Search

Presented is a committee report which gives background information about the science of physiology and discusses the roles of academic physiology departments and the American Physiological Society. Recommendations for the future of the discipline in its various dimensions are provided. (CW)

Potassium channels in the apical and basolateral membranes of tubule cells serve several important functions. They contribute to the generation of the cell-negative potential, mediate volume reductions following cell swelling and play a key role in secretion of potassium in both the thick ascending limb of Henle's loop and principal tubule cells of the initial and cortical collecting tubules. Secretion of potassium occurs via a well-defined class of potassium channels distinguished by their low single channel conductance, mild inward rectification, high sensitivity to inhibition by low pH, millimolar concentrations of ATP, arachidonic acid and PKC, and stimulation by vasopressin and pretreatment with a high potassium diet. Genes encoding several isoforms of this channel have been cloned and the proteins located to the apical membranes of cells lining the thick ascending limb of Henle's loop and the collecting tubules, and progress made concerning their structure-function relationship.

To study the effects of ADH on the transport of potassium by the distal tubule and collecting duct system, we performed simultaneous clearance and micropuncture experiments in homozygous Brattleboro rats (with hereditary hypothalamic diabetes insipidus), before and after intravenous infusion of the hormone. Final urinary flow rate was reduced by a factor of 7 after ADH, but fractional potassium excretion increased by 77% for the group as a whole. During free-flow micropuncture, there was no significant difference in fractional delivery of potassium up to the late distal tubule between control (water diuresis) and ADH conditions; thus, the increase in final urinary potassium excretion was mediated beyond this tubular site. However, flow rate of tubular fluid was decreased significantly after ADH in late distal tubular segments, where potassium secretion is a flow-dependent process. To evaluate the possibility of a direct effect of ADH on distal tubular potassium secretion, independent of changes in flow rate, we studied another group of animals by continuous microperfusion, in vivo, of single distal tubules, using an isotonic perfusion fluid so that water reabsorption would be minimal after as well as before the addition of ADH. Under these conditions, a significant stimulation of distal tubular potassium secretion by ADH could be demonstrated. We suggest that this property of ADH may serve to prevent potassium retention during periods of antidiuresis.

Potassium depletion (KD) causes renal chloride-wasting. To investigate the effects of KD on renal tubular reabsorption of chloride, balance, clearance, micropuncture, and microinjection studies were performed on potassium-depleted rats. KD was produced by omitting potassium from the diet and by administration of DOCA on days 2 and 3; rats were studied on days 9 to 12. Diets were chloride-free in both control and KD groups. In the KD group, balance experiments confirmed greater chloride depletion and continued chloride-wasting, and clearance studies showed an increased FECl. Muscle potassium was reduced by 27% as compared to control. Whole kidney and single nephron GFR were reduced in KD rats to 72 and 74% of control. Fractional (6 +/- 6% vs. 22 +/- 4%, P less than 0.05) and absolute chloride reabsorption in the proximal tubule was not different. Fractional reabsorption of delivered chloride was reduced in the loop of Henle (92 +/- 0.8% in KD vs. 95 +/- 0.7% in control, P less than 0.02). Transtubular chloride ratio (0.28 +/- 0.02 vs. 0.21 +/- 0.02, P less than 0.02) was increased at the early distal tubule. Fractional delivery of chloride (8 +/- 0.9 vs. 5 +/- 0.5%, P less than 0.02), and fluid (26 +/- 1 vs. 22 +/- 1%, P less than 0.05) were also increased in KD at the early distal tubule. Recovery of chloride 36 injected into late distal tubules was 88 +/- 1% on a normal chloride intake, 62 +/- 2% in chloride depletion, and 88 +/- 2% in potassium and chloride depletion. Thus, KD depresses chloride reabsorption in the proximal tubule and in the loop of Henle, and it decreases chloride 36 efflux from the collecting duct.

The paracellular pathway permeability is known to increase in perfused amphibian kidneys if the luminal fluid is made hyperosmotic with mannitol or urea. To investigate whether luminal hypertonicity increases paracellular pathway permeability in the mammalian nephron, early rat distal tubules were micropunctured and perfused through one micropipette with either isosmotic saline (IS), hyperosmotic urea (HU) or hyperosmotic mannitol (HM) solutions. A second micropipette was placed down-stream in the same tubule and test solutions of 30 nl of a mixture of 14C-inulin and 3H-mannitol or of 3H-inulin and 14C-urea were injected. Similar intratubular injections of tracers were performed in a second group of rats undergoing diuresis induced either by infusing intravenously saline alone (VS) or receiving saline plus 0.4 M urea (VU). In the latter group (VU) luminal urea concentration was increased without the tubular lumen being made hyperosmotic to its peritubular fluid. Urinary unulin recovery was essentially complete and unaffected by experimental procedures. Difference between mannitol recoveries in isosmotic saline and hyperosmotic urea perfusions IS-HU was 2.6 +/- 0.8% (P less than 0.001). Difference in urea recoveries IS-HM was 4.1 +/- 5.1% (P greater than 0.40), IS-HU was 13.9 +/- 5.3% (P equal to 0.015) and, VS-VU equal to 17.0 +/- 3.4 (P less than 0.001). Therefore, elevated luminal urea concentration increased tracer mannitol and also tracer urea permeability, both in the presence and absence of tubular hyperosmolarity. Electron microscopic observations showed changes in geometry of tubular junctional complexes compatible with the observed increase in permeability.

Chronic high-dose mineralocorticoid hormone treatment of rabbits results in marked alterations of the structure and function of the cortical collecting duct. Most importantly, the reabsorption of Na+ and the secretion of K+ are increased. Intracellular microelectrode measurements provide evidence consistent with the idea that the increased transport of these ions is a result of changes in the membrane conductances and electrochemical driving forces for passive ion movement and of the activity of the Na+,K+-ATPase. Specifically, the Na+ and K+ conductances of the apical membrane are increased, and the cellular potential profile is altered to promote transcellular movement of K+ from the peritubular to the luminal fluid compartments. The associated increase in the activity of the Na+,K+-ATPase facilitates extrusion of Na+ from and accumulation of K+ into the cell. The resistance of both the apical and basolateral cell membranes are reduced with DOCA treatment, while the resistance of the paracellular pathway is increased. Consequently, the electrophysiological properties of the tubule epithelium reflect to a greater degree the properties of the transcellular pathway.

Ring annelation of the [(aminomethyl)aryloxy]acetic acids produced a series of substituted 6,7-dichloro-2,3-dihydrobenzofuran-2-carboxylic acids. Pharmacologic evaluation of these compounds in rats and dogs indicated that several congeners are extremely potent salidiuretics. Clearance and micropuncture experiments in rats for compound 5a confirmed the high-ceiling diuretic profile and demonstrated that 5a has a site of action at the thick ascending limb of Henle's loop.

Studies were performed to 1) systematically compare Ling-Gerard microelectrodes and electrodes with large tips (3 to 5 mu O.D.) in the measurement of the transepithelial potential difference (PD) in the mammalian distal tubule and 2) to examine the sign and magnitude of the transepithelial PD along the length of the distal tubule. Recordings made with the tips of both types of electrodes placed together in the same tubule segment demonstrated no difference in transepithelial PD. Rapid influx of tubular fluid into the macroelectrode, however, was found to depolarize the tubular membrane, as recorded by both types of electrodes simultaneously. Technical critera were therefore established to prevent rapid influx of fluid and efflux of potassium chloride, filling the electrode, in the use of exploring electrodes with large tips. The sign of the transepithelial PD in early distal tubule was found to be negative and averaged -17.7 +/- 9.4 (mean +/- SEM) in Sprague-Dawley rats and approximately -12 mV in Wistar-Munich rats. The site of puncture was identified by dye transit time rate, microdissection, and cell morphology. The transepithelial PD increased along the length of the distal tubule and averaged -41.9 +/- 8.5 in the last portion accessible to examination.

The urinary bladder of Amphiuma exhibits stable transport properties and an electrical potential difference in vitro. The lumen is significantly negative to the serosa and under short-circuited conditions flux rations for Na and Cl of 5.92 +/- 0.42 and 1.81 +/- 0.20, respectively, were observed. The close agreement between the short-circuit current and net Na flux suggests that most, if not all, of the current is carried by Na. Both ouabain and amiloride decreased the short-circuit current and the mucosal-to-serosal (M leads to S) flux of Na. Furosemide caused a transient increase in the M leads to S flux of Na and Cl but ADH was without effect. In bladders that had high transmural resistance, a net movement of K in the M leads to S direction under short-circuited conditions with flux ratios of up to 2 could be observed. The epithelium of the Amphiuma bladder consists of three cell types: granular cells, basal cells, and mitochondria-rich cells. No goblet cells are present. The mitochondria-rich cells comprise less than 5% of the population of the surface epithelium in Amphiuma in contrast to other amphibian bladders, where it accounts for up to 25% of the population.