Chronic urotensin II receptor antagonist treatment does not alter hypertrophy or fibrosis in a rat model of pressure-overload hypertrophy.
Urotensin II (UII) is a potential mediator in the pathogenesis of cardiovascular disease, and inhibition of its actions at the urotensin receptor (UT) has been shown to improve cardiac function and structural changes of the myocardium in a model of myocardial infarction. In this study we utilized a model of pressure-overload hypertrophy induced by abdominal aortic constriction (AAC) which resulted in hypertrophy, increased fibrosis and impaired diastolic and systolic function. These changes were associated with a 4-fold increase in UII protein expression in the myocardium. Treatment of animals with a selective UT (SB-657510) antagonist for 20 weeks at a dose of 1500 ppm did not improve cardiac function as assessed by echocardiography and pressure-volume loop analysis, nor did it inhibit left ventricular hypertrophy or fibrosis. We hypothesize that other neurohumoral pathways may have a greater involvement in the pathogenesis of this model. Targeting the UII system appears to be insufficient to observe a beneficial outcome.
Kompa
Andrew R
AR
Department of Medicine, Monash University, Alfred Hospital, Victoria, Australia. andrew.kompa@med.monash.edu.au
Wang
Bing H
BH
Phrommintikul
Arintaya
A
Ho
Pei Y
PY
Kelly
Darren J
DJ
Behm
David J
DJ
Douglas
Stephen A
SA
Krum
Henry
H
D000818:Animals; D000831:Animals, Newborn; D006332:Cardiomegaly / Q000378:metabolism / Q000517:prevention & control; D002316:Cardiotonic Agents / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D018450:Disease Progression; D004353:Drug Evaluation, Preclinical; D005347:Fibroblasts / Q000187:drug effects; D005355:Fibrosis / Q000517:prevention & control; D006321:Heart / Q000187:drug effects / Q000503:physiopathology; D006333:Heart Failure / Q000401:mortality / Q000503:physiopathology / Q000517:prevention & control*; D017379:Hypertrophy, Left Ventricular / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D009203:Myocardial Infarction / Q000188:drug therapy / Q000378:metabolism; D009206:Myocardium / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors*; D013449:Sulfonamides / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use*; D015854:Up-Regulation / Q000187:drug effects; D014579:Urotensins / Q000037:antagonists & inhibitors / Q000378:metabolism
D002316:Cardiotonic Agents; D043562:Receptors, G-Protein-Coupled; C553589:SB 657510; D013449:Sulfonamides; D014579:Urotensins; C473142:Uts2r protein, rat; C029677:urotensin II