In renal fluid regulation there is a balance between glomerular filtration and tubular reabsorption controlled by the tubuloglomerular feedback mechanism (TGF). The load to the distal nephron is sensed at the macula densa (MD) site and the information used to adjust the tone of the afferent arteriole. Dr Bianchi has shown that in Milano Hypertensive Strain of rats (MHS) and in many patients there is a defect in the gene for a-adducin leading to increased tubular fluid reabsorption. We have found that the sensitivity of the TGF system is increased in the MHS rats compared with controls due to a large reduction in the MD NO concentration. In a-adducin defect animals MD cell in-transport of NaCl is expected to increase. The sensitivity of the TGF system seem to be dependant on a balance between reactive oxygen species (ROS) production related to the entry of NaCl into the macula densa cells and nitric oxide (NO) concentration produced there by macula densa nNOS. Increased ROS and decreased NO lead to increased TGF. Thus, a large increase in TGF sensitivity in the MHS rats can explain the fluid retention that occurs in these animals and as a consequence blood pressure will increase.