1 Vasorelaxant properties of three nitric oxide (NO) donor drugs (glyceryl trinitrate, sodium nitroprusside and spermine NONOate) in mouse aorta (phenylephrine pre-contracted) were compared with those of endothelium-derived NO (generated with acetylcholine), NO free radical (NO´; NO gas solution) and nitroxyl ion (NO 7 ; from Angeli's salt). 2 The soluble guanylate cyclase inhibitor, ODQ (1H-(1,2,4-)oxadiazolo(4,3-a)-quinoxalin-1-one; 0.3, 1 and 10 mM), concentration-dependently inhibited responses to all agents. 10 mM ODQ abolished responses to acetylcholine and glyceryl trinitrate, almost abolished responses to sodium nitroprusside but produced parallel shifts (to a higher concentration range; no depression in maxima) in the concentration-response curves for NO gas solution, Angeli's salt and spermine NONOate. 3 The NO´scavengers, carboxy-PTIO, (2-(4-carboxyphenyl)-4,4,5,5-tetramethyl-imidazoline-1-oxyl-3-oxide; 100 mM) and hydroxocobalamin (100 mM), both inhibited responses to NO gas solution and to the three NO donor drugs, but not Angeli's salt. Hydroxocobalamin, but not carboxy-PTIO, also inhibited responses to acetylcholine. 4 The NO 7 inhibitor, L-cysteine (3 mM), inhibited responses to Angeli's salt, acetylcholine and the three NO donor drugs, but not NO gas solution. 5 The data suggest that, in mouse aorta, responses to all three NO donors involve (i) activation of soluble guanylate cyclase, but to di ering degrees and (ii) generation of both NO´and NO 7 . Glyceryl trinitrate and sodium nitroprusside, which generate NO following tissue bioactivation, have pro®les resembling the pro®le of endothelium-derived NO more than that of exogenous NO. Spermine NONOate, which generates NO spontaneously outside the tissue, was the drug that most closely resembled (but was not identical to) exogenous NO.

Vegf-B may have a role in the development of chronic hypoxic pulmonary hypertension in mice by contributing to pulmonary vascular remodelling. If so, the effect of Vegf-B appears to be different from that of Vegf-A which is reported to protect against, rather than contribute to, hypoxia-induced pulmonary vascular remodelling.

1 Vasorelaxant responses to the nitric oxide (NO) donor, FK409 ((+)-(E)-4-ethyl-2-[(E)-hydroxyimino]-5-nitro-3-hexenamide), were evaluated on precontracted isolated ring preparations of main pulmonary artery and intralobar pulmonary artery from rats. 2 On main pulmonary artery FK409 fully reversed the precontractions. Responses were inhibited by methylene blue but were independent of the endothelium. The potency (7log EC 50 ) of FK409 was the same on preparations contracted with noradrenaline (7.62) or the thromboxane-mimetic, U44619 (7.63). 3 On intralobar pulmonary artery FK409 caused only 80% reversal of the precontraction and was 2 fold less potent than on main pulmonary artery. These di erences in maximum response and potency between main and intralobar arteries are in keeping with previous ®ndings with other NO donors. 4 Pulmonary hypertension was induced in rats by chronic exposure to hypoxia (10% O 2 ) for 1 or 4 weeks. Main pulmonary arteries from 1 week hypoxic rats had inherent tone and showed spontaneous contractile activity. In these arteries FK409 reversed not only the precontraction induced by noradrenaline but also the inherent tone. However, FK409 was 17 fold less potent than in control arteries, re¯ecting previous ®ndings with other NO donors. Main pulmonary arteries from 4 week hypoxic rats had minimal inherent tone and were quiescent and FK409 was 4.5 fold less potent than in control arteries. In intralobar pulmonary arteries from 4 week hypoxic rats FK409 was 12 fold less potent than in controls. 5 Treatment of arteries with either (a) in vitro hypoxic conditions (PO 2 of solution in organ bath 510 mmHg) or (b) superoxide dismutase (SOD; 150 u ml 71 ) together with catalase (1200 u ml 71 ) signi®cantly increased the potency of FK409 in preparations from hypoxic rats but had no e ect on the potency in control preparations. Neither SOD nor catalase, alone, nor the nitric oxide synthase inhibitor, N G -nitro-L-arginine methyl ester, had any e ect on the potency of FK409 in preparations from control or hypoxic rats. 6 It is concluded that the reduction in potency of FK409 seen in pulmonary arteries from rats with chronic hypoxic pulmonary hypertension may be due in part to the presence of one or more reactive oxygen species (either hydroxyl or superoxide plus hydrogen peroxide).

The aim was to determine whether uptake of 5-hydroxytryptamine (5-HT) by the 5-HT transporter (SERT) modulates contractile responses to 5-HT in rat pulmonary arteries and whether this modulation is altered by exposure of rats to chronic hypoxia (10% oxygen; 8 h/day; 5 days). The effects of the SERT inhibitor, citalopram (100 nM), on contractions to 5-HT were determined in isolated ring preparations of pulmonary artery (intralobar and main) and compared with data obtained in systemic arteries. In intralobar pulmonary arteries citalopram produced a potentiation (viz. an increase in potency, pEC(50)) of 5-HT. The potentiation was endothelium-dependent in preparations from normoxic rats but endothelium-independent in preparations from hypoxic rats. In main pulmonary artery endothelium-independent potentiation was seen in preparations from hypoxic rats but no potentiation occurred in preparations from normoxic rats. In systemic arteries, citalopram caused endothelium-independent potentiation in aorta but no potentiation in mesenteric arteries; there were no differences between hypoxic and normoxic rats. It is concluded that SERT can influence the concentration of 5-HT in the vicinity of the vasoconstrictor receptors in pulmonary arteries. The data suggest that in pulmonary arteries from hypoxic rats, unlike normoxic rats, the SERT responsible for this effect is not in the endothelium and, hence, is probably in the smooth muscle. The data are compatible with reports that, in the pulmonary circulation, hypoxia induces/up-regulates SERT, and hence increases 5-HT uptake, in vascular smooth muscle. The findings may have implications in relation to the suggested use of SERT inhibitors in the treatment of pulmonary hypertension.

1 On rat isolated pulmonary arteries, vasorelaxation by S-nitrosocaptopril (SNOcap) was compared with S-nitrosoglutathione (GSNO) and nitroprusside, and inhibition by SNOcap of contractions to angiotensin I was compared with the angiotensin converting enzyme (ACE) inhibitor, captopril. 2 SNOcap was equipotent as a vasorelaxant on main (i.d. 2 ± 3 mm) and intralobar (i.d. 600 mm) pulmonary arteries (pIC 50 values: 5.00 and 4.85, respectively). Vasorelaxant responses reached equilibrium rapidly (2 ± 3 min). 3 Pulmonary vasorelaxant responses to SNOcap, like GSNO, were (i) partially inhibited by the soluble guanylate cyclase inhibitor, ODQ (1H-(1,2,4) oxadiazolo(4,3-a)-quinoxalin-1-one; 3 mM) whereas responses to nitroprusside were abolished and (ii) potentiated by hydroxocobalamin (HCOB; NO´free radical scavenger; 100 mM) whereas responses to nitroprusside were inhibited. 4 The relative potencies for pulmonary vasorelaxation compared with inhibition of platelet aggregation were: SNOcap 7 : 1; GSNO 25 : 1; nitroprusside 42000 : 1. 5 SNOcap, like captopril, concentration-dependently and time-dependently increased the EC 50 for angiotensin I but not angiotensin II. The dependence on incubation time was independent of the presence of tissue but diered for SNOcap and captopril. This dierence re¯ected the slow dissociation of SNOcap and instability of captopril, and precluded a valid comparison of the potency of the two drugs. After prolonged incubation (55.6 h) SNOcap was more eective than captopril. 6 Thus, in pulmonary arteries SNOcap (i) possesses NO donor properties characteristic of Snitrosothiols but dierent from nitroprusside and (ii) inhibits ACE at least as eectively as captopril. These properties suggest that SNOcap could be valuable in the treatment of pulmonary hypertension.