INHIBITION OF SUBSTANCE-P-INDUCED MICROVASCULAR LEAKAGE BY INHALED METHOXAMINE IN RAT AIRWAYS

1 The effect of the inhaled alpha-adrenoceptor agonist, methoxamine (M TX), was studied on experimental airway oedema induced by injection of substance P (SP) in the rat. Sprague-Dawley rats (300-350 g) were ana esthetized with sodium thiopentone, tracheotomized and artificially ve ntilated. 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 b efore SP (14.8 nmol kg(-1)). Airways were dissected out, weighed and p laced in formamide for EB extraction and determination by spectrophoto metry. 3 EB extravasation induced by SP was significantly reduced in d istal intraparenchymal bronchi by inhaled MTX at doses of 50 mu g kg(- 1) (58 +/- 9 vs 96 +/- 9 ng EB mg(-1) tissue after vehicle, P< 0.001) and 100 mu g kg(-1) (69 +/- 11 vs 137 +/- 26 ng EB mg(-1) tissue after vehicle, P<0.01). Inhaled MTX by itself (100 mu g kg(-1)) increased b lood pressure: 172 +/- 6 vs 132 +/- 10 mmHg baseline (P<0.02), but nei ther induced extravasation nor increased airway resistance. 4 In anoth er set of experiments without SP, MTX was administered intravenously 1 min after EB. At 100 mu g kg(-1), i.v. MTX increased blood pressure t o a similar extent as inhaled MTX (180 vs 147 mmHg baseline, P<0.01), increased airway resistance and caused leakage of plasma proteins in d istal intraparenchymal bronchi (79 +/- 7 vs 47 +/- 1 ng EB mg(-1) tiss ue, P<0.02). 5 Similarly, after sequential i.v. injections of doubling doses of MTX (50-800 mu g kg(-1)), a marked EB extravasation was foun d in the airways. This was abrogated by pretreatment with prazosin (10 0 mu g 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 circulat ion, 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 v asculature 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.