Hemodynamic, renal, and endocrine responses to acute ET(A) blockade at different ANG II plasma levels.
Angiotensin (ANG) II effects may be partly mediated by endothelin (ET)-1. This study analyses the hemodynamic, renal, and hormonal responses of acute ET(A) receptor antagonism (LU-135252) at two ANG II plasma levels in eight conscious dogs. Protocol 1 involved a 60-min baseline, followed by two doses of ANG II for 60 min each (4 and 20 ng. kg(-1). min(-1)), termed ANG II 4 (slightly increased) and ANG II 20 (pathophysiologically increased ANG II plasma concentration). Protocol 2 was the same as protocol 1 but included 15 mg/kg iv LU-135252 after the baseline period. Protocol 3 was a 3-h time control. ANG II without LU-135252 did not increase plasma big ET-1 and ET-1, whereas LU-135252 increased ET-1 transiently after injection. This transient ET-1 increase was not reflected in urinary ET-1 excretion. The ANG II induced decreases in sodium, water, and potassium excretion, glomerular filtration rate, and fractional sodium excretion were not different with and without LU-135252. Mean arterial pressure increased during ANG II and was not lower with LU-135252 (-6 mmHg, not significant). Most importantly, during ANG II 20 LU-135252 prevented the decrease in cardiac output. Simultaneously, systemic vascular resistance increased 40% less, pulmonary vascular resistance was maintained at baseline levels, and central venous and wedge pressure were lower. Because ANG II stimulated endothelin de novo synthesis should just have started after 2 h of ANG II infusion, there must be mechanisms other than blocking the coupling of de novo synthesized endothelins to the ET(A) receptors to explain the effects of acute ET(A) receptor inhibition in our setting.
Boemke
W
W
Experimental Anesthesia, Campus Virchow-Klinikum, Medical Faculty of Charité, 13353 Berlin, Germany. willehad.boemke@charite.de
Hocher
B
B
Schleyer
N
N
Krebs
M O
MO
Kaczmarczyk
G
G
D000450:Aldosterone / Q000097:blood; D000804:Angiotensin II / Q000008:administration & dosage / Q000097:blood* / Q000494:pharmacology*; D000818:Animals; D003404:Creatinine / Q000378:metabolism; D004285:Dogs; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000097:blood* / Q000652:urine; D016232:Endothelins / Q000652:urine; D005260:Female; D005919:Glomerular Filtration Rate / Q000187:drug effects / Q000502:physiology; D006439:Hemodynamics / Q000187:drug effects / Q000502:physiology*; D007262:Infusions, Intravenous; D007275:Injections, Intravenous; D010666:Phenylpropionates / Q000008:administration & dosage / Q000494:pharmacology*; D011498:Protein Precursors / Q000652:urine; D011652:Pulmonary Circulation / Q000502:physiology; D011743:Pyrimidines / Q000008:administration & dosage / Q000494:pharmacology*; D044022:Receptor, Endothelin A; D012016:Reference Values; D012083:Renin / Q000097:blood; D012084:Renin-Angiotensin System / Q000187:drug effects / Q000502:physiology; D014563:Urodynamics / Q000187:drug effects / Q000502:physiology*; D014655:Vascular Resistance / Q000502:physiology
D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D016232:Endothelins; D010666:Phenylpropionates; D011498:Protein Precursors; D011743:Pyrimidines; D044022:Receptor, Endothelin A; D000804:Angiotensin II; C107831:darusentan; D000450:Aldosterone; D003404:Creatinine; D012083:Renin