Downregulation of ANG II receptor is associated with compensated pressure-overload hypertrophy in the young dog.
We studied the gradual onset of pressure overload (PO) induced by a mildly constricting aortic band in 8-wk-old puppies (n = 8) that increased to 98 +/- 11 mmHg at 9 mo. Left ventricular (LV) weight/body weight was increased in PO versus sham-operated littermate controls [8.11 +/- 0.60 (SE) vs. 4.46 +/- 0.38 g/kg, P < 0.001]. LV end-diastolic diameter, diastolic pressure, and fractional shortening did not differ in PO versus control dogs. There were no inducible arrhythmias in response to an aggressive electrophysiological stimulation protocol in PO dogs. Furthermore, isolated cardiomyocyte function did not differ between control and PO dogs. LV angiotensin II (ANG II) levels were increased (68 +/- 12 vs. 20 +/- 5 pg/g, P < 0.01) as steady-state ANG II type 1 (AT(1)) receptor mRNA was decreased 40% and endothelial nitric oxide synthase mRNA levels were increased 2.5-fold in PO versus control dogs (P < 0.05). Total ANG II receptor binding sites of freshly prepared cardiac membranes demonstrated no difference in the dissociation constant, but there was a 60% decrease in maximum binding (B(max)) in PO versus control dogs (P < 0.01). LV ANG II levels correlated negatively with AT(1) receptor mRNA levels (r = -0.75, P < 0.01) and total AT(1) receptor B(max) (r = -0.77, P < 0.02). These results suggest that LV ANG II negatively regulates AT(1) receptor expression and that this is an adaptive response to chronic PO before the onset of myocardial failure in the young dog.
Schultz
David
D
Emory University, Atlanta, Georgia 30322, USA.
Su
Xuefeng
X
Wei
Chih-Chang
CC
Bishop
Sanford P
SP
Powell
Pamela
P
Hankes
Gerald H
GH
Dillon
A Ray
AR
Rynders
Patricia
P
Spinale
Francis G
FG
Walcott
Gregory
G
Ideker
Raymond
R
Dell'Italia
Louis J
LJ
D000222:Adaptation, Physiological / Q000502:physiology; D000367:Age Factors; D000804:Angiotensin II / Q000378:metabolism; D000818:Animals; D001011:Aorta; D001145:Arrhythmias, Cardiac / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D001794:Blood Pressure / Q000502:physiology; D002306:Cardiac Volume / Q000502:physiology; D006332:Cardiomegaly / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D004195:Disease Models, Animal; D004285:Dogs; D015536:Down-Regulation / Q000502:physiology; D004594:Electrophysiology; D015870:Gene Expression / Q000502:physiology; D018485:Muscle Fibers, Skeletal / Q000502:physiology; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D012333:RNA, Messenger / Q000032:analysis; D044140:Receptor, Angiotensin, Type 1; D011945:Receptors, Angiotensin / Q000235:genetics* / Q000378:metabolism*; D012084:Renin-Angiotensin System / Q000502:physiology; D016277:Ventricular Function, Left / Q000502:physiology
D012333:RNA, Messenger; D044140:Receptor, Angiotensin, Type 1; D011945:Receptors, Angiotensin; D000804:Angiotensin II