Intestinal Inhibition of the Na+/H+ Exchanger 3 Prevents Cardiorenal Damage in Rats and Inhibits Na+ Uptake in Humans

An inhibitor of intestinal NHE3 reduces absorption of dietary sodium in rats and humans and prevents salt-induced cardiorenal injury in nephrectomized rats. Pass the Salt Whether life arose on earth or elsewhere, our ancestors certainly spent some time in the Earth’s oceans: We still carry the evidence for that in the saltiness of our bodily fluids. When the salty balance of our body goes awry (through diet, for example), disease can result. Now, Spencer and colleagues have found a way to prevent the absorption of dietary sodium through the intestine without requiring the drug be present throughout the body, a safer approach. Normally, most of the sodium chloride that is consumed is taken up by a dedicated transporter in the membranes of intestinal cells. This sodium-proton exchanger, NHE3, pumps one sodium ion in and one proton out, bringing dietary sodium into the body. The authors used an NHE3 inhibitor called tenapanor that does not cross the intestinal barrier. They tested its effects on sodium uptake in normal rats and normal healthy humans, as well as in a rat model of salt-driven hypertension that resembles the patients that might benefit from this treatment. In healthy humans and rats, tenapanor decreased sodium uptake from the intestine and increased its concentrations in the stool, as expected for an NHE3 inhibitor acting exclusively in the intestine. It had no other damaging effects to the animals or subjects. The rats with salt-driven hypertension exhibited numerous problems—heart hypertrophy, excess fluid, arterial stiffening, and high blood pressure. Treatment with the drug before the disease onset and—important for a therapeutic agent—after disease onset improved all of these measures. A combination of tenapanor and the popular antihypertensive drug enalapril (which acts to inhibit angiotensin-converting enzyme) was more effective against certain outcomes than either drug alone. The combination improved cardiac function (left ventricular hypertrophy and arterial stiffness) and kidney function markedly, which enalapril alone did not. Modern humans often eat too much salt or have other reasons to limit the amount of sodium they consume. The inhibition of sodium uptake transporters in the intestine may prove a better way to combat these problems than our current approaches. The management of sodium intake is clinically important in many disease states including heart failure, kidney disease, and hypertension. Tenapanor is an inhibitor of the sodium-proton (Na+/H+) exchanger NHE3, which plays a prominent role in sodium handling in the gastrointestinal tract and kidney. When administered orally to rats, tenapanor acted exclusively in the gastrointestinal tract to inhibit sodium uptake. We showed that the systemic availability of tenapanor was negligible through plasma pharmacokinetic studies, as well as autoradiography and mass balance studies performed with 14C-tenapanor. In humans, tenapanor reduced urinary sodium excretion by 20 to 50 mmol/day and led to an increase of similar magnitude in stool sodium. In salt-fed nephrectomized rats exhibiting hypervolemia, cardiac hypertrophy, and arterial stiffening, tenapanor reduced extracellular fluid volume, left ventricular hypertrophy, albuminuria, and blood pressure in a dose-dependent fashion. We observed these effects whether tenapanor was administered prophylactically or after disease was established. In addition, the combination of tenapanor and the blood pressure medication enalapril improved cardiac diastolic dysfunction and arterial pulse wave velocity relative to enalapril monotherapy in this animal model. Tenapanor prevented increases in glomerular area and urinary KIM-1, a marker of renal injury. The results suggest that therapeutic alteration of sodium transport in the gastrointestinal tract instead of the kidney—the target of current drugs—could lead to improved sodium management in renal disease.