Pressure-independent enhancement of cardiac hypertrophy in natriuretic peptide receptor A-deficient mice

Mice lacking natriuretic peptide receptor A (NPRA) have marked cardiac hype rtrophy and chamber dilatation disproportionate to their increased blood pr essure (BP), suggesting, in support of previous in vitro data, that the NPR A system moderates the cardiac response to hypertrophic stimuli. Here, we h ave followed the changes in cardiac function in response to altered mechani cal 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 wei ght/body weight. In the reverse direction, we used transverse aortic constr iction (TAC) to induce pressure overload. In the Npr1(-/-) mice, TAC result ed 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 Np r1(+/+) mice showed only a threefold increase in ANP expression, an 11% inc rease in LV/BW, a 0.2 mm decrease in LV end diastolic dimension, and no cha nge in fractional shortening. The activation of mitogen-activated protein k inases that occurs in response to TAC did not differ in the Npr1(+/+) and N pr1(-/-) mice. Taken together, these results suggest that the NPRA system h as direct antihypertrophic actions in the heart, independent of its role in BP control.