1 The 5-hydroxytryptamine (5-HT) receptors mediating contraction of human isolated pulmonary artery rings were investigated. Responses to the agonists 5-carboximidotryptamine (5-CT, non-selective 5-HT, agonist), sumatriptan (5-HTD-like receptor agonist), 5-HT and 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT, 5-HTA receptor agonist) were studied. Responses to 5-HT and sumatriptan in the presence of the antagonists, methiothepin (non-selective 5-HT,+2-receptor antagonist), ketanserin (5-HT2A receptor antagonist) and the novel antagonist, GR55562 (5-HTID receptor antagonist) were also studied. 2 All agonists contracted human pulmonary artery ring preparations in the following order of potency 5-CT > 5-HT = sumatriptan > 8-OH-DPAT. Maximum responses to 5-HT, 5-CT and sumatriptan were not significantly different. 3 Methiothepin 1 nM and 10 nM, but not 0.1 nM reduced the maximum contractile responses to 5-HT but did not alter tissue sensitivity to 5-HT. Methiothepin 0.1 nM, 1 nM and 10 nM had a similar effect on responses to sumatriptan.4 The 5-HT2A receptor antagonist ketanserin (10 nM, 100 nM and 1 gM) also reduced the maximum contractile response to both 5-HT and sumatriptan without affecting tissue sensitivity to these agonists. 5 The novel 5-HTlD receptor antagonist, GR55562, inhibited responses to 5-HT and sumatriptan in a true competitive fashion. 6 The results suggest that the human pulmonary artery has a functional population of 5-HTID-like receptors which are involved in the contractile response to 5-HT.

1. We have reported that the renin-angiotensin system is activated in acute asthma, and also by high-dose nebulized beta 2-agonists. The contribution of other possible stimuli such as hypoxia is unknown. The present study examined the effect of hypoxia alone and also combined with beta 2-agonists on the activity of the renin-angiotensin system. 2. In a double-blind crossover study, eight healthy subjects were randomized to inhale a hypoxic (FiO2 = 12%) or normoxic mixture for a period of 30 min, with either nebulized salbutamol (5 mg) or placebo administered into the circuit after 10 min. Plasma renin, angiotensin II and serum angiotensin-converting enzyme were measured at baseline and at intervals up to 2 h. Pulse rate and oxygen saturation were monitored continuously throughout the study. 3. After hypoxia alone, there was no change in the levels of plasma renin or angiotensin II. When salbutamol was added to the hypoxic mixture, there was a significant rise in plasma renin and angiotensin II [mean (SEM) maximal increase in angiotensin II of 5.6 (2.9) pg/ml and renin of 15.5 (6.3) mu-units/ml at 60 min, P < 0.05 compared with normoxia]. When salbutamol was administered in the normoxic mixture, plasma renin and angiotensin II also increased but this effect was similar to the effect of salbutamol in the hypoxic mixture. Serum angiotensin-converting enzyme levels were unaffected by hypoxia or salbutamol. 4. We conclude from these results that there is activation of the renin-angiotensin system in healthy subjects by salbutamol, but not hypoxia. (ABSTRACT TRUNCATED AT 250 WORDS)

1 This study examined the activity and mechanisms of action of urodilatin in bovine bronchi. For comparison, the ability of urodilatin to evoke bronchodilatation or protect against subsequent challenge was compared to that of the closely related peptide a-human atrial natriuretic peptide (ANP). 2 Urodilatin reversed methacholine-evoked contraction in a concentration-dependent manner in bovine bronchi. In the absence of any attempt to prevent degradation by neutral endopeptidases, urodilatin was more potent than ANP in this tissue. 3 The bronchodilator properties of urodilatin were significantly augmented by the neutral endopeptidase inhibitor, phsophoramidon (3.68 x 10-i M). This provides evidence for at least partial degradation of urodilatin by neutral endopeptidases. With phosphoramidon present, urodilatin and ANP were equipotent. 4 In the presence of phosphoramidon (3.68 x 10-i M), pre-incubation with urodilatin (10-6 M) had a protective effect against subsequent methacholine-induced contraction. This action of urodilatin was quantitatively similar to that of ANP in the presence of this endopeptidase inhibitor. 5 The actions of urodilatin appear to involve ATP-sensitive K+ channels since tolbutamide (10-6 10-5 M) significantly attenuated the relaxations induced by this peptide. 6 Small conductance Ca2+-activated K+ channels seem likewise to be implicated in the actions of urodilatin since blockade of these channels with apamin (10-1-10-6 M) resulted in a marked attenuation of urodilatin-evoked responses. 7 The presence of charybdotoxin (10-9 M-10-1i) had no significant effect on subsequent responses to urodilatin suggesting that large conductance Ca2+-activated K+ channels are not involved in the relaxations evoked by this peptide.8 In the presence of phosphoramidon (3.68 x 10-5 M), urodilatin (10-6 M) evoked elevation of cyclic GMP levels within bovine bronchial tissue. Levels of cyclic GMP increased significantly within 5-10 s in response to this peptide and preceded the initiation of relaxant responses. Maximum increases in cyclic GMP levels were reached within 5 min; the time required for maximal relaxation evoked by this peptide. 9 In conclusion, urodilatin, like ANP reversed and protected against, subsequent methacholine-induced bronchoconstriction; an action enhanced by the presence of phosphoramidon (3.68 x 1O-M). Associated with these actions of urodilatin was a rise in cyclic GMP levels as well as the opening of ATP-sensitive K+ and small conductance Ca2+-activated K+ channels.