The selective a2-adrenoceptor antagonist, RX78 1094, evoked a dose-related pressor response in the pithed rat preparation when administered in bolus doses by the intravenous route. This response was enhanced following depletion of endogenous amines by reserpine, and inhibited by the selective al-adrenoceptor antagonist, prazosin. Two other selective a2-adrenoceptor antagonists, Wy 26703 and Wy 26392, had no marked effect on the blood pressure of this preparation. Pretreatment of the preparation with Wy 26703 had no significant effect on the pressor response evoked by RX781094.It is concluded that RX78 1094 is an ocladrenoceptor agonist at similar doses to those at which it exhibits x2-adrenoceptor antagonist properties. The agonist activity exhibited by RX78 1094 is not a general property of all c2-adrenoceptor antagonists and should be considered when this compound is employed as an c2-adrenoceptor antagonist.

1Ro 31-6930 (0.001-0.3 MM), cromakalim (0.03-3.0OUM), salbutamol (0.001-0.3 pM) and theophylline (0.3-100pM) evoked dose-related reductions in guinea-pig spontaneous tracheal tone with IC,0 values of 0.044, 0.20, 0.021 and 21.OpM respectively. All four agents also relaxed tone supported by betahistine, carbachol, 5-hydroxytryptamine (5-HT), leukotriene D4 (LTD4), U46619 and prostaglandin D2 (PGD2). The order of potency of tracheal relaxants was always salbutamol > Ro 31-6930 > cromakalim > theophylline. 2 All four agents evoked dose-related reductions in 5-HT-and histamine-induced bronchoconstriction in pithed vagotomised guinea-pigs. The dose of Ro 31-6930 producing 50% inhibition of a 5-HT bronchoconstriction was 11.6 pgkg-' and the dose producing 50% inhibition of a histamine bronchoconstriction was 4.4pgkg-. Salbutamol was approximately 4-5 times more potent than Ro 31-6930 whilst cromakalim was approximately 10 times less potent than Ro 31-6930 as a bronchodilator. Theophylline was markedly less potent than any of the other agents. 3 Ro 31-6930, cromakalim, salbutamol and theophylline each protected conscious guinea-pigs from histamine-induced respiratory distress. Ro 31-6930 and salbutamol were each effective at oral doses of 1.0 and 3.Omgkg-1 whilst cromakalim was effective at oral doses of 3.0 and 10.0mgkg-'. Theophylline showed activity only at 300 mg kg-1 p.o. 4 Ro 31-6930 is a novel potassium channel opener which is a potent relaxant of guinea-pig tracheal smooth muscle in vitro and a bronchodilator in vivo.

Tumor necrosis factor (TNF) is an inflammatory cytokine produced by many cell types which may contribute to the pathophysiology of a variety of lung diseases. In this study we have used Ro 45-2081 (a soluble receptor composed of the human p55 TNF receptor and human heavy-chain immunoglobulin G) to explore the role of TNF in the acute inflammatory response in the rat lung to intravenous injection of Sephadex beads. The effects of Ro 45-2081 have also been compared with those of dexamethasone. At 24 and 72 h after Sephadex, there was a significant increase in the total number of leukocytes in bronchoalveolar lavage fluid (BALF). At 24 h, the number of neutrophils comprised around 50% of the total leukocyte number, decreasing to around 10% of total by 72 h. The eosinophil count was maintained at around 10% of the total leukocyte number. Pretreatment with either Ro 45-2081 [1 and 3 mg kg-1, intraperitoneally (i.p.)] or dexamethasone (0.1 and 0.3 mg kg-1, i.p.) inhibited the neutrophilia at 24 h after Sephadex, although Ro 45-2081 had no significant effect on total cell number. At 72 h after Sephadex, Ro 45-2081 (1 and 3 mg kg-1, i.p., daily) significantly reduced the neutrophil influx into BALF but had no inhibitory effect on eosinophil number. In contrast, dexamethasone (0.1 and 0.3 mg kg-1, i.p., daily) virtually abolished the infiltration of neutrophils and eosinophils into BALF. The lack of effect of Ro 45-2081 on eosinophil infiltration into the rat lung and the inhibition caused by dexamethasone suggest that factors other than TNF are involved in this part of the inflammatory response induced by Sephadex. However, the inhibitory effects of Ro 45-2081 show that TNF may play an important role in the recruitment of neutrophils into the lungs of Sephadex-treated rats.

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1 The cardiovascular effects of the opioid mixed agonist-antagonist, meptazinol, and the opioid antagonist, naloxone, have been evaluated in conscious rats, anaesthetized rats and anaesthetized cats following the induction of haemorrhagic shock. 2 The mean arterial pressure of conscious rats decreased by 17-29 mmHg following a haemorrhage of 20% of blood volume. Meptazinol (17mg kg-1, i.m.) administered after haemorrhage evoked a rapid and sustained increase in mean arterial pressure to pre-haemorrhage levels. Naloxone (10 mg kg-', i.v.) also increased mean arterial pressure to a level significantly higher than posthaemorrhage values. 3 Neither haemorrhage nor subsequent drug treatments evoked significant changes in the heart rates of conscious rats. 4 In anaesthetized rats, 20% haemorrhage evoked decreases in mean arterial pressure, heart rate and cardiac output. Blood flow to the heart, skin, skeletal muscle, kidneys, spleen and liver (arterial) was decreased. Meptazinol and naloxone increased blood pressure and total peripheral resistance, but did not significantly alter heart rate or cardiac output. Hepatic arterial flow decreased further in both drug and vehicle treated groups. In addition meptazinol slightly reduced skeletal muscle flow. 5 In anaesthetized cats 40% haemorrhage decreased mean arterial pressure by 46 ± 3 mmHg. An intravenous infusion of either meptazinol or naloxone (cumulative 2 mg kg-', i.v.) partially restored blood pressure. 6 In experimental animal models of haemorrhagic shock, meptazinol has a similar cardiovascular profile to naloxone. The established analgesic activity of meptazinol may confer an advantage in some shock states.