Angiotensin converting enzyme inhibition modulates endogenous endothelin in chronic canine thoracic inferior vena caval constriction.
Endothelin (ET) is a potent vasoconstrictor peptide which is elevated in plasma in congestive heart failure. Recent studies suggest an important role for angiotensin II (AII) in the activation of ET in cultured cardiomyocytes. Chronic thoracic inferior vena caval constriction (TIVCC) is a model of reduced cardiac output that mimics the neurohumoral activation observed in congestive heart failure. We hypothesized that activation of the renin-angiotensin system in TIVCC plays a role in the activation of ET and that the elevation of endogenous ET contributes to the systemic and renal vasoconstriction that characterizes this model of venous congestion. We studied conscious dogs after 7 d of TIVCC in the presence or absence of chronic angiotensin converting enzyme inhibition with enalapril. TIVCC resulted in marked activation of plasma AII and ET in plasma, right atrium, lung, and renal medulla which was further localized to cardiomyocytes, pulmonary, and renal epithelial cells. Chronic angiotensin converting enzyme inhibition abolished the increases in plasma AII and ET during TIVCC. Acute endothelin A receptor blockade with FR-139317 resulted in significant decreases in mean arterial pressure and systemic vascular resistance in TIVCC. We conclude that activation of the renin-angiotensin system contributes to the activation of circulating and local ET in TIVCC and that this activation plays an important role in the regulation of arterial pressure and systemic vascular resistance in this model of congestive failure.
Clavell
A L
AL
Cardiorenal Research Laboratory, Department of Internal Medicine, Mayo Clinic and Foundation, Rochester, Minnesota 55905, USA.
Mattingly
M T
MT
Stevens
T L
TL
Nir
A
A
Wright
S
S
Aarhus
L L
LL
Heublein
D M
DM
Burnett
J C
JC
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D001381:Azepines / Q000494:pharmacology; D004195:Disease Models, Animal; D004285:Dogs; D016232:Endothelins / Q000378:metabolism*; D006333:Heart Failure / Q000378:metabolism*; D006439:Hemodynamics / Q000187:drug effects; D007211:Indoles / Q000494:pharmacology; D008297:Male; D014682:Vena Cava, Inferior
D000806:Angiotensin-Converting Enzyme Inhibitors; D001381:Azepines; D016232:Endothelins; D007211:Indoles; C079574:FR 139317