COTRANSPORT INHIBITORY FACTOR - A CLUE TO UNDERSTANDING THE ROLE OF RENAL NA-K-CL COTRANSPORTERS IN ESSENTIAL-HYPERTENSION

Na-K-Cl cotransport system has a predominant role in the thick ascendi ng limb of Henle's loop, where it accounts for almost all luminal NaCl reabsorption. The activity of this transport protein is regulated by an humoral factor, cotransport inhibitory factor (CIF), which is secre ted in the circulation in response to excess salt intake. The site of origin of CIF seems to be the neurohypophysis. Purification and chemic al analysis of CIF are ongoing in our laboratory. Recently, a first ur inary compound with ''furosemide-like'' activity was purified in suffi cient amounts (in rats) to allow structural analysis. Mass spectroscop y revealed a molecular mass of 242 Da. Nuclear magnetic resonance show ed a spectrum identical to that of 4-dihydro-3-(4-hydroxyphenyl)-2H-1- benzopyran-7-ol (an ''estrogen-like'' isoflavonoid: equol). Equol inhi bited cotransport fluxes at similar concentrations as furosemide. Conv ersely, equol was unable to inhibit Na-K pump fluxes, clearly showing that it was different from the previously described ''digitalis-like'' factor (EDLF: ouabain or a closely related isomer or a bufodienolide) . Cotransport inhibitory activity of urines from rats drinking tap wat er was fully explained by urinary equol concentrations. Salt-loading i ncreased urinary equol excretion, but not sufficiently high to fully e xplain the very important increase in cotransport inhibitory potency. Therefore, salt-loading evokes the appearance of other cotransport inh ibitors (salt-dependent CIF). Some essential hypertensive patients see m characterized by increased plasmatic levels of CIF (salt-dependent) and EDLF, which reduce cotransport and pump fluxes in circulating cell s. These hypertensives seem identical to the ''low-renin, salt-sensiti ve'' hypertensives, where increased CIF (and perhaps EDLF) can be comp ensatory mechanisms against sodium retention. Besides salt-sensitive h ypertension, CIF can play a compensatory role in other cardio-vascular disease with a tendency to fluid retention. Finally, defective or exc essive CIF can be perhaps a primary cause of disorders of salt and wat er metabolism.