Effects of tezosentan, a dual endothelin receptor antagonist, on the cardiovascular and renal systems of neonatal piglets.
OBJECTIVE
Endothelin is a potent biological vasoactive mediator in the cardiovascular and renal systems. Little is known of the effects of endothelin antagonism on the developing heart and kidney, and we hope to show that endothelin does have an important role in the cardiovascular and renal systems of the developing neonate. In this study the authors have examined the effects of tezosentan, a nonselective endothelin-A and endothelin-B receptor antagonist designed for parenteral use, on the cardiovascular and renal systems of healthy neonatal piglets.


METHODS
Eight, 7- to 10-day old domestic piglets weighing 2.5 to 3.0 kg were anesthetized, intubated, and ventilated with catheters placed into the jugular vein, left ventricle, and femoral artery. Urine output was monitored via a suprapubic cystostomy. After baseline data were obtained the piglets received tezosentan (1 mg/kg/h) for 1 hour. A set of data was collected just before discontinuation of the 1-hour infusion of tezosentan and another set was collected 1 hour after the discontinuation of the drug. Mean arterial pressure (MAP), heart rate (HR), and urine output (UV) were monitored continuously and cardiac index (CI), systemic vascular resistance (SVR), renal blood flow (RBF), and renal vascular resistance (RVR) were calculated from gamma counts obtained from injections of radio-labeled microspheres at end of the different time periods. Glomerular filtration rate (GFR) was obtained by the sodium iothalamate method. Data were averaged and plotted versus time and analyzed statistically by a Student's t test.


RESULTS
(P <.05 versus baseline*). In our experimental animals the infusion of tezosentan diminished MAP and SVR from baseline values of 94 +/- 7 mm Hg and 0.14 +/- 0.03 mm Hg/mL/min, respectively to TEZO values of 62 +/- 4* mm Hg and 0.07 +/- 0.02* mm Hg/mL/min. CI increased from 278 +/- 58 to 367 +/- 75* mL/min/kg with tezosentan. There also was a statistically significant increase in RBF from 1.16 +/- 0.38 to 1.86 +/- 0.37* mL/min/kg, an increase in UV from 0.57 +/- 0.24 to 0.64 +/- 0.12* mL/min, a decrease in RVR from 4.60 +/- 1.47 to 2.03 +/- 0.36* mm Hg/mL/min, and no change in the GFR.


CONCLUSIONS
The inhibition of endothelin receptors with tezosentan produced a statistically significant effect on the piglet cardiovascular system with a drop in MAP and SVR and an increase in CI and HR. It also produced a statistically significant increase in RBF and UV and a decrease in RVR without affecting GFR. J Pediatr Surg 36:1824-1828.
Chin
A
A
Divisions of Pediatric Surgery and Pediatric Nephrology, The University of Illinois College of Medicine at Chicago, Chicago, IL, USA.
Radhakrishnan
J
J
Fornell
L
L
John
E
E
D000818:Animals; D000831:Animals, Newborn; D001794:Blood Pressure / Q000187:drug effects; D002319:Cardiovascular System / Q000187:drug effects*; D065128:Endothelin Receptor Antagonists; D005919:Glomerular Filtration Rate / Q000187:drug effects; D006339:Heart Rate / Q000187:drug effects; D007668:Kidney / Q000187:drug effects*; D023421:Models, Animal; D011725:Pyridines / Q000494:pharmacology*; D012079:Renal Circulation / Q000187:drug effects; D013552:Swine; D013777:Tetrazoles / Q000494:pharmacology*; D014655:Vascular Resistance / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology*
D065128:Endothelin Receptor Antagonists; D011725:Pyridines; D013777:Tetrazoles; D014665:Vasodilator Agents; C120582:tezosentan