Introduction: Adducin is a heterodimeric protein composed of combinations of α, β and γ subunits. It is a prominent component of the cytoskeleton and contributes to a number of signal transduction pathways. Recently we have observed that rats with mutations in the β-subunit develop proteinuria. Conversely, rats with mutations in the α-subunit are protected from proteinuria despite a higher blood pressure. This study was designed to examine the effects of adducin subunit mutations on myogenic tone and to investigate how this may be related to the development of target organ damage. Methods: Structure and function of isolated renal, middle cerebral and skeletal muscle arteries from congenic rats with mutations in α-subunits (NA rat) and in β-subunits (NB rat) were studied using pressure myography. Blood pressure was measured using a tail cuff method and urinary protein excretion was assayed. Experiments were performed before (6 weeks) and after (4 months) the development of renal disease. Results: NB rats developed lower systolic blood pressure, greater urinary protein loss and showed profound damage to myogenic tone in renal arteries at both ages studied. The reduction in tone was associated with an increase in arterial stiffness at 4 months (n=9, P<0.05). Myogenic tone in the middle cerebral arteries was also damaged at 4 months, but in skeletal muscle arteries was normal. In NA rats there was a reduction in myogenic tone in renal arteries from 6 weeks to 4 months of age and this was associated with a rise in urinary protein loss. Both the reduction in tone and increase in proteinuria were significantly less than that seen in the NB rat (Proteinuria in NB rat: 360 ±25mg/day vs NA rat: 144±11mg/day, p<0.05, n=5). There were no differences in contraction to vasoconstrictors, responses of preconstricted arteries to acetylcholine or arterial structure between the strains. Conclusion: While the α-adducin subunit mutation contributes to elevated blood pressure, the β-subunit mutation is more important for the generation of myogenic tone in renal and middle cerebral arteries. Whether the decline in tone in the NA arteries is due to the adducin α-subunit mutation or the rise in blood pressure is unclear. While other studies have shown that loss of myogenic tone in renal arteries is associated with proteinuria, this is the first study to demonstrate this pathology where the genetic defect is known.