Caroline Touvay

Effect of endothelin-1 on blood pressure and bronchopulmonary system of the guinea pig.

Summary The bronchopulmonary and pressor effects of endothelin-1 (ET-1), a newly described vasoconstrictor peptide produced by endothelial cells, were investigated in the guinea pig. Intravenous injection of ET-1 (1 nmol/kg) induced an increase in pulmonary inflation pressure (PIP) as well as an important and sustained increase in arterial blood pressure (BP). Pretreatment of these animals with propranolol (1 mg/kg i.v.), provoked a significant enhancement of the ET-1-induced increase in PIP, accompanied by a dramatic and significant decrease of BP. When administered by aerosol for 1 min, ET-1 (1, 5, or 10

A ligand-receptor fusion of growth hormone forms a dimer and is a potent long-acting agonist

mUg/ml) induced a dose-dependent increase in PIP that was maximal by 4–5 min, but no significant change of BP. Pretreatment of guinea pigs with propranolol (1 mg/kg), mepyramine (1mg/kg i.v.), nifedipine (50 mg/kg i.p.), or verapamil (0.3 mg/kg i.v.) did not inhibit the bronchopulmonary response evoked by aerosol administration of 10

Interference of BN 52021 (ginkgolide B) with the bronchopulmonary effects of PAF-acether in the guinea-pig

mUg/ml of ET-1. In contrast, pretreatment of the animals with indomethacin (10 mg/kg i.v.) or BN 52021 (10 mg/kg i.v.) significantly reduced the bronchopulmonary response of ET-1 given by aerosol. Injection of ET-1 (0.1, 0.3, and 1

Inhibition of antigen-induced lung anaphylaxis in the guinea-pig by BN 52021 a new specific paf-acether receptor antagonist isolated from Ginkgo biloba.

mUg) into isolated guinea pig lungs caused significant increases in PIP that were accompanied by the release of T

Bronchopulmonary and vascular effect of endothelin in the guinea-pig

B2 but not histamine. These results demonstrate that ET-1 induces bronchopulmonary alterations in the guinea pig that appear to be dissociated from the systemic vascular effects of the peptide.

Preclinical gastrointestinal prokinetic efficacy and endocrine effects of the ghrelin mimetic RM-131

Cytokine hormones have a short plasma half-life and require frequent administration. For example, growth hormone replacement involves daily injections. In common with other cytokines, the extracellular domain of the growth hormone receptor circulates as a binding protein, which naturally prolongs the biological half-life of growth hormone. Here we have studied the biological actions of a ligand-receptor fusion of growth hormone and the extracellular domain of its receptor. The genetically engineered ligand-receptor fusion protein was purified from mammalian cell culture. In rats, the ligand-receptor fusion had a 300-times reduced clearance as compared to native growth hormone, and a single injection promoted growth for 10 d, far exceeding the growth seen after administration of native growth hormone. The ligand-receptor fusion forms a reciprocal, head-to-tail dimer that provides a reservoir of inactive hormone similar to the natural reservoir of growth hormone and its binding protein. In conclusion, a ligand-receptor fusion of cytokine to its extracellular receptor generates a potent, long-acting agonist with exceptionally slow absorption and elimination. This approach could be easily applied to other cytokines.

Characterization of platelet activating factor (PAF)-acether-induced contractions of guinea-pig lung strips by selected inhibitors of arachidonic acid metabolism and by PAF-acether antagonists

The interaction between the ginkgolide BN 52021 and the effects of PAF-acether on the bronchopulmonary system of the guinea-pig was studied. In pentobarbitone or ethyl carbamate-anaesthetized animals, BN 52021 (1 mg/kg i.v. or 10 mg/kg p.o.) inhibited bronchoconstriction, the hematocrit increase and the accompanying thrombopenia and leukopenia induced by PAF-acether (33-100 ng/kg) and failed to block the bronchoconstriction produced by collagen, arachidonic acid and the tripeptide formyl-Met-Leu-Phe (FMLP). BN 52021, 3 mg/kg, reduced the bronchoconstriction induced by aerosolized PAF-acether. BN 52021, 300 microM, also inhibited the superoxide production by PAF-acether-stimulated alveolar macrophages and failed to reduce the same effects when triggered by FMLP (0.01-1 microM). BN 52021 blocked the formation of thromboxane-triggered by PAF-acether (100 ng) injected into perfused lung, under conditions where the effects of arachidonic acid where not modified. Finally, pretreatment of parenchyma lung strips with BN 52021 (100 microM) partially inhibited the contraction induced by PAF-acether (0.1 microM) and suppressed the accompanying release of thromboxane. BN 52021 is a selective antagonist of the effects of PAF-acether on the bronchopulmonary system and on circulating blood cells of the guinea-pig.

Involvement of a phosphoramidon-sensitive endopeptidase in the processing of big endothelin-1 in the guinea-pig

Paf-acether appears to be a potent mediator released in response to allergen exposure in sensitized animals and it could contribute to clinical manifestations of allergic asthma. In order to ascertain this assumption the inhibition of antigen-induced lung anaphylaxis in guinea-pig by BN 52021, a new highly specific paf-acether antagonist, was studied. Ovalbumin injected into passively sensitized guinea-pig induced a large bronchoconstriction which was accompanied by thrombocytopenia and leukopenia. Treatment of animals with BN 52021 i.v., five minutes before challenge, strongly (at the doses of 1 and 2 mg/kg) or totally (at 0.1 mg/kg) inhibited the bronchoconstriction and partially reduced the thrombocytopenia and leukopenia the thrombocytopenia occurring after challenge. These results confirm that paf-acether and platelets might play a key role in asthma. BN 52021 and other paf-acether antagonist could provide a new group of potent prophylactic anti-asthma drugs.

Phosphoramidon potentiates the endothelin-1-induced bronchopulmonary response in guinea-pigs.

1 Intra‐arterial injection of endothelin‐1 (ET‐1, 400 pmol; 1 μg) in guinea‐pig isolated perfused lungs, induced increases in pulmonary inflation pressure (PIP) and perfusion pressure (PPP), associated with oedema formation and thromboxane B2 (TxB2) release but not with the generation of sulphidopeptide leukotrienes or release of histamine. In contrast, aerosol administration of ET‐1 (3, 6, 10 μg ml−1, for 2 min) evoked a dose‐dependent increase in PIP, without significant changes in PPP, oedema formation or TxB2 release. 2 Addition of indomethacin (5 μm) or BW 755C (10 or 100 μm), but not nordihydroguaiaretic acid (NDGA, 50 μm) or FPL 55712 (10 μm), to the perfusion medium led to a significant inhibition of the increases in PIP and PPP, TxB2 release and oedema formation evoked by intra‐arterial injection of 400pmol ET‐1. In contrast, indomethacin (5 μm), BW 755C (100 μm) or FPL 55712 (10 μm), added to the perfusion medium 10 min prior to challenge, did not affect the increase in PIP induced by a 2‐min aerosol of a solution of ET‐1 10 μg ml−1. 3 In vivo aerosol administration of indomethacin (100 mg ml−1, for 20 min) to non‐anaesthetized guinea‐pigs, 15 min before lung removal, did not modify the bronchopulmonary response evoked in isolated perfused lungs by an aerosol of ET‐1 10 μg ml−1. However, under the same experimental conditions, indomethacin significantly inhibited TxB2 release evoked by aerosolized arachidonic acid (2 mg ml−1). 4 In conclusion, the present study shows that when injected by the intra‐arterial route, ET‐1 effects are mediated primarily via the generation of cyclo‐oxygenase metabolites of arachidonic acid, whereas when the aerosol route is used, the peptide appears to act on airway smooth muscle cells, through an indomethacin‐insensitive process which may involve some other, as yet unidentified, mediator(s).