Involvement of nitric oxide and eicosanoids in platelet‐activating factor‐induced haemodynamic and haematological effects in dogs

Abstract

1 Platelet-activating factor (PAF) is a phospholipid mediator with potent cardiovascular and haematological actions. But its mechanisms of action in vivo have not been fully elucidated, probably due to difficulties arising from previous findings that the effects of PAF are largely mediated by the release of a variety of other autacoids. In the present study, the roles of nitric oxide and eicosanoids in the effects of PAF (0.01 -0.25 pg kg-1 i.v.) on systemic and pulmonary vasculatures and circulating blood cell count were pharmacologically evaluated in anaesthetized dogs. 2 Higher doses of PAF (>0.1 yg kg-1) produced a biphasic systemic hypotension. The first hypotension seen 30 s after the injection was accompanied by a decrease in systemic vascular resistance, thrombocytopenia and leukopenia, while the second hypotension seen 1-2 min after PAF was accompanied by a marked rise in pulmonary vascular resistance and decreases in aortic blood flow and cardiac contractility. Lower doses of PAF (0.01-0.05 Mg kg-') caused only the first responses in a dosedependent manner. 3 Pretreatment with indomethacin inhibited the second responses to PAF without affecting the first responses. The thromboxane A2/prostaglandin H2 (TP)-receptor antagonist vapiprost blocked the PAFinduced rise in pulmonary vascular resistance. AA-861, a 5-lipoxygenase inhibitor, attenuated the PAFinduced cardiac depression. The nitric oxide synthase inhibitor NG-nitro-L-arginine methyl ester inhibited the PAF-induced early decrease in systemic vascular resistance. 4 All observed changes in haemodynamics and blood cell count after PAF were almost abolished by TCV-309, a PAF-receptor antagonist. 5 Reproducible hypotension and thrombocytopenia produced by a lower dose of PAF (0.05 Mg kg-1) were respectively attenuated and potentiated by pretreatment with NG-nitro-L-arginine, another nitric oxide synthase inhibitor. Administration of L-arginine reversed the effects of the nitric oxide synthase inhibitor. 6 These results indicate that PAF-receptor-mediated production of not only eicosanoids but also nitric oxide may contribute to the cardiovascular and haematological responses to PAF in the dog.

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

“…Pretreatment with L-NAME did not aect PAF-dependent pulmonary hypertension in pigs (Albertini & Clement, 1994) and yielded controversial results in dogs. Indeed, in the latter species, PAF-induced pulmonary hypertension has been shown to be potentiated by L-NAME in a recent work of Wang et al (1998), whereas it was unaected by the same NOS inhibitor in previous experiments by Noguchi et al (1996). In the latter work, however, an increase in the baseline PAP value after L-NAME was observed.…”

“…In rats, endothelially released NO appeared to contribute to the vasodilator action of PAF in in vitro preparations (Moritoki et al, 1992;Kamata et al, 1996), but not to the Paf-induced systemic hypotension in in vivo experiments (Yoshikawa et al, 1997). Conversely, a contribution of NO to the systemic hypotension induced by PAF has been demonstrated in dogs in vivo, but with opposite results concerning the involvement of NO in pulmonary hypertension (Noguchi et al, 1996;Wang et al, 1998). Therefore, the ®rst aim of our work was to examine the role of endogenous NO on PAF-induced cardiopulmonary actions in the blood-perfused heart-lung preparation of guinea-pig (HLP), which may be considered an intermediate situation between in vitro and in vivo experimental models, and makes it possible to simultaneously assess bronchial, pulmonary vascular and cardiac parameters.…”

Pentadecapeptide BPC157 reduces bleeding and thrombocytopenia after amputation in rats treated with heparin, warfarin, L-NAME and L-arginine

“…Recently, we demonstrated the effect of BPC 157 against bleeding/thrombocytopenia after amputation, with or without anticoagulant and aspirin administration and abdominal aorta anastomotic site-thrombosis [1,2]. Thus, as a proper extension to the disturbed NO-system in hemostasis [3][4][5][6][7][8][9], the present work showed that L-NAME-induced thrombocytopenia and L-arginine-induced increased hemorrhage. These were counteracted by BPC 157, indicating the modulatory and balancing role of BPC 157 with rescued NO-hemostatic mechanisms.…”

“…For instance, counteraction of both the L-arginine-induced disturbance and L-NAME-induced disturbance was seen, while maintaining blood pressure against both L-arginine (hypotension) and L-NAME (hypertension) (note, BPC 157 by itself does not affect basal blood pressure values [25] and likewise, BPC 157 by itself does not affect basal coagulation/platelets values [1]). Thus, this analogy might be the principal advantage for this and previous studies [14,15,[18][19][20][21][22][23][24][25][26], with a challenge in methodology and in general, since in other studies (not related to this model) L-NAME-thrombocytopenia antagonization was not attempted [3][4][5][6][7][8][9]32], nor were L-arginine and L-NAME simultaneously investigated. Furthermore, we could argue that with the prolonged bleeding time, specifically disturbed coagulation factors, with heparin (less) and warfarin (more), would affect BPC 157, L-arginine and L-NAME.…”

“…NO is an endogenously produced vasodilator and is largely implicated in hemostatic mechanisms [3][4][5][6][7][8][9] while, in tail amputation and heparin-/warfarin-administration models, both the NOsynthase (NOS)-blocker, L-NAME (thought to have a prothrombotic effect) [3] and NOS-substrate, L-arginine [presented with an antithrombotic effect) [3] were little investigated. The simultaneous counteraction of these two NO-mediated opposite effects in vivo has never been addressed.…”