title: Pressure-independent enhancement of cardiac hypertrophy in natriuretic peptide receptor A-deficient mice.
abstract: Mice lacking natriuretic peptide receptor A (NPRA) have marked cardiac hypertrophy and chamber dilatation disproportionate to their increased blood pressure (BP), suggesting, in support of previous in vitro data, that the NPRA system moderates the cardiac response to hypertrophic stimuli. Here, we have followed the changes in cardiac function in response to altered mechanical load on the heart of NPRA-null mice (Npr1-/-). Chronic treatment with either enalapril, furosemide, hydralazine, or losartan were all effective in reducing and maintaining BP at normal levels without affecting heart weight/body weight. In the reverse direction, we used transverse aortic constriction (TAC) to induce pressure overload. In the Npr1-/- mice, TAC resulted in a 15-fold increase in atrial natriuretic peptide (ANP) expression, a 55% increase in left ventricular weight/body weight (LV/BW), dilatation of the LV, and significant decline in cardiac function. In contrast, banded Npr1+/+ mice showed only a threefold increase in ANP expression, an 11% increase in LV/BW, a 0.2 mm decrease in LV end diastolic dimension, and no change in fractional shortening. The activation of mitogen-activated protein kinases that occurs in response to TAC did not differ in the Npr1+/+ and Npr1-/- mice. Taken together, these results suggest that the NPRA system has direct antihypertrophic actions in the heart, independent of its role in BP control.
authors: Department of Pathology and Laboratory Medicine and Curriculum in Genetics and Molecular Biology, University of North Carolina, Chapel Hill, NC 27599-7525, USA.
authors: J W
authors: JW
authors: Knowles
authors: G
authors: G
authors: Esposito
authors: L
authors: L
authors: Mao
authors: J R
authors: JR
authors: Hagaman
authors: J E
authors: JE
authors: Fox
authors: O
authors: O
authors: Smithies
authors: H A
authors: HA
authors: Rockman
authors: N
authors: N
authors: Maeda
mesh_terms: D000818:Animals; D000959:Antihypertensive Agents / Q000627:therapeutic use; D001794:Blood Pressure; D006332:Cardiomegaly / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology*; D004656:Enalapril / Q000627:therapeutic use; D005665:Furosemide / Q000627:therapeutic use; D006162:Guanylate Cyclase / Q000502:physiology*; D006830:Hydralazine / Q000627:therapeutic use; D019808:Losartan / Q000627:therapeutic use; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009206:Myocardium / Q000473:pathology; D009929:Organ Size; D011433:Propranolol / Q000627:therapeutic use; D017461:Receptors, Atrial Natriuretic Factor / Q000502:physiology*; D013686:Telemetry / Q000379:methods; D018487:Ventricular Dysfunction, Left / Q000503:physiopathology
chemical_list: D000959:Antihypertensive Agents; D006830:Hydralazine; D004656:Enalapril; D005665:Furosemide; D011433:Propranolol; D020928:Mitogen-Activated Protein Kinases; D006162:Guanylate Cyclase; D017461:Receptors, Atrial Natriuretic Factor; C091715:atrial natriuretic factor receptor A; D019808:Losartan