Nitric oxide (NO) modulation of PAF‐induced cardiopulmonary action: interaction between NO synthase and cyclo‐oxygenase‐2 pathways

Abstract

1 To further investigate into the mechanisms of PAF-induced cardiopulmonary actions, we examined the eects of the nitric oxide synthase (NOS) inhibitor L-N o -nitro-L-arginine (L-NNA), of the speci®c cyclooxygenase-2 (COX-2) inhibitor NS 398, and of the combined presence of both COX and NOS inhibitors on the PAF responses in the heart lung preparation of guinea-pig (HLP). 2 In HLPs perfused with homologous blood, dose-response curves for the haemodynamic and bronchial eects of PAF (1 ± 32 ng) were carried out in the absence or presence of L-NNA (200 mM). L-NNA caused an increase in the resting pulmonary arterial pressure (PAP) without aecting the other basal values, and strongly potentiated the bronchoconstriction and pulmonary hypertension elicited by PAF. An enhancement of the PAF-induced actions on right atrial pressure (RAP) and cardiac output (CO) was also observed. All the eects of L-NNA were antagonized by L-arginine (2 mM).3 The presence of L-NNA in the perfusing blood of HLPs failed to aect the pulmonary hypertensive and bronchoconstrictor responses induced by the thromboxane A 2 mimetic U46619 (0.05 ± 1.6 mg), 5-hydroxytryptamine (0.1 ± 1.6 mg), and histamine (0.1 ± 1.6 mg), thus suggesting that these PAF secondary mediators are not responsible for the hyper-responsiveness to PAF induced by L-NNA.4 Blocking COX-2 pathway with NS 398 (15 ± 30 mM) did not alter the cardiopulmonary resting variables. However, a reduction of the PAF-mediated pulmonary hypertension, but not of bronchoconstriction, was observed. When L-NNA was added to the perfusing medium of HLPs pretreated with NS 398 or with indomethacin (15 mM), the basal PAP values were enhanced. However, in the combined presence of COX and NOS inhibitors, only a slight increase in the hypertensive responses to the highest doses of PAF was observed, whereas the PAF mediated actions at bronchial and cardiac level were unaected. 5 This study indicates that (i) the cardiopulmonary actions induced by PAF are speci®cally modulated by endogenous NO through the NOS pathway, and (ii) COX-2 isoform is involved in the pulmonary hypertensive, but not bronchoconstrictor, eects of PAF. Furthermore, an interaction between PAF stimulated COX, particularly COX-2, and NOS pathways appears to take a functional role at both bronchial and cardiovascular level.

Effects of selective and non-selective COX inhibitors on antigen-induced release of prostanoid mediators and bronchoconstriction in the isolated perfused and ventilated guinea pig lung

“…COX-2 was constitutively expressed also in isolated guinea pig trachea (Nieri et al, 2006) and appeared to mediate the spontaneous tone in this preparation (Charette et al, 1995). Constitutively expressed COX-2 contributed also to the arachidonic acid-induced (Ermert et al, 1998a) and the PAFinduced (Fabi et al, 2001) vascular response in isolated rat lungs. COX-2 can also be induced in most cell types in the lung by a broad range of proinflammatory stimuli (Belvisi et al, 1997;Bradbury et al, 2002;Mitchell et al, 1994) Non-steroidal anti-inflammatory drugs The COX enzyme is an important pharmacological target.…”

Antisense versus proopiomelanocortin mRNA reduces vascular risk in a murine model of type-2 diabetes following stress exposure in early post-natal life

“…Differences were considered to be significant when P < 0.05. For details see our previous studies [8,9].…”

Candidate's Thesis: Platelet‐Activating Factor–Induced Hearing Loss: Mediated by Nitric Oxide?

“…Recent studies reported that PAF stimulates nitric oxide synthase (NOS) to release nitric oxide (NO) and that PAF actions are mediated by this endogenous NO in endotoxic shock, cardiopulmonary actions, microvascular permeability, and bowel injury in animal experiments. 24–28 NO is produced by a family of NOS, including neuronal NOS (nNOS, type 1), inducible NOS (iNOS, type 2), and endothelial NOS (eNOS, type 3). All three major isoforms of NOS have been demonstrated immunohistochemically in different cells of the organ of Corti and other parts of the auditory systems of guinea pigs.…”