Impaired flow-induced arterial remodeling in DOCA-salt hypertensive rats.
Arteries from young healthy animals respond to chronic changes in blood flow and blood pressure by structural remodeling. We tested whether the ability to respond to decreased (-90%) or increased (+100%) blood flow is impaired during the development of deoxycorticosterone acetate (DOCA)-salt hypertension in rats, a model for an upregulated endothelin-1 system. Mesenteric small arteries (MrA) were exposed to low blood flow (LF) or high blood flow (HF) for 4 or 7 weeks. The bioavailability of vasoactive peptides was modified by chronic treatment of the rats with the dual neutral endopeptidase (NEP)/endothelin-converting enzyme (ECE) inhibitor SOL1. After 3 or 6 weeks of hypertension, the MrA showed hypertrophic arterial remodeling (3 weeks: media cross-sectional area (mCSA): 10±1 × 10(3) to 17±2 × 10(3) μm(2); 6 weeks: 13±2 × 10(3) to 24±3 × 10(3) μm(2)). After 3, but not 6, weeks of hypertension, the arterial diameter was increased (Ø: 385±13 to 463±14 μm). SOL1 reduced hypertrophy after 3 weeks of hypertension (mCSA: 6 × 10(3)±1 × 10(3) μm(2)). The diameter of the HF arteries of normotensive rats increased (Ø: 463±22 μm) but no expansion occurred in the HF arteries of hypertensive rats (Ø: 471±16 μm). MrA from SOL1-treated hypertensive rats did show a significant diameter increase (Ø: 419±13 to 475±16 μm). Arteries exposed to LF showed inward remodeling in normotensive and hypertensive rats (mean Ø between 235 and 290 μm), and infiltration of monocyte/macrophages. SOL1 treatment did not affect the arterial diameter of LF arteries but reduced the infiltration of monocyte/macrophages. We show for the first time that flow-induced remodeling is impaired during the development of DOCA-salt hypertension and that this can be prevented by chronic NEP/ECE inhibition.
Department of Pharmacology, Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, The Netherlands.
Pieter
P
Lemkens
Jelly
J
Nelissen
Merlijn J P M T
MJ
Meens
Gregorio E
GE
Fazzi
Ger J M
GJ
Janssen
Jacques J M
JJ
Debets
Ben J A
BJ
Janssen
Paul M H
PM
Schiffers
Jo G R
JG
De Mey
D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors / Q000187:drug effects; D001552:Benzazepines / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology*; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology; D003900:Desoxycorticosterone / Q000009:adverse effects*; D004195:Disease Models, Animal; D000072396:Endothelin-Converting Enzymes; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006973:Hypertension / Q000139:chemically induced / Q000473:pathology* / Q000503:physiopathology*; D006984:Hypertrophy / Q000139:chemically induced; D008264:Macrophages / Q000473:pathology; D008638:Mesenteric Arteries / Q000473:pathology* / Q000503:physiopathology*; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors / Q000187:drug effects; D009000:Monocytes / Q000473:pathology; D015260:Neprilysin / Q000037:antagonists & inhibitors / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D012039:Regional Blood Flow / Q000187:drug effects / Q000502:physiology*; D014655:Vascular Resistance / Q000187:drug effects / Q000502:physiology
C577035:2-((1-(((1-(carboxymethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl)amino)carbonyl)cyclopentyl)methyl)-4-((3-(methylamino)propyl)(methyl)amino)-4-oxobutanoic acid; D001552:Benzazepines; D004791:Enzyme Inhibitors; D003900:Desoxycorticosterone; D016282:Aspartic Acid Endopeptidases; D008666:Metalloendopeptidases; D015260:Neprilysin; D000072396:Endothelin-Converting Enzymes