High blood pressure is a complex phenotype that involves many body control systems operating at each level of the biological organization. 2. One possible approach to try to identify the major genes involved in the development of hypertension is to dissect the sequence of events that go from a primary protein abnormality that is responsible for organ and cellular dysfunction to arterial hypertension and, then, to go back to the gene coding the protein of interest. 3. Using this approach, our group has been able to identify a candidate protein, adducin, and two point mutations within the two genes coding for the subunits of this protein that are involved in blood pressure variation both in an animal model of primary hypertension and in essential hypertension patients. 4. In the present paper we review the results obtained in the Milan hypertensive rat strain (MHS) and in its appropriate normotensive controls (MNS) to define, at each level of the biological organization, the intermediate phenotypes associated with the development of hypertension. 5. We also demonstrate that this model has many similarities with human hypertension and, in particular, that the same genetic mechanisms linked to a mutation in the adducin gene can explain some of the blood pressure variation in both rats and, at least, in a subgroup of patients. 6. This portion of the increase in blood pressure seems to be able to be selectively inhibited by compounds that interfere with the sequence of events that are triggered by the adducin gene abnormality.
