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1. Previous studies on the pathogenetic mechanisms of hypertension in the Milan hypertensive strain of rat (MHS) showed that a polymorphism within the alpha-adducin gene is responsible for up to 50% of the blood pressure difference between MHS and their MNS normotensive control strain. A case-control study has shown also in humans an association between alpha-adducin locus and hypertension using 4 multiallelic markers surrounding the alpha-adducin locus. 2. With a multiple regression approach we provide an estimate of the contribution of the genotype for each marker to the blood pressure variability in comparison to that provided by sex, body mass index and age. 3. While sex, body mass index and age contributed by about 40-45% to the overall blood pressure variability, the inclusion of the genotype for the marker closer to the alpha-adducin locus provided a further increase of the variability explained of about 5%. 4. The contribution independently provided by the other markers decreased exponentially with the increase of distance from alpha-adducin locus.

Previous studies have shown that erythrocytes from the Milan hypertensive strain of rats (MHS) differ from erythrocytes from the control normotensive strain (MNS). These differences are determined within the stem cells, are genetically associated with the development of hypertension, and are similar to those found between the tubular cells of the two strains. Moreover they seem to be dependent upon the presence of the membrane skeleton proteins. In this paper we describe our studies aimed at identifying some precise protein difference between the membrane skeletons of the two strains, which may cause the cellular differences described above. Milan hypertensive strain and MNS rats were immunized with ghost or membrane skeleton extracts prepared from the other or their own strains. Only MHS rats immunized with MNS ghost or membrane skeleton extracts produced an antibody against a 105 KD protein in about 95% of the animals. This protein has been identified with the recently described cytoskeletal protein adducin on the following bases: the protein binds calmodulin (CaM) and protein kinase C (PKc) in a Ca2+ dependent way. It also binds phosphatidylserine, is the substrate of exogenous PKc, and finally it is purified by high salt extraction of Triton-X100 insoluble erythrocyte cytoskeletons followed by affinity chromatography on CaM-sepharose. Using this antibody the isolation from a mouse spleen library, the characterization and sequencing of a partial cDNA clone coding for this protein has been carried out. In conclusion adducin may be considered a very useful tool to test the hypothesis that the cellular differences between MHS and MNS may be caused by a difference in a membrane skeleton protein.

Evidence indicates that an alteration in kidney function has a causal role in the pathogenesis of hypertension in the Milan hypertensive strain (MHS) rat. At the prehypertensive stage, these animals have increased glomerular filtration rate and 24-hour urinary output, whereas plasma renin activity and urinary kallikrein are lower. After transplantation, the MHS kidney increases the blood pressure of a normotensive recipient. Micropuncture experiments, where single nephron filtration rate, tubuloglomerular feedback, proximal tubular reabsorption, micro-pressures in tubuli, and interstitium and interstitial oncotic pressure were measured, suggest that the intrinsic ability of MHS proximal tubular epithelium to reabsorb solute and water is greater in prehypertensive MHS rats than in Milan normotensive strain (MNS) rats. Also rheogenic Na transport across the brush-border vesicles isolated from proximal tubular cells is faster. When erythrocytes and proximal tubular cells of MHS rats are compared to those of MNS rats, the former have smaller volume and Na content, whereas the Na transport is faster and the Ca ATPase at Vmax is lower. This indicates that the genetic cellular abnormality responsible for the renal functional abnormality and hypertension is also present in erythrocytes. Moreover, MHS erythrocyte abnormalities are genetically determined within the stem cells and are genetically associated with hypertension. Because a correlation was also found in human hypertension between erythrocyte Na transport abnormality and renal function, it is proposed that the erythrocyte may be used for studying the genetic molecular mechanisms of hypertension.

We measured red blood cell Na+-K+ pump, Na+-Li+ countertransport and Na+-K+ cotransport activities, together with intraerythrocyte sodium content before and after 3 months therapy with captopril and two other antihypertensive drugs (atenolol and canrenoate potassium) in subjects suffering from essential hypertension. All patients discontinued any previous treatment at least 3 months before the basal evaluation of cell membrane activities. All three drugs significantly lowered blood pressure but only captopril and canrenoate potassium induced significant modifications in red blood cell parameters. After three months of captopril therapy intraerythrocyte Na+ content was significantly decreased (P less than 0.01) without any detectable change in cation transport system activity. After 3 months of canrenoate potassium therapy we also observed a significant decrease in internal Na content (P less than 0.01), together with a significant increase in Na+-K+ pump (P less than 0.02) and Na+-Li+ countertransport (P less than 0.05) activities.