Translating molecular physiology of intestinal transport into pharmacologic treatment of diarrhea: stimulation of Na+ absorption

Abstract

Diarrheal diseases remain a leading cause of morbidity and mortality for children in developing countries, while representing an important cause of morbidity worldwide. The World Health Organization recommended that low osmolarity oral rehydration solutions plus zinc save lives in patients with acute diarrhea, but there are no approved, safe drugs that have been shown to be effective against most causes of acute diarrhea. Identification of abnormalities in electrolyte handling by the intestine in diarrhea, including increased intestinal anion secretion and reduced Na(+) absorption, suggest a number of potential drug targets. This is based on the view that successful drug therapy for diarrhea will result from correcting the abnormalities in electrolyte transport that are pathophysiologic for diarrhea. We review the molecular mechanisms of physiologic regulation of intestinal ion transport and changes that occur in diarrhea and the status of drugs being developed to correct the transport abnormalities in Na(+) absorption that occur in diarrhea. Mechanisms of Cl(-) secretion and approaches to anti-Cl(-) secretory therapies of diarrhea are discussed in a companion review.

Keywords: BB; CaSR; DRA; Diarrhea; ENaC; GI; Intestine; NHE3; Na Absorption; Na(+) D-glucose linked co-transporter 1; ORS; SCFA; SGLT1; WHO; World Health Organization; brush border; cAMP; cGMP; calcium-sensing receptor; cyclic adenosine monophosphate; cyclic guanosine monophosphate; down-regulated in adenoma; epithelial Na(+) channel; gastrointestinal; oral rehydration solution; short-chain fatty acid; sodium/hydrogen exchanger 3.