Endothelin A receptor blockade prevents capillary/myocyte mismatch in the heart of uremic animals.
In the heart of uremic animals and patients, the number of capillaries per volume of myocardium is reduced. Immunohistochemical studies demonstrated increased cardiac endothelin-1 (ET-1) expression in the left ventricle of uremic animals. Therefore, whether treatment with a selective ET(A)-receptor antagonist prevented such capillary-myocyte mismatch was investigated. Twenty-four h after subtotal nephrectomy, rats were left untreated or started on treatment with the ET(A)-receptor antagonist LU 135252 (20 mg/kg per d) and with the angiotensin-converting enzyme (ACE) inhibitor trandolapril (0.3 mg/kg per d), respectively. BP was monitored by telemetry. Myocardial capillary length density was analyzed by stereologic techniques that avoid anisotropy artifacts. In addition, cardiac ET-1 protein and mRNA were measured using immunohistochemistry, in situ hybridization, and quantitative reverse transcription-PCR. Changes in cardiac ET(A)-and ET(B)-PCR. receptor mRNA were measured using reverse transcription-PCR. Fifteen wk after subtotal nephrectomy, significantly reduced left ventricular capillary length density (3307 +/- 535 mm/mm(3)) was found compared with sham-operated controls (3995 +/- 471 mm/mm(3)); this was also seen in animals that were treated with trandolapril (3503 +/- 533 mm/mm(3)) but not in animals that were treated with LU 135252 (3800 +/- 303 mm/mm(3)). The results support a role of ET-1 in the genesis of left ventricular capillary/myocyte mismatch in uremia.
Amann
Kerstin
K
Departments of Pathology, University of Heidelberg, Heidelberg, Germany.|Departments of Pathology, University of Erlangen, Erlangen, Germany.
Münter
Klaus
K
Department of Internal Medicine, Knoll AG, Ludwigshafen, Germany.
Wessels
Sabine
S
Departments of Pathology, University of Heidelberg, Heidelberg, Germany.
Wagner
Jürgen
J
Department of Internal Medicine, Heidelberg, Germany.
Balajew
Vitali
V
Departments of Pathology, University of Heidelberg, Heidelberg, Germany.
Hergenröder
Stefan
S
Department of Internal Medicine, Knoll AG, Ludwigshafen, Germany.
Mall
Gerhard
G
Departments of Pathology, University of Darmstadt, Darmstadt, Germany.
Ritz
Eberhard
E
Department of Internal Medicine, Heidelberg, Germany.
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000818:Animals; D002196:Capillaries / Q000473:pathology; D003326:Coronary Circulation / Q000187:drug effects; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000235:genetics; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D007211:Indoles / Q000494:pharmacology; D008297:Male; D008967:Molecular Biology / Q000379:methods; D009206:Myocardium / Q000473:pathology*; D009392:Nephrectomy / Q000379:methods; D010666:Phenylpropionates / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D044022:Receptor, Endothelin A; D014511:Uremia / Q000473:pathology* / Q000503:physiopathology*
D000806:Angiotensin-Converting Enzyme Inhibitors; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D007211:Indoles; D010666:Phenylpropionates; D011743:Pyrimidines; D012333:RNA, Messenger; D044022:Receptor, Endothelin A; C052035:trandolapril; C107831:darusentan