The presence of several naturally occurring amino acids in the serosal bath of toad urinary bladder significantly alters the hydrosmotic response of this tissue to vasopressin. We found that histidine, glutamate, and lysine increase vasopressinstimulated water flow by 75%, 60%, and 43%, respectively. In contrast, alanine did not alter vasopressin-stimulated water flow, whereas glutamine decreased it by 25%. The effect of each amino acid represents intracellular events because their effects on theophylline-stimulated water flow were similar to those found with vasopressin. However, the site of action of amino acids varied, with some operating at steps before and others at steps after cyclic AMP generation. The fact that the metabolically inactive D-histidine and D-glutamate are as effective as their metabolically active L-counterparts suggests that the action of amino acids depends upon some physicochemical properties of their molecules. The ability of amino acids to influence the hydrosmotic effects of vasopressin was shown to be independent of prostaglandin generation, ionic composition, and molecular charge.In the case of histidine, we were able to obtain some understanding of the mechanism responsible for its action. We first showed that the effect of histidine does not depend upon its metabolism. In addition to D-histidine being as effective as the metabolically active L-histidine, we also showed that histidine is effective when its metabolism is abolished by low ambient temperature and also when its incorporation into proteins was prevented by cycloheximide. These findings suggest that histidine operates through some physicochemical property localized on its molecule. We were able to show that this property resides on the imidazole part of histidine. Imidazole, similar to histidine, increases vasopressin-stimulated water flow. Methylation of histidine on the imidazole ring completely abolished its effectiveness in increasing vasopressin-stimulated water flow. In contrast, methylation of histidine at the side chain increased vasopressin action similar to that found for histidine.We provide evidence that the physicochemical property of the imidazole ring of histidine is that of chelating Zn++
I present a technique that permits evaluation of the permeability to water of the luminal membrane of the toad urinary bladder, independently of constraints to water flow imposed by the remainder of the tissue. This technique essentially depends on fixation of the luminal membrane with 1% glutaraldehyde for 5 min, and subsequent elimination of cytosolic constraints by decreasing the tonicity of the serosal bath to 1/2 normal strength. The increased hydraulic conductivity found with serosal hypotonicity is readily reversible, as the bladder returns to an isotonic serosal bath. By evaluating water flow in luminally fixed bladders during bathing in normal and hypotonic bath, one may identify the relative contribution of the luminal membrane and the "cytosol" on water flow. Using this technique, I found that the effect of the prostaglandin inhibitor Naproxen to increase vasopressin-stimulated water flow is due to increased luminal membrane permeability. The effect of histidine to increase vasopressin-stimulated water flow, however, depends on increased permeability of both the luminal membrane as well as the underlying structures. The action of serosal hypertonicity to induce water flow is due to an increased luminal permeability. However, serosal hypertonicity decreases "cytosolic" permeability, so that its overall function is a composite effect of its action at the luminal membrane and the "cytosolic" level.
Studies in vitro have shown that L-histidine increases the hydroosmotic response to vasopressin. We examined whether this phenomenon occurs also in vivo. Homozygous Brattleboro rats (di/di) were fed a regular diet (0.5% histidine) or a diet enriched with histidine and received 1 ng of 1-deamino-8->-arginine vasopressin (dDAVP) daily. Addition of histidine (1% by weight) increased post-dDAVP urine osmolality to a level higher than that of control (502±62 vs. 316±36 mosmol/kg, P < 0.05). Similar results were seen with 3.0% and 5.5% dietary histidine. There were significant increases in free-water reabsorption and in the ratio of free-water reabsorption to osmolar clearance, but no difference in osmolal clearance. No significant effect was found with supplemental histidine of 0.5% or less. The cause for these findings appears not to be the metabolism of histidine, since the nonmetabolizable D-histidine had a significant, albeit smaller, effect, and the isonitrogenous addition of albumin, alanine, arginine, or glutamine was ineffective. In part, histidine may operate by increasing cAMP since the renal cAMP content in response to vasopressin is increased in histidine-fed rats (13.1±0.9 vs. 9.8±0.8 nmol/g dry weight, P < 0.01). The role of prostaglandins appears less clear. Histidine greatly decreased urinary PGE2 during baseline (1.5±03 vs. 7.0±2.3 ,g/mg creatinine, P < 0.001), but it profoundly augmented urinary prostaglandin excretion after dDAVP stimulation (40.0±4.2 vs. 7.0±2.0 ,g/mg creatinine, P < 0.001). (J. Clin. Invest. 1990. 85:921-928.) cyclic AMP -histidineprostaglandins -vasopressin
Addition of histidine to the serosal bath of the toad bladder increases the hydrosmotic response of vasopressin in this tissue. Because this represents primarily the effect of the imidazole ring of histidine, which is a known inhibitor of the production of prostaglandins, we evaluated whether histidine increases the response to vasopressin through decreased prostaglandin production. Histidine increases the response to vasopressin much more than 10(-5) M naproxen, even though the latter was equipotent to histidine in reducing prostaglandin E2 (PGE2) production. Furthermore, histidine was additive to naproxen in increasing the hydrosmotic effect of vasopressin, without causing a further decrease in PGE2 production. These findings suggest that histidine has an effect over and above that due to inhibition of prostaglandin synthesis. Our results suggest that histidine enhances the permeability of the tissue beneath the luminal membrane, an effect not found with naproxen. We propose that histidine increases the hydrosmotic response to vasopressin through at least two distinct mechanisms: 1) it decreases prostaglandin synthesis and thus increases luminal permeability; 2) it decreases the resistance to water movement of the tissues beneath the luminal membrane.
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