Renal Na handling and blood pressure are regulated by mechanisms either intrinsic (Na transporters) or extrinsic (hormones nerves etc...) to the kidney. For instance, the regulation of luminal Na transport at the distal tubule includes both constitutive renal transports (Na⁺ channel and the proteins regulating its residential time on the plasma membrane) and aldosterone that tries to regulate the activity of this channel according to the body need. Genetic modification of all the proteins involved may produce different types of hypertension that require specific therapeutic interventions. During the last 20 years we have been studying two mechanisms: adducin polymorphisms and endogenous ouabain (EO) that affect renal Na⁺ handling and blood pressure throughout the modulation of the Na-K pump activity on the renal basolateral membrane. These mechanisms have been studied in rodents and in humans at the different levels of biological organisation: whole organism, isolated cells and cell free system. In addition, a very selective, safe, and potent (active at 10^–11 M in vitro and at nanomoles oral doses in vivo) inhibitor of these mechanisms have been developed and studied in the two species. This inhibitor normalizes blood pressure in hypertensive carriers of previously shown functional SNP on genes coding for adducins or enzymes involved in EO synthesis and transport. The approach of using a selective inhibitor as a common tool across the different levels of organisation in rodents and patients may also be considered a novel strategy to dissect the complex network of genetic-environmental mechanisms regulating renal Na⁺ handling and blood pressure.