Vascular responses to leukotriene B4, C4 and D4 following FPL 55712, indomethacin, saralasin, phentolamine and verapamil in the conscious rat

Battistini

Sirois

1991

1The aim of the present experiments was to study the possible involvement of known bronchoconstrictor substances in mediating the myotropic action of endothelin-l (ET-1, human-porcine endothelin) in guinea-pig isolated airways. 2 ET-1 (1-100nm) caused a dose-dependent contraction of guinea-pig trachea, upper bronchus and parenchyma. The contractions developed slowly, reaching maximal values 4-6 min after addition of the peptide. 3 The contractile action of ET-1 was significantly attenuated by indomethacin (10uM), a cyclo-oxygenase blocker, BM 13505 (5,UM), a thromboxane receptor antagonist, FPL 55712 (19 pM) and YM 16638 (1pM), antagonists of the sulphidopeptide leukotrienes, BN 52021 (10pM) and WEB 2086 (1 pM), plateletactivating factor receptor antagonists in all three tissue preparations studied.4 Pretreatment of the airway tissues with compound U 75302 (3 guM), a selective leukotriene B4 receptor antagonist, or with a mixture of antagonists containing methysergide (0.75,UM), phentolamine (0.4UM), propranolol (13juM), atropine (0.4 pM) and diphenhydramine (0.45 pM) did not modify the myotropic action of ET-1. 5 ET-1, 10 and lOOnM induced three, and nine fold increases in thromboxane A2 release from lung parenchymal strips. 6 ET-1-induced thromboxane A2 release was completely abolished by indomethacin, and was significantly attenuated by BN 52021, WEB 2086 and FPL 55712. Neither BM 13505 nor YM 16638 exerted a significant effect on thromboxane release. 7 The present findings show that contraction of guinea-pig airway smooth muscle by ET-1 is mediated, in part, by the release of thromboxane A2, sulphidopeptide leukotrienes and platelet-activating factor, and suggest that the increased thromboxane A2 release following ET-1 is partly a consequence of enhanced synthesis of sulphidopeptide leukotrienes and platelet-activating factor.

Section: Resultsmentioning

confidence: 99%

Pharmacological modulation of endothelin‐induced contraction of guinea‐pig isolated airways and thromboxane release

Battistini

Sirois

1991

“…The experiments were performed on conscious, chronically catheterized male Wistar rats weighing 225-290 g. The animals were kept in individual metabolic cages and were prepared as described previously (Filep et al, 1987 (Rawson, 1943).…”

Section: Methodsmentioning

confidence: 99%

Enhancement by endothelin‐1 of microvascular permeability via the activation of ET_A receptors

Sirois

Földes-Filep

et al. 1993

Self Cite

1 The objective of the present experiments was to assess the involvement of endothelin-A (ETA) receptors in mediating the effects of endothelin-1 on microvascular permeability in conscious rats.2 Bolus injection of endothelin-1 (0.1 and 1 nmol kg-', i.v.) resulted in a dose-dependent prolonged pressor effect preceded by a transient depressor response. These changes were accompanied by a dose-dependent loss of plasma volume. Endothelin-1 (1 nmol kg-') enhanced the vascular permeability of the upper and lower bronchi, kidney, stomach, duodenum and spleen (up to 270%) as measured by the extravasation of Evans blue dye. 3 Pretreatment of the animals with the selective ETA receptor antagonist, BQ-123 (1 mg kg-1, i.v.) significantly blunted the pressor response to endothelin-1 without affecting the depressor response.BQ-123 inhibited by 87% the endothelin-l (1 nmol kg-')-induced plasma volume loss. BQ-123 markedly attenuated protein extravasation elicited by endothelin-l in the upper and lower bronchi and kidney, whereas it completely inhibited the permeability effect of endothelin-l in the stomach and duodenum. BQ-123 by itself had no significant effect on the parameters studied. 5 The present findings suggest that endothelin-1 enhances microvascular permeability, in part, via the activation of ETA receptors.

“…Constant, Quebec, Canada). The animals were housed in individual metabolic cages'and were prepared as described previously (Filep et al, 1987). Briefly, under anaesthesia (ketamine, 75 mg kg' and sodium pentobarbitone, 15 mg kg-') catheters were implanted into the abdominal aorta and vena cava through the central tail artery and left femoral vein, respectively.…”

Section: Methodsmentioning

confidence: 99%

Modulation by nitric oxide of platelet‐activating factor‐induced albumin extravasation in the conscious rat

Földes-Filep

1993

Self Cite

Canada HIT 2M41 The objective of this study was to assess whether or not endogenous nitric oxide (NO) could mediate the hypotensive response to platelet-activating factor (PAF) and modulate PAF-induced microvascular albumin leakage in the conscious rat. 2 PAF (0.19 and 1.9 nmol kg-', i.v.) evoked dose-dependent hypotension and significantly enhanced albumin extravasation in the large airways, pancreas, stomach and duodenum 15 min after its administration. Inhibition of NO synthesis by N0-nitro-L-arginine methyl ester (L-NAME, 0.125-2 mg kg-', i.v.) produced marked dose-dependent increases in albumin accumulation (up to 290%) in large airways, liver, spleen, pancreas, kidney, stomach and duodenum as measured by the extravasation of Evans blue dye. L-NAME (2mg kg-') treatment markedly potentiated PAF (1.9 nmol kg-')-induced albumin extravasation in these tissues, whereas it did not modify the hypotensive response to PAF.3 Maintenance of mean arterial blood pressure at the level observed following 2 mg kg-' L-NAME by infusion of noradrenaline (620-790 ng kg' min-') neither affected significantly albumin extravasation nor potentiated the permeability effect of PAF in the vascular beds studied with the exception of large airways, where noradrenaline mimicked the effects of L-NAME. 4 These results indicate that inhibition of endogenous NO formation leads to an increase in albumin extravasation and to potentiation of the vascular permeability effect of PAF, whereas the hypotensive action of PAF seems to be independent of NO formation in the conscious rat. These data suggest an important role for NO in the regulation of albumin extravasation.