Inhibition of substance P-induced microvascular leakage by inhaled methoxamine in rat airways.
1. The effect of the inhaled alpha-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 micrograms kg-1 (58 +/- 9 vs 96 +/- 9 ng EB mg-1 tissue after vehicle, P < 0.001) and 100 micrograms kg-1 (69 +/- 11 vs 137 +/- 26 ng EB mg-1 tissue after vehicle, P < 0.01). Inhaled MTX by itself (100 micrograms 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 micrograms 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 microg kg-1), a marked EB extravasation was found in the airways. This was abrogated by pretreatment with prazosin (100 microg 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.
Larrazet
F
F
Laboratoire de physiologie respiratoire, UFR Cochin Port-Royal, Paris, France.
Chauveau
M
M
Weber
S
S
Lockhart
A
A
Frossard
N
N
D000280:Administration, Inhalation; D000403:Airway Resistance / Q000187:drug effects; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D001798:Blood Proteins / Q000378:metabolism; D002199:Capillary Permeability / Q000187:drug effects*; D005070:Evans Blue; D006339:Heart Rate / Q000187:drug effects; D008729:Methoxamine / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012137:Respiratory System / Q000187:drug effects / Q000378:metabolism; D013373:Substance P / Q000037:antagonists & inhibitors* / Q000494:pharmacology
D001798:Blood Proteins; D013373:Substance P; D005070:Evans Blue; D008729:Methoxamine