Importance of molecular size and hydrogen bonding in vasopressin-stimulated urea transport

Abstract

We have employed a variety of urea and thiourea analogues to elucidate further the vasopressin-stimulated urea transport mechanism. In the urea series there was a progressive inhibition of tracer urea transport as cylindrical radius of analogue increased from 2.9 to 3.5 A. Above 3.8 A no inhibition was found. Thiourea analogues were more potent inhibitors for comparable cylindrical radii, and compounds greater than 3.8 A again were not inhibitory. Inhibition was comparable when the inhibitor was moving in the same or opposite directions. Urea transport and its inhibition were preserved in bladders fixed with glutaraldehyde. Osmotic water flow, tritiated water flow, and uric acid transport were not affected by any analogues tested. Analogues of urea and thiourea affected the transport of labeled methylurea and thiourea in a manner similar to their effect on urea. We therefore propose that the urea transport mechanism is a channel with a cylindrical radius between 3.5 and 3.8 A that is capable of interaction with the moving species by hydrogen bonding. This model can account for the selectivity of the vasopressin-stimulated urea transport, its inhibition by urea and thiourea analogues, the facilitated transport of urea, inhibition of tracer urea flux from either the cis or the trans position, and finally the preservation of the urea transport machinery following glutaraldehyde fixation.