Effects of tezosentan, a dual endothelin receptor antagonist, on the cardiovascular and renal systems of neonatal piglets during endotoxic shock.
OBJECTIVE
Endothelin is a potent mediator of the cardiovascular and renal systems. Studies have found that endothelin has an important role in regulating cardiac function and renal perfusion in neonates who are suffering from endotoxic shock. The authors believe that blockade of the endothelin response during endotoxemia will have a beneficial effect on neonatal cardiac and renal functions. In this study the authors have examined the effects of tezosentan, a dual endothelin-receptor antagonist, on the cardiovascular and renal systems of neonatal piglets during endotoxemia.


METHODS
Thirteen piglets were subjected to endotoxic shock and divided into a fluid-therapy group that received 0.9% normal saline and a group that received tezosentan (1 mg/kg/h). Mean arterial pressure (MAP), heart rate (HR), and glomerular filtration rate (GFR) were plotted at baseline, 1, 2, and 3 hours. Cardiac index (CI), renal blood flow (RBF), systemic vascular resistance (SVR), and renal vascular resistance (RVR) were obtained at baseline, 1, and 3 hours after baseline.


RESULTS
(P <.05 for 3 hours versus baseline and tezosentan versus fluid). Although fluid therapy in endotoxemia had no significant effect on MAP and RVR, it significantly increased HR (139 plus minus 17 to 246 plus minus 17 beats/min) and SVR (0.08 plus minus 0.05 to 0.33 plus minus 0.09 mm Hg/mL/min) and decreased CI (407 plus minus 208 to 98 plus minus 13 mL/min/kg), RBF (1.84 plus minus 0.38 to 0.97 plus minus 0.34 mL/min/kg kidney), and GFR (0.20 plus minus 0.05 to 0.11 plus minus 0.04 mL/min/kg) at 3 hours. The use of tezosentan also significantly increased HR (130 plus minus 14 to 220 plus minus 31 beats/min), but unlike in the fluid therapy group, there was a significant fall in MAP (77 plus minus 10 to 54 plus minus 9 mm Hg) and RVR (1.92 plus minus 0.44 to 1.77 plus minus 0.64 mm Hg/mL/min) and a less severe decrease in CI (482 plus minus 188 to 176 plus minus 67 mL/min/kg) at 3 hours. SVR, RBF, and GFR were maintained.


CONCLUSIONS
Endotoxic shock affected cardiac and renal functions in both treatment groups. Fluid therapy alone could not prevent a statistically significant fall in CI, RBF, and GFR or prevent the increase in HR and SVR. Endothelin antagonism with tezosentan resulted in a statistically significant fall in MAP and RVR from baseline, not seen in the fluid-therapy group. CI and RBF were significantly higher, and MAP, SVR, and RVR were significantly lower when compared with the fluid-therapy group at 3 hours. GFR also was maintained at baseline with tezosentan. During endotoxemia, endothelin antagonism maintained renal and cardiac functions better than with fluid therapy alone.
Chin
Anthony
A
Divisions of Pediatric Surgery, Department of Surgery and Pediatrics, The University of Illinois College of Medicine at Chicago, Chicago, IL, USA.
Radhakrishnan
Jayant
J
Fornell
Linda
L
John
Eunice
E
D000818:Animals; D000831:Animals, Newborn / Q000378:metabolism*; D002319:Cardiovascular System / Q000187:drug effects*; D004195:Disease Models, Animal; D065128:Endothelin Receptor Antagonists; D019446:Endotoxemia / Q000188:drug therapy / Q000378:metabolism; D004926:Escherichia coli; D006439:Hemodynamics / Q000187:drug effects; D007668:Kidney / Q000187:drug effects*; D011725:Pyridines / Q000494:pharmacology* / Q000627:therapeutic use; D012772:Shock, Septic / Q000188:drug therapy / Q000378:metabolism*; D013552:Swine; D013777:Tetrazoles / Q000494:pharmacology* / Q000627:therapeutic use; D014665:Vasodilator Agents / Q000494:pharmacology*
D065128:Endothelin Receptor Antagonists; D011725:Pyridines; D013777:Tetrazoles; D014665:Vasodilator Agents; C120582:tezosentan