-adrenoceptor subtypes, in view of their less ubiquitous nature, could provide migraine abortive potential. Thus, the present results may aid further understanding of the mode of action of some current antimigraine agents and may eventually be helpful in the development of future treatment in migraine

Investigations with GMC2021 in experimental models predictive of antimigraine activity and coronary side-effect potential

Abstract Several acutely acting antimigraine drugs, including sumatriptan and other second generation 5-HT1D receptor agonists, have the ability to constrict porcine carotid arteriovenous anastomoses as well as the human isolated coronary artery. These two experimental models seem to serve as indicators, respectively, for the therapeutic and coronary side-effect potential of the compounds. Using these two models, we have now investigated the effects of GMC2021 (3-[2-(dimethylanimo)ethyl]-5-[(trifluoromethyl)sulfonyl]oxy][1 H]indole oxalate, a close analogue of sumatriptan. GMC2021 (30, 100, 300 and 1000 μg · kg−1, i.v.) decreased the total carotid blood flow by exclusively decreasing arteriovenous anastomotic blood flow; capillary blood flow to the skin and ears was moderately increased. The mean ± S.E.M. dose of GMC2021 eliciting a 50% decrease (ED50) in the porcine carotid arteriovenous anastomotic blood flow was found to be 1.1 ± 0.3 μmol · kg−1 and the highest dose (1000 μg · kg−1) produced a 67 ± 4% reduction. The carotid haemodynamic effects of GMC2021 were reduced by the selective 5-HT1D receptor antagonist, GR127935 (N-[methoxy-3-(4-methyl-1-piperazinyl)phenyl]-2′-methyl-4′-(5-methyl-1,2,4-oxadiazol-3-yl)[1,1-biphenyl]-4-carbboxamide hydrochloride), which completely antagonizes porcine carotid haemodynamic responses to sumatriptan (ED50: 0.16 μmol · kg−1, i.v.). Compared to sumatriptan (pD2: 6.12 ± 0.15; Emax: 31.3 ± 12.3% of contractions to 100 mM K+), GMC2021 was less potent in constricting the human isolated coronary artery (pD2: 5.45 ± 0.2; Emax: 21.0 ± 4.8% of contractions to 100 mM K+). The above results suggest that GMC2021 constricts carotid arteriovenous anastomoses partly by a 5-HT1D receptor and partly by another, probably novel, receptor and that GMC2021 should be able to abort migraine headaches in patients, with perhaps a less propensity for coronary side effects

Effects of avitriptan, a new 5 HT(1B/1D) receptor agonist, in experimental models predictive of antimigraine activity and coronary side-effect potential

Abstract Several acutely acting antimigraine drugs, including ergotamine and sumatriptan, have the ability to constrict porcine arteriovenous anastomoses as well as the human isolated coronary artery. These two experimental models seem to serve as indicators, respectively, f