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Claire de Thoisy-Méchin

Press Relations

Tel. +33 (0)1 44 27 23 34

Email: claire.de_thoisy-mechin@upmc.fr

 

In English:

Katherine Tyrka

International Press Relations

tel. +33 (0)1 44 27 51 05

Email: katherine.tyrka@upmc.fr

The oldest treatment for hypertension

Massively used to treat hypertension, thiazides follow a simple mode of action: they promote the urinary excretion of body water, which reduces blood pressure and, consequently, reduces hypertension. Until now, a single target was known for this class of drugs. A team of researchers led by Dominique Eladari (Inserm Unit 872 "Cordeliers Research Centre Nouvelle fenêtre- INSERMNouvelle fenêtre, CNRSNouvelle fenêtre, UPMC, Université Paris DescartesNouvelle fenêtre), in collaboration with scientists from Germany, Switzerland and U.S. , have characterized a new target of thiazides. Their work was published in the Journal of Clinical InvestigationNouvelle fenêtre.

 

Hypertension is a common disease which increases with age. It has several origins and can be caused in some cases by an abnormal retention of salt (or sodium chloride). When we do not present with hypertension, the amount of salt in our body remains constant through a balance between our dietary intake and our urinary excretion. These are the carriers of sodium which are responsible for maintaining this balance.
Thiazide diuretics are the drugs most widely used against hypertension. They are also the oldest treatment used to combat hypertension. By inhibiting a specific transporter of sodium they promote urinary excretion of this ion. This reduces blood volume and cardiac output, and by concequences blood pressure. Like all medications that increase the urinary excretion of water and sodium, they are called diuretics. The mode of action of diuretics is well known to selectively block the protein responsible for the reabsorption of sodium which are present on the surface of renal epithelial cells. This action results in an increase in sodium excretion in the urine.

The target of thiazide diuretics is already known, it is a specialized protein, the sodium carrier NCC. This carrier is found in renal epithelial cells in the distal convoluted tubule. Yet, although the target of thiazides is expressed exclusively in the kidney, some effects caused by this drug class occurs outside of the kidney: altered glucose tolerance, increased bone mineral mass, etc. Nothing so far explains these observations, if not the existence of another possible target for these molecules. This hypothesis had already been issued a few years ago. Studies then showed that thiazides could block half the sodium re-absorption in the terminal part of néphron1 where the only sodium carrier identified - the epithelial sodium channel ENaC - is insensitive to the drug. All these findings led Dominique Eladari and his team to seek a new target that is both sensitive to thiazide diuretics and present in the terminal nephron.

Researchers first completely inactivated the epithelial sodium channel ENaC. Remarkably this inactivation did not block the transport of sodium. This first observation suggests the existence of a second sodium carrier present in the terminal nephron, which would be sensitive to thiazides. Researchers then looked again into the sodium transporters NCC, which are the conventional target of thiazides. They tested their activity in mice for which the carrier sodium NCC was inactive. Thiazide treatment remained all also effective in these mice, as they saw their urinary excretion of sodium increased. The second observation confirms the hypothesis that thiazides have a different molecular target.
After physiological studies on renal tubules microdissected and perfused vitro, researchers have determined that the new target system based on parallel operation of two different proteins of NCC. The role of these two proteins in the re-absorption of sodium was previously unsuspected. They are also not exclusively present in the kidney but are widely scattered throughout the body.

This work has identified a new target of thiazide diuretics which may affect renal failure.

This would suggest that a number of side effects reported with thiazides are not due to their diuretic effect but would rather result from an extrarenal effect. According to Dominique Eladari, "it becomes easier to explain the therapeutic efficacy of thiazide if these molecules have a more extensive action than initially identified."



18/05/10