Endotoxin induced pulmonary hypertension is a reproducible f

Endotoxin induced-pulmonary Cetrorelix sale is a reproducible finding in various animal models Leeper-Woodford et al., 1991, Weitzberg et al., 1993 and is also a feature of human sepsis where it may affect right ventricular function (Vincent, 1998). Mechanisms such as vasoconstriction and leukocyte aggregation have been suggested (Bigatello and Zapol, 1996) and endothelin-1 has been shown to cause such changes Helset et al., 1994, Curzen et al., 1996. The second increase in mean pulmonary artery pressure and pulmonary vascular resistance index was completely counteracted by combined endothelin ETA/ETB receptor antagonism. We have previously shown that selective endothelin ETA receptor antagonism alone has the ability to reverse endotoxin-induced pulmonary hypertension in supporting that endothelin ETA receptor activation contributes to this increase in pulmonary vascular tone (Wanecek et al., 1999). Despite this we could not exclude some contribution to the pulmonary hypertension by endothelin ETB receptor activation which has been suggested by some authors (Fukuroda et al., 1996). However, this mechanism seems to be of less importance in this model, since A-192621 appeared to be without effect on these parameters. Pulmonary gas exchange decreased after onset of endotoxin infusion reflected by an increase in PaCO2 and decreased SaO2 and PaO2 as well as an increase in pulmonary shunt fraction. Despite tendencies towards an improvement, by endothelin ETA/ETB receptor antagonism, no significant changes in these parameters was obtained. Hypoxia-induced pulmonary vasoconstriction in a similar porcine model has been suggested to be endothelin ETA receptor mediated (Holm et al., 1998). In this study as well in studies using selective endothelin ETA receptor antagonism (Wanecek et al., 1999), no effect on PaO2 was obtained. Therefore hypoxia-induced pulmonary vasoconstriction appears to be of less importance in the present endotoxin model. The decrease in SvO2, mainly reflecting cardiac index, seen among control animals was prevented by A-192621/PD 155080 administration. Absence of an increased pulmonary shunt fraction from combined endothelin ETA/ETB receptor antagonism indicates an unaffected ventilation/perfusion ratio upon A-192621/PD 155080 administration. Both arterial and pulmonary artery plasma endothelin-1-like immunoreactivity levels increased in response to endotoxaemia. These results are in line with earlier studies in both experimental and human sepsis Weitzberg et al., 1991, Curzen et al., 1997. After administration of combined endothelin ETA/ETB receptor antagonism, a further elevation in plasma endothelin-1-like immunoreactivity levels were seen analogous with previous results from our group (Wanecek et al., 1997b) and others (Dupuis et al., 1996) and is thought to be caused by antagonism of the clearing function of endothelin ETB receptors. This is also supported in this study where selective endothelin ETB receptor antagonism by A-192621 increased plasma endothelin-1-like immunoreactivity levels to values similar to those in the A-192621/PD 155080 group. The pulmonary circulation has been suggested to be an important producer of endothelin-1 during diseased conditions (Stewart et al., 1991). In the present study, a tendency towards net pulmonary endothelin-1 release was seen, which to some degree supports the concept of the pulmonary circulation as a net producer of endothelin-1 during endotoxaemia. Another supportive finding for a net release is the fact that during endothelin-1 infusion in the pig, a pulmonary uptake is seen (Weitzberg et al., 1995). If other sources of endothelin-1 production are of importance during endotoxaemia remains to be elucidated. In vitro receptor characterisation on membrane preparations from porcine heart shows that both antagonists used in this study have high selectivity for its receptor. In addition, the in vivo effect of each drug was studied. The splenic artery and portal vein are known to respond strongly to endothelin-1 and sarafotoxin 6c, respectively, suggesting high population of endothelin ETA/ETB receptors Hemsen, 1991, Filippelli et al., 1996. Arterial plasma endothelin-1-like immunoreactivity levels after endothelin-1 infusion were similar to those seen during endotoxaemia among the control animals (not shown). Both PD 155080 and A-192621 counteracted the vasoconstrictive properties of endothelin-1 and sarafotoxin 6c, respectively, indicating that both drugs affects the receptor activation in these vascular beds. Together this suggests that both PD 155080 and A-192621 are suitable substances for in vivo studies of both endothelin ETA/ETB receptor mediated-mechanisms.