Renal Transport Of Cationic Diuretics

The diuretics triamterene and amiloride exist in the blood as cations. These agents are secreted into the lumen of the renal tubule through an organic cation transport system. The cation transport system is also located in the proximal tubule. Evidence in almost all species demonstrates that this system is separate from the systems used to transport anions. Quantitative cation transport capacity, however, differs significantly between species. From studies in rabbits it appears that the cation transporters are most abundant in the Sr segment of superficial proximal tubules and decrease through the S3 segment. Juxtamedul-lary proximal tubules have cation transporters in equal abundance in both the Si and S2 segments. Tetraethyl-ammonium (TEA) and N-methylnicotinamide (NMN) have been the compounds used most frequently to delineate the renal cation transport systems. Many studies of these systems have used the chicken as the test animal since chicken kidneys have a portal blood supply which allows test compounds to be delivered directly into the kidney without entering the systemic circulation. This is desirable as many of these substances are toxic to other organs. Transport by the organic cation system can also be competitively inhibited. Interestingly, probenecid can also function as an inhibitor of this cation transport system. Endogenous compounds secreted by renal cation transporters include acetylcholine, choline, dopamine, epinephrine, norepinephrine, serotonin, and creatinine, while drugs removed by this system include trimethoprim, quinidine, quinine, atropine, cimetidine, morphine, and the insecticide paraquat as well as the diuretics amiloride and triamterene. The sequence of steps for renal organic cation transport is similar to that described for organic anion transport. However, albumin does not appear to have a regulatory influence on the renal transport of cations. Transport across the basola-teral membrane is carrier mediated (Fig. 5). While this was originally thought to occur through facilitated diffusion, recent studies have shown that electro-neutral increases in intracellular organic cation concentration stimulate baso-lateral TEA transport. This finding is most consistent with transport at the basolateral membrane occurring through a cation exchanger [4], At the brush border membrane, movement of organic cations into the lumen occurs in parallel with sodium hydrogen exchange. The increase in luminal hydrogen ion concentration is then linked to a luminal brush border hydrogen ion cation exchanger powered by the inward hydrogen ion gradient. Energy for all these processes is supplied by the sodium potassium ATPase pump on the basolateral membrane which establishes an inward electrochemical gradient for the basolateral cation transporter. It appears that transport at the luminal membrane is the rate limiting step for organic cation transport and that this transporter has wide range of potential substrates.

Amiloride appears to have an extremely high affinity for the luminal transporter compared with that seen with either TEA or NMN. Thus, antagonism of diuretic action by competitive inhibition for transport into the tubule lumen is an infrequent clinical problem. Although amiloride has been found to inhibit the renal sodium hydrogen exchanger in high concentrations, it does not actu-

Lumen

Proximal Tubule Cell

Peritubular Space

Lumen

Amiloride

Amiloride

Orgs Cati<

Orgs Cati<

Amiloride k+

1 Amiloride

Amiloride

FIGURE 5. Transport system for cationic diuretics. At the basolateral border of proximal tubule cells organic cations are transported across cell membrane either by cation exchange for a reabsorbed cation or by facilitated diffusion down an electrical and chemical gradient. The former is created by passive K exit down a concentration gradient. At the luminal membrane secretion of the diuretic occurs in parallel with Na-H exchange, which allows secretion of the diuretic to be coupled to inward H+ gradient through a second antiporter. Energy for these processes is provided by the NaK ATPase pump (solid circle).

ally bind to the transporter. Additionally the concentration of amiloride required to inhibit sodium hydrogen exchange is higher than concentrations usually achieved in the proximal tubule. Finally, while triamtene is transported by the renal cationic transport system, most of this drug appears to reach the lumen through glomerular filtration. Few studies have examined the contribution of the tubule secretion of triamterene to its overall effect.

In summary, secretion of diuretics into the lumen of the proximal tubule is an essential step for the action of these agents. It is this event that allows loop diuretics to maintain potency in the setting of reductions in glomerular filtration rate. Competitive inhibition for transport between diuretics and other endogenous and exogenous compounds is an important component of diuretic resistance in a number of circumstances, especially in chronic renal failure. For diuretics with a high affinity for the transporters, increasing the diuretic dose may improve tubule secretion and efficacy.

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