Transgenic Mice With Overexpression of Atrial Natriuretic Factor

The circulatory effects associated with lifelong plasma atrial natriuretic factor (ANF) elevation were examined by generating transgenic mice, which constitutively express a fusion gene consisting of the transthyretin promoter and the ANF structural gene. These mice have chronically elevated ANF levels as compared with their nontransgenic siblings. Transgenic animals exhibited immunoreactive ANF levels that were nearly fivefold higher than those measured in nontransgenic littermates. Systemic and regional hemodynamics and blood volumes were explored by using modifications of the reference microsphere and dilution techniques. Mean arterial pressure was reduced by 24 mm Hg, associated with a 27% reduction in total heart weight. This chronic reduction in blood pressure was due to a 21% reduction in total peripheral A trial natriuretic factor (ANF) is perhaps the bestA known peptide in a family of compounds inti..Lk mately involved in pressure and volume homeostasis.'-3 Although bolus injection or acute infusion of ANF is generally linked with hypotensive and/or natriuretic responses,4,5 the chronic effects of ANF are not clearly understood. Harrison-Bernard et a16 and Parkes et a17 have shown that chronic infusion of ANF to normotensive animals in the pathophysiological range is associated with a reduction in mean arterial pressure (MAP), mediated initially by a fall in cardiac output (CO). This response is followed by a diminished total peripheral resistance (TPR), while CO returns to normal. However, this is not a universal finding.8 Furthermore, these "chronic" studies normally involve only a few days of ANF infusion because of technical and economic limitations. Hemodynamic variables may not reach steady-state values during these infusion periods; some effects of ANF may require much longer to develop. To overcome these obstacles, a transgenic mouse model with chronically elevated ANF levels was generated.9 In this model, constitutive expression of the murine ANF gene was targeted to hepatocytes with the transthyretin (TTR) promoter. The transgenic mice have elevated ANF levels and reductions in MAP compared with the nontransgenic siblings. These changes occur without modifications in basal urine output or sodium excretion, suggesting a leftward shift Received June 17, 1993; accepted December 6, 1993. From the Cardiology Section (J.P.M.) and the Division of Research (R.W.B., B.D.P., R.N.R.), Alton Ochsner Medical Institutions, New Orleans, La, and the Krannert Institute of Cardiology (L.J.F.), Indiana University School of Medicine, Indianapolis. Correspondence to R. Wayne Barbee, PhD, Division of Research, Alton Ochsner Medical Foundation, 1520 Jefferson Hwy, New Orleans, LA 70121. resistance, whereas cardiac output, stroke volume, and heart rate were not significantly altered, despite a 15% elevation in plasma volume. Transgenic mice displayed reductions of 35%, 33%, 32%, and 19% in muscle, skin, brain, and renal vascular resistance, respectively, whereas coronary and splanchnic resistances were not significantly altered. The findings complement earlier data from chronically infused normotensive mammals and suggest that these mice are an excellent model for investigating the effects of lifelong ANF elevation. (Circ Res.