BACKGROUND AND PURPOSEUnder conditions of increased oxidative stress, such as pre-eclampsia and diabetes, overstimulation of PARP leads to endothelial dysfunction. Inhibition of PARP has been demonstrated to reverse the vascular dysfunction associated with diabetes in vivo. The present study was carried out to investigate the role of PARP in mediating the endothelial dysfunction associated with pre-eclampsia. EXPERIMENTAL APPROACHUteroplacental perfusion was surgically reduced in pregnant rats to produce the reduced uterine perfusion pressure (RUPP) rat model of pre-eclampsia and the PARP inhibitor, PJ34, was administered either before or after surgery. Mean arterial BP and vascular function were measured in normal pregnant (NP) and both control and PJ34-treated RUPP rats. Mesenteric vessels from NP rats were incubated with either 3% RUPP or NP plasma alone or in combination with PJ34. Finally, immunohistochemical staining was carried out to measure nitrotyrosine (byproduct of peroxynitrite) immunoreactivity. KEY RESULTSRUPP rats were characterized by hypertension, fetal growth restriction and endothelial dysfunction when compared with NP rats. PJ34 administered in vivo before, but not after, surgery prevented the development of both endothelial dysfunction and hypertension. RUPP plasma-induced impaired vasorelaxation was prevented following co-incubation with PJ34 in vitro. Furthermore, the protective effect of PARP inhibition in vivo was accompanied by a reduction in nitrotyrosine immunoreactivity. CONCLUSIONS AND IMPLICATIONSPJ34 prevented the development of both endothelial dysfunction and hypertension and reduced vascular nitrotyrosine immunoreactivity, thus suggesting a role for oxidative-nitrosative stress/PARP activation in the aberration in both vascular and haemodynamic function in this rat model of pre-eclampsia. Abbreviations3% NPP, 3% normal pregnant plasma; 3% RP, 3% RUPP plasma; AOI, area of interest; BK, bradykinin; KPSS, potassium physiological salt solution; MABP, mean arterial blood pressure; NP, normal pregnant; PJ34, N-(6-oxo-5,6-dihydrophenanthridin-2-yl)-N,N-dimethylacetamide.HCl; PJ34-Post, PJ34 post-surgery; PJ35-Pre, PJ34 pre-surgery; PSS, physiological salt solution; Rmax, maximal relaxation; ROS, reactive oxygen species; RUPP, reduced uterine perfusion pressure; U46619, 9,11-dideoxy-11a,9a-epoxymethanoprostaglandin F2a

These results demonstrate for the first time that when given prior to ischaemia ET-1 mediates its anti-arrhythmic effects, at least in part, via cardiac mast cell degranulation.

Cannabidiol (CBD) has been shown to be anti-arrhythmic (Walsh et al, 2010) and tissue sparing (Durst et al, 2007) in an in vivo rat model of coronary artery occlusion (CAO), although the receptors through which this occurs have yet to be identified. This study was designed to investigate whether the antiarrhythmic effects of CBD are modified by co-administration with a CB1 receptor antagonist (AM251). Experimental CAO was induced by ligation of the LAD coronary artery for 30 min; in sodium pentobarbitone anaesthetised male SD rats. Experimental groups included; (i) vehicle, (ii) CBD (50 μg/kg) alone, (iii) AM251 (1 mg/kg) alone, (iv) CBD followed by AM251, and (v) AM251 followed by CBD. CBD or AM251 alone each reduced the incidence of VT and the total number of VEBs compared with the control group, as did AM251 when administered 5 min after CBD. However, in animals treated with AM251 followed by CBD, the antiarrhythmic effect was significantly more pronounced 1274±303 (VT, P<0.01) and 1727±416 (total VEBs, P<0.001) when compared with all other treatment groups. The ability of AM251 to suppress arrhythmias suggests that endocannabinoids may exert pro-arrhythmic effects via the CB1 receptor. The preservation of anti-arrhythmic effects of both AM251 and CBD when co-administered, implies that a simple agonist/antagonist relationship at the CB1 receptor, may not be responsible for the antiarrhythmic effects of either alone. The observed synergism which persists when CB1 receptors are blocked prior to CBD administration, suggests cross-talk between CB1 and other CB receptors in the heart during ischaemia.

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