The effect of combined A and PD treatment on the

The effect of combined A-192621 and PD 155080 treatment on the Berberine hydrochloride sale during endotoxin infusion is quite different compared to either drug used alone (Wanecek et al., 1999). After administration of both antagonists in combination, cardiac index increased to baseline values within 30 min, and was due to the increased stroke volume index since heart rate was unchanged. The issue of sepsis/endotoxin induced cardiac depression is still under debate. Advocated mechanisms include the release of myocardial depressant factors such as tumour necrosis factor-α (TNF-α), interleukin-1, NO Herbertson et al., 1996, Kumar et al., 1996 and, although less forwarded in human septic shock, coronary artery vasoconstriction (Peyton et al., 1976). TNF-α as well as endothelin-1 causes coronary artery vasoconstriction during endotoxic conditions and the vasoconstrictive properties of TNF-α has been suggested to be mediated by endothelin-1 (Hohlfeld et al., 1995). Although indications of the existence of coronary constrictive endothelin ETB receptors has been shown in dogs with heart failure (Cannan et al., 1996) the endothelin ETAreceptor has been suggested to be the major coronary vasoconstrictive endothelin receptor (Wang et al., 1995). We have previously shown that selective endothelin ETA receptor antagonism by PD 155080 is without beneficial effects on cardiac performance during porcine endotoxin shock (Wanecek et al., 1999). The markedly improved cardiac index and stroke volume index from combined endothelin ETA/ETB receptor antagonism might be explained by a larger reduction in both right- and left-sided afterload compared to selective endothelin ETA receptor antagonism. This is probably due to the large vascular population of constrictive endothelin ETB receptors (Lodge et al., 1995). Afterload reduction has also been forwarded as an explanation behind the increased cardiac output seen from mixed endothelin antagonism during human congestive heart failure (Kiowski et al., 1995). Also, the left ventricular stroke work index actually increased among the A-192621/PD 155080 treated animals. Meanwhile, the right ventricular stroke work index did not differ between groups which to a certain degree speaks against a negative inotropic effect of combined endothelin ETA/ETB receptor antagonism, which has been described by others Ishikawa et al., 1988, Mebazaa et al., 1993. Therefore, this study together with our previous study using PD 155080 alone (Wanecek et al., 1999), strongly suggests that dual endothelin ETA/ETB receptor antagonism is necessary to obtain favourable effects. Mean arterial blood pressure did not significantly decrease upon mixed endothelin ETA/ETB antagonism despite a marked decrease in systemic vascular resistance, a result of the improvement in cardiac index. As a consequence of the increased cardiac index, systemic oxygen delivery index significantly increased after administration of A-192621/PD 155080. This did not result in an overall increase in oxygen consumption. However, lack of changes in global systemic oxygen consumption index does not rule out a more favourable local oxygen utilisation. Antagonism of the vasoconstrictive properties of vessels in vital organs such as the heart, brain, splanchnicus and kidneys could direct blood flow from skeletal muscle and skin. Also, oxygen is used for purposes other then oxidative phosphorylation like the formation of reactive oxygen species seen during endotoxaemia, consuming large amounts of oxygen (Vlessis et al., 1995). Interestingly, endothelin-1 has been shown to promote leukocyte activation (Caramelo et al., 1997) resulting in production of reactive oxygen species and therefore endothelin receptor antagonism might result in better oxygen utilisation. In fact, the lesser degree of metabolic acidosis, reflected in a higher pH and base excess and a tendency towards lower arterial plasma lactate levels, among A-192621/PD 155080 treated animals suggests a more adequate oxygen utilisation in response to combined endothelin ETA/ETB receptor antagonism.