The endothelin receptor antagonist tezosentan improves renal microcirculation in a porcine model of endotoxemic shock.
BACKGROUND
Impaired renal microcirculation has been suggested as a factor contributing to the development of renal dysfunction in sepsis. This study was conducted to elucidate the role of endothelin-1 (ET-1)in mediating reductions in renal microcirculatory blood flow during endotoxemic shock.


METHODS
A prospective, randomized, and experimental study was performed with 16 anesthetized and mechanically ventilated pigs. After 2 h of lipopolysaccaride-induced endotoxemia, eight animals received a bolus dose of the dual endothelin receptor antagonist tezosentan (1 mg/kg), followed by a continuous infusion of 1 mg/kg/h throughout the experiment. Eight animals served as the control group. Renal microcirculation, total renal blood flow, plasma creatinine levels, cardiac index, and mean arterial pressure were measured. Plasma samples were collected for the measurement of tumor necrosis factor alpha (TNF-alpha), interleukin-6 (IL-6), interleukin-10 (IL-10), ET-1, angiotensin II, and aldosterone.


RESULTS
Endotoxin infusion resulted in a state of circulatory shock with impairment of renal microcirculation. An increase in the plasma levels of TNF-alpha, IL-6, IL-10, ET-1, angiotensin II, and aldosterone was also observed. Tezosentan attenuated the decrease in renal microcirculation and renal blood flow, and attenuated the increase in plasma creatinine. Treatment with tezosentan did not significantly affect the plasma cytokine, angiotensin II, or aldosterone response to endotoxemia.


CONCLUSIONS
These results indicate that treatment with the dual endothelin receptor tezosentan in endotoxemic shock attenuates the reduction of renal microcirculation and total renal blood flow independently of plasma changes in the renin-angiotensin-aldosterone system or early plasma cytokine response.
Fenhammar
J
J
Department of Anaesthesia and Intensive Care, Karolinska University Hospital, Stockholm, Sweden. johan.fenhammar@karolinska.se
Andersson
A
A
Frithiof
R
R
Forestier
J
J
Weitzberg
E
E
Sollevi
A
A
Hjelmqvist
H
H
D000450:Aldosterone / Q000097:blood; D000804:Angiotensin II / Q000097:blood; D000818:Animals; D004195:Disease Models, Animal; D065128:Endothelin Receptor Antagonists; D019446:Endotoxemia / Q000188:drug therapy* / Q000503:physiopathology; D005260:Female; D006439:Hemodynamics / Q000187:drug effects; D007378:Interleukins / Q000097:blood; D007668:Kidney / Q000098:blood supply*; D008833:Microcirculation / Q000187:drug effects* / Q000502:physiology; D009994:Osmolar Concentration; D011725:Pyridines / Q000494:pharmacology*; D011897:Random Allocation; D013552:Swine; D013777:Tetrazoles / Q000494:pharmacology*; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha / Q000097:blood; D014665:Vasodilator Agents / Q000494:pharmacology*
D065128:Endothelin Receptor Antagonists; D007378:Interleukins; D011725:Pyridines; D013777:Tetrazoles; D014409:Tumor Necrosis Factor-alpha; D014665:Vasodilator Agents; D000804:Angiotensin II; D000450:Aldosterone; C120582:tezosentan