Search

Background Microcirculatory dysfunction is a common feature of sepsis. The potent vasoconstrictor endothelin (ET) is released in sepsis and endotoxemia, potentially contributing to sepsis-induced microcirculatory failure. In this study we tested the hypothesis that mixed ET receptor antagonism with tezosentan would improve splanchnic microcirculatory blood flow in acute porcine endotoxemia. Materials and methods Sixteen anesthetized and mechanically ventilated pigs received an infusion of endotoxin for 300 min. After 120 min eight pigs received a bolus dose of tezosentan 1 mg/kg followed by an infusion of tezosentan of 1 mg/kg/h throughout the experiment. Eight pigs served as endotoxin controls. Laser Doppler flowmetry was used to measure microcirculatory blood flow in the liver and in the ileal and colon mucosa. PCO2 in the ileal mucosa was measured by air tonometry and portal vein flow by an ultrasonic flow probe. Results Endotoxin administration induced a state of shock with impaired splanchnic microcirculatory blood flow. Microcirculation in the mucosa of the colon and ileum and mucosal-arterial PCO2 gap were improved by tezosentan. Portal vein flow was increased, but hepatic microcirculatory blood flow was not significantly improved. Tezosentan preserved cardiac index and decreased pulmonary capillary wedge pressure compared to controls, without causing any differences in the heart rate or mean arterial blood pressure response. Tezosentan also distinctly improved pH and arterial lactate values. Conclusions The findings of this study indicate that ET is involved in the microcirculatory dysfunction seen in the ileal and colon mucosa in early endotoxemia. Moreover, this detrimental effect was counteracted by i.v. administration of the mixed ET receptor antagonist tezosentan.

During progressive blood loss several mechanisms act in concert to compensate for the reduced intravascular volume with the overall aim to provide sufficient blood supply to vital organs. The hemodynamic responses in this situation follow a characteristic course of events in conscious individuals with an initial phase of largely maintained blood pressure and tachycardia followed by an abrupt fall in pressure, accompanied by bradycardia and widespread inhibition of sympathetic nervous activity when 20–30% of the blood volume is lost. Our research has focussed on Na + and angiotensin II effects on the brain for the cardiovascular compensatory mechanisms in response to hypotensive hemorrhage in sheep. We have found that intracerebroventricular infusion of hypertonic NaCl solution improves the tolerance to blood loss, i.e., increases the amount of blood loss needed to induce hypotension. Inhalation anesthesia abolished this effect of the infusion. Similarly, corresponding infusions of angiotensin II also increased the resistance to blood loss in conscious animals only, although accompanied by different hemodynamic compensatory mechanisms. The effects of intracerebroventricular hypertonic NaCl infusion on cardiovascular compensation during hemorrhage are similar to those achieved with treatment of hemorrhagic shock with intravenous infusions of small volumes of hypertonic NaCl solutions. We therefore suggest that a substantial part of the beneficial effect of that treatment is mediated via direct effects of the hypernatremia on the brain. These observations also illustrate the need for further elucidation of more possible influences on autonomic functions by increased Na + concentration which, together with hypovolemia, is a hallmark of dehydration.