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Inhibition of substance P‐induced microvascular leakage by inhaled methoxamine in rat airways
Author(s) -
Larrazet Fabrice,
Chauveau Michel,
Weber Simon,
Lockhart Alain,
Frossard Nelly
Publication year - 1994
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1994.tb17039.x
Subject(s) - methoxamine , pharmacology , medicine , chemistry , receptor , agonist
1 The effect of the inhaled α‐adrenoceptor agonist, methoxamine (MTX), was studied on experimental airway oedema induced by injection of substance P (SP) in the rat. Sprague‐Dawley rats (300–350 g) were anaesthetized with sodium thiopentone, tracheotomized and artificially ventilated. 2 MTX or its vehicle was administered by inhalation. Airway resistance and blood pressure were monitored continuously. Evans Blue dye (EB, 20 mg kg −1 ) was injected through a jugular catheter 1 min before SP (14.8 nmol kg −1 ). Airways were dissected out, weighed and placed in formamide for EB extraction and determination by spectrophotometry. 3 EB extravasation induced by SP was significantly reduced in distal intraparenchymal bronchi by inhaled MTX at doses of 50 μg kg −1 (58 ± 9 vs 96 ± 9 ng EB mg −1 tissue after vehicle, P < 0.001) and 100 μg kg −1 (69 ± 11 vs 137 ± 26 ng EB mg −1 tissue after vehicle, P < 0.01). Inhaled MTX by itself (100 μg kg −1 ) increased blood pressure: 172 ± 6 vs 132 ± 10 mmHg baseline ( P < 0.02), but neither induced extravasation nor increased airway resistance. 4 In another set of experiments without SP, MTX was administered intravenously 1 min after EB. At 100 μg kg −1 , i.v. MTX increased blood pressure to a similar extent as inhaled MTX (180 vs 147 mmHg baseline, P < 0.01), increased airway resistance and caused leakage of plasma proteins in distal intraparenchymal bronchi (79 ± 7 vs 47 ± 1 ng EB mg −1 tissue, P < 0.02). 5 Similarly, after sequential i.v. injections of doubling doses of MTX (50–800 μg kg −1 ), a marked EB extravasation was found in the airways. This was abrogated by pretreatment with prazosin (100 μg kg −1 ) but not with propranolol (2 mg kg −1 ). 6 These results suggest that microvascular leakage and airway oedema induced by i.v. MTX may be linked to an increase in pressure in the pulmonary circulation, resulting from vasoconstriction of the pulmonary vasculature and acute cardiac dysfunction due to systemic hypertension. 7 Our results with inhaled MTX show that direct deposition of MTX at the bronchial vasculature induces a reduction in SP‐induced microvascular leakage in rat airways and that inhaled MTX does not share the untoward effect of i.v. MTX inducing airway oedema.