Adenosine type 1 receptor antagonists in fluid retaining disorders.

Adenosine is a vasoactive hormone whose action is mediated through at least four receptors. The most prevalent receptors are type 1, which promote vasoconstriction, and type 2, comprised of 2 subtypes (a,b) that promote vasodilation. In the kidney, type 1 receptors located on preglomerular vessels and in the tubule are involved in the regulation of glomerular filtration. Whole body fluid balance is strongly dependent on the ability of the kidney to maintain stable glomerular filtration. Several antagonists to adenosine type 1 receptors have been developed. These agents generate excess fluid (diuresis) and sodium (natriuresis) excretion in control animals and animal models of fluid retention, as well as in normal and oedematous humans. In both animals and humans, these effects are generally achieved without major changes in glomerular filtration. Animal studies have confirmed the location of adenosine type 1 receptors in relevant tissue sites in the kidney. More highly selective antagonists for adenosine type 1 receptors are regularly developed, improving their use in fluid retaining disorders. Clinical trials with these agents have commenced for the treatment of hypertension, renal failure and congestive heart failure, all disorders that include varying levels of fluid retention. The clinical trial results have been mixed. The early results with congestive heart failure suggest great promise for these agents, whereas trials in hypertension and renal failure have been equivocal.