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Biomedical subjects

F G Knox

Publications and source records attributed to F G Knox.

At least 181 records · Page 10Linked to original sources
PubMed1977

Mechanism of resistance to the phosphaturic effect of the parathyroid hormone in the hamster.

The effect of parathyroid hormone and calcitonin on the renal excretion of phosphate, calcium, and cyclic AMP was evaluated in the thyroparathyroidectomized hamster, a mammal apparently reisstant to the phosphaturic effect of parathyroid hormone. Parathyroid hormone did not increase phosphate excretion, although it decreased excretion of calcium and increased urinary excretion of cyclic AMP. This lack of a phosphaturic response to parathyroid hormone was not reversed by administration of 25-OH vitamin D or infusions of calcium or phosphate. Calcitonin, another potentially phosphaturic hormone, also vailed to increase phosphate excretion but markedly elevated urinary excretion of cyclic AMP. In hamsters pretreated with infusion of urinary ammonium chloride, which decreased plasma and urinary pH, both parathyroid hormone and calcitonin increased excretion of phosphate as well as that of cyclic AMP. Acetazolamide had no phosphaturic effect in ammonium chloride-loaded hamsters, and it decreased cyclic AMP and calcium excretion. Alkalinization of urine by acetazolamide did not prevent the phosphaturic effect of parathyroid hormone in ammonium chloride-loaded hamsters, but it blocked the increase in urinary cyclic AMP excretion. Parathyroid hormone and calcitonin both stimulated adenylate cyclase in a cell-free system (600-g pellet) from hamster renal cortex, elevated tissue cyclic AMP levels, and activated protein kinase in tissue slices from hamster renal cortex. In acid medium, the increase in cyclic AMP and activation of protein kinase in response to parathyroid hormone was diminished, but addition of acetazolamide restored responsiveness of both parameters to control values. Acetazolamide, on the other hand, did not influence adenylate cyclase or its response to parathyroid hormone or cyclic AMP phosphodiesterase activity. We conclude that the lack of a phosphaturic effect of parathyroid hormone and calcitonin in the hamster depends on steps in the cellular action of these hormones, steps that are sensitive to pH subsequent to cyclic AMP generation and protein kinase activation. In addition, acetazolamide may potentiate the phosphaturic effect of parathyroid hormone by promoting accumulation of cyclic AMP in tissue. Thus, the hamster is a particularly useful model for studies of syndromes in which there is renal resistance to phosphaturic hormones.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1977

Filtration dynamics in dogs: glomerular capillary pressure.

Hydrostatic pressure in the glomerular capillaries, the primary driving force for glomerular ultrafiltration, is directly measurable only in those species with glomeruli present on the capsular surface of the kidney. Accordingly, this crucial measurement must be made indirectly in species not so endowed, such as the dog. Several different methods have been utilized in the dog; unfortunately each is indirect. This review deals with an assessment of the following methods for the determination of glomerular capillary pressure in dogs: a) reduction of arterial pressure method; b) ureteral occlusion method; c) the Winton or venous occlusion method; d) fraction of arterial pressure method; e) back calculation from forces opposing filtration; f) sieving method; and g) single nephron occlusion of the Gertz stop-flow method. Recent studies in the dog, utilizing single nephron occlusion techniques, provide estimates of glomerular capillary pressures of approximately 60 mn Hg in the autoregulatory range of blood pressure.

Animals↗
PubMed1976

Effect of parathyroid hormone on phosphate reabsorption in the presence of acetazolamide.

The hypothesis that parathyroid hormone and carbonic anhydrase inhibitors have a common mechanism or site of action on phosphate reabsorption by the renal tubule was tested by administration of parathyroid hormone in the absence and presence of acetazolamide in thyroparathyroidectomized dogs. Re-collection micropuncture and electron probe microanalysis methodologies were utilized. In the absence of acetazolamide, parathyroid hormone increased fractional delivery of phosphate (and volume) from the proximal tubule from 25 +/- 2 to 38 +/- 3%, P less than 0.025, and increased fractional phosphate excretion from 3.8 +/- 1.2 to 19.9 +/- 3.7%, P less than 0.005 (eight dogs). In the presence of acetazolamide, parathyroid hormone increased fractional delivery of phosphate (but not volume) from the proximal tubule from 50 +/- 4 to 58 +/- 5%, P less than 0.025, and increased fractional excretion of phosphate from 8.7 +/- 2.2 to 31.0 +/- 4.3%, P less than 0.001 (12 dogs). Thus, the effects of parathyroid hormone were additive to the effects of maximal inhibition of carbonic anhydrase indicating that parathyroid hormone and carbonic anhydrase inhibitors have different mechanisms of action on phosphate reabsorption by the renal tubule. In addition, phosphate reabsorption beyond the point of micropuncture in the late proximal tubule was much more markedly inhibited by parathyroid hormone than by acetazolamide.

Acetazolamide↗
PubMed1976

Intrarenal calcium in phosphate handling.

The intrarenal role of plasma ionized calcium (Ca), on fractional phosphate excretion (FE PO4) was investigated in dogs with control of parathyroid hormone (PTH). In series 1, acute thyroparathyroidectomy was immediately followed by a constant infusion of bovine PTH (0.01 U/kg per min). Subsequent calcium chloride infusions increased Cai in plasma phosphate and decreased in the percentage of ultrafiltrable phosphate. A 20% increase in Cai significantly increased FE PO4 by +3.82 +/- 0.97% (P less than 0.01) when infused intravenously and by +2.62 +/- 1.06% (P less than 0.05) when infused in the renal artery. In contrast, a 75% increase in Cai did not significantly change FE PO4. In series 2, dogs were thyroparathyroidectomized 18 h before experiments, and no PTH infusion was initiated. A bolus of bovine PTH (30 U/kg) increased FE PO4 + 8.9 +/- 0.9% (P less than 0.001) in hypocalcemic dogs, +19.1 +/- 4.4% (P less than 0.001) in normolcalcemic dogs, and +15.5 +/- 1.5% (P less than 0.001) in hypercalcemic dogs. We conclude that increases in plasma calcium potentiate the phosphaturic effect of PTH. This potentiating effect is attenuated in marked hypercalcemia by superimposed hemodynamic and/or metabolic changes.

Animals↗
PubMed1976

Sodium balance and the natriuresis of hypertonic saline infusion in dogs.

Recently, a paradoxical effect of dietary salt intake on the natriuresis following hypertonic saline infusion was observed in rats. In these experiments the effects of alterations in dietary sodium on the natriuretic response to a hypertonic saline load was studied in dogs. Dogs maintained on a high-sodium diet did not have a significantly different natriuresis than those on a low-sodium diet. When differences in sodium balance were amplified by the use of deoxycorticosterone, furosemide, and manipulation of dietary sodium, dogs in positive sodium balance showed a significantly enhanced initial excretion of sodium followed by a reversal of the pattern. Consequently, the cumulative sodium excretion was not different between low- and high-sodium groups. Since the cumulative natriuretic response to isotonic saline infusion was larger in dogs in positive sodium balance compared to those in negative sodium balance, the failure to detect a difference following hypertonic saline infusion was probably because of the increased plasma sodium concentration.

Animals↗
PubMed1976

Determinants of glomerular filtration rate in the dog.

Micropuncture techniques were used to evaluate the determinants of glomerular filtration in hydropenic dogs. Stop-flow and servo-null techniques were used to estimate the glomerular capillary and proximal tubule hydrostatic pressures. The validity of stop-flow estimates was verified by comparisons with direct puncture of glomerular capillaries in Munich-Wistar rats. Efferent arteriolar oncotic pressure was calculated from the filtration fraction and systemic protein concentrations. This calculation was verified in separate experiments by measurement of the protein concentration in blood collected directly from efferent arterioles. In 14 dogs, estimated glomerular capillary pressure (GCP) averaged 65.8 +/- 2.9 mmHg and proximal tubule pressure (PT) averaged 20.5 +/- 1.3 mmHg. The net hydrostatic filtration pressure (GCP - PT) of 45.3 +/- 2.7 mmHg was significantly higher than the efferent arteriolar oncotic pressure (piEA) of 33.2 +/- 2.8 mmHg (P less than .001). These findings indicate that filtration dynamics in the dog are characterized by filtration pressure disequilibrium.

Animals↗
PubMed1976

Effect of colchicine on urinary phosphate and regulation by parathyroid hormone.

The possible role of cytoplasmic microtubules in the renal handling of phosphate and its regulation by parathyroid hormone (PTH) was evaluated with colchicine, a microtubule-disrupting agent. Colchicine-treated rats were thyroparathyroidectomized (TPTX) and subsequently infused with PTH. Treatment with a total dose of 1 mg colchicine had no effect on glomerular filtration rate or fractional excretions of sodium and potassium. Fractional excretion of phosphate in colchicine-treated TPTX rats was significantly higher compared with TPTX controls. After PTH infusion, control rats responded with increases in fractional excretion of phosphate and urinary cyclic AMP but colchicine-treated rats had variable and insignificant changes in both parameters. Fractional excretion of sodium and potassium did not change significantly after PTH. Renal cortical activities of cyclic AMP phosphodiesterase, soluble alkaline phosphatase, cytochrome oxidase, leucine aminopeptidase, or basal adenylate cyclase were not significantly affected by colchicine treatment. On the other hand, stimulation of adenylate cyclase by a submaximal dose of PTH was markedly decreased in colchicine-treated rats, and the activity of membrane-bound alkaline phosphatase was also significantly decreased. The binding of radioactive colchicine in renal cortical extracts from rats treated with colchicine was significantly diminished. These results suggest that disruption of cytoplasmic microtubules in renal cortical cells interferes with phosphate transport and its regulation by PTH.

Alkaline Phosphatase↗
PubMed1976

Comparison of proximal tubule fluid-to-plasma ultrafiltrate chloride ratio in rats and dogs.

Previous studies in rats have demonstrated that the concentration of chloride in proximal tubule fluid is greater than that in plasma. The gradient reaches a free-flow steady-state level in the early proximal tubule and is maintained throughout the accessible proximal tubule. On the other hand, studies in dogs are in conflict regarding either the existence of a gradient or the development of a free-flow steady-state level. Since a species difference of tubule fluid to plasma chloride (TF/PC1) may exist, the present study was done to systematically compare the tubule fluid to ultrafiltrate chloride ratio (TF/UFC1) in hydropenic rats and dogs during normal acid-base balance. Chloride was analyzed by microelectrometric titration. In the rat the TFC1 and UFC1 concentrations were 139 +/- 1.4 and 120 +/- 1.2 meq/1, respectively. In the dog the TFC1 and UFC1 concentrations were 138 +/- 1.3 and 121 +/- 1.5 meq/1, respectively. Thus, there was no significant difference in the TF/UFC1 ratio between the rat (1.17 +/- 0.02) and the dog (1.14 +/- 0.01). Furthermore, regression analysis indicates that there is no correlation between TF/UFC1 and TF/PIn in either the rat or dog, which suggests that the gradient originates early in the proximal tubule and is maintained throughout the accessible proximal tubule in both species.

Animals↗
PubMed1976

Phosphaturic effect of dopamine in dogs. Possible role of intrarenally produced dopamine in phosphate regulation.

A possible role for dopamine in phosphate handling by the dog kidney was investigated by intrarenal artery infusions of dopamine. Dopamine increased fractional phosphate excretion both in the presence and absence of control of parathyroid hormone and calcitonin. In addition, dopamine increased both renal blood flow and sodium excretion, however, the phosphaturia was independent of these changes; since 30 min after completion of dopamine infusion, renal blood flow and sodium excretion returned to control levels and phosphate excretion remained elevated. For comparison, the vasodilator isoproterenol increased renal blood flow and sodium excretion without a significant change in fractional phosphate excretion. Thus, the phosphaturic effect of dopamine is probably independent of its vasodilator effect. The phosphaturic effect of dopamine could not be accounted for by subsequent conversion to norepinephrine, since norepinephrine was antiphosphaturic in the dog. The effect of endogenous dopamine on renal phosphate excretion was investigated by intrarenal infusion of the precursor dopa. Dopa was phosphaturic both in the presence and absence of parathyroid hormone and calcitonin. In dogs pretreated with carbidopa, which blocks conversion of dopa to dopamine, dopa was no longer phosphaturic, although the kidney remained responsive to dopamine. It is postulated that dopamine may play a role in the intrarenal regulation of phosphate excretion.

Animals↗
PubMed1976

Influence of renin depletion on renal function after release of 24-hour ureteral obstruction.

A marked increase in preglomerular resistance mediated through the renin-angiotensin system has been proposed as the mechanism for the sustained decrease in glomerular filtration rate seen following release of 24-hour ureteral obstruction. The importance of the renin-angiotensin system in mediating this response was evaluated by determining whole kidney and single nephron function following release of 24-hour ureteral obstruction in rats with normal renal renin content and in rats depleted of renal renin by desoxycorticosterone acetate acetate (DOCA) and saline treatment. The DOCA and saline treatment was effective in reducing renal renin content to less than 10% of the normal values. However, when compared to nonobstructed kidneys, both whole kidney filtration rate and single nephron filtration rate were similarly and significantly reduced in both groups following release of 24-hour ureteral obstruction. Single nephron stopflow techniques were used to determine the net hydrostatic force for filtration. The net hydrostatic force for filtration in control nonobstructed nephrons averaged 37.8 +/- 1.1 mm. Hg, but was significantly decreased to 22.5 +/- 2.2 mm. Hg in the normal renin obstructed kidney and to 18.8 +/- 1.0 mm. Hg in the renin-depleted obstructed kidney. It is concluded that the marked depression in glomerular filtration rate seen following release of 24-hour ureteral obstruction is due to increased afferent arteriole resistance and that the renin-angiotensin system is apparently not important in mediating the response.

Aminohippuric Acids↗
PubMed1976

Tissue pressures and fluid dynamics in the kidney.

The kidney has several characteristics which make renal pressures and fluid dynamics unique when compared to other organs. Renal blood flow is roughly 100 times that of skeletal muscle. The renal circulation consists of two distinct capillary beds in series: a high pressure system in the glomerulus that favors filtration and a low pressure system in the peritubule network that favors reabsorption. The hydrostatic pressure in the glomerular capillary is 4-6 times higher than the hydrostatic pressure in the peritubule capillary so that approximately 25% of the plasma is filtered. The bulk of the filtrate is subsequently reabsorbed by the peritubule capillary network. Micropuncture techniques have been used to obtain quantitative measurements of the pressures and fluid dynamics of the peritubule microcirculation. The net force for uptake of all the fluid reabsorbed by a single proximal tubule up to the point of micropuncture is 21 mm Hg acting over a capillary bed with a permeability surface area product of 2 nl/min per mm Hg. In contrast to subcutaneous tissue and muscle, the renal interstitial fluid pressure is positive. The consequence of a positive interstitial fluid pressure is that normal lymph flow is relatively high and changes in interstitial fluid pressure have relatively little effects on lymph flow.

Animals↗
PubMed1976

Lack of effect of hypocalcemia on renal phosphate handling.

A possible effect of decreased plasma ionized calcium concentration on renal phosphate handling was investigated in dogs with control of parathyroid hormone. Intrarenal artery infusion of either EDTA or sodium citrate decreased ionized calcium concentration 25 per cent in renal vein blood but had no significant effect on fractional phosphate excretion. Similarly, intravenous infusion of chelators had no significant effect on fractional phosphate excretion. It is concluded that acute decreases in ionized calcium have no significant effect on the renal handling of phosphate.

Animals↗
PubMed1975

Role of parathyroid hormone in the phosphaturia of extracellular fluid volume expansion.

Role of parathyroid hormone in the phosphaturia of extracellular fluid volume expansion. Acute expansion of the extracellular fluid volume increases the urinary excretion of phosphate. The present study examined the importance of increased plasma parathyroid hormone concentration in the phosphaturia accompanying acute extracellular fluid volume expansion (ECVE). Infusion of a calcium-free Ringer's solution into dogs was associated with increased urinary phosphateexcretion and serum immunoreactive parathyroid hormone concentration (iPTH), the latter being significantly correlated with a decrease in plasma ionized calcium concentration. Prevention of the fall in plasma ionized calcium concentration by infusion of a calcium containing Ringer's solution prevented the increase in serum iPTH but the magnitude of the phosphaturia was not affected.

Animals↗
PubMed1975

Effects of extracellular fluid volume contraction and expansion on the bicarbonaturia of parathyroid hormone.

To evaluate the effect of extracellular fluid volume alterations on the bicarbonaturia of parathyroid hormone, thyroparathyroidectomized dogs were made alkalotic and volume-contracted or expanded through hemodialysis. Clearance studies were performed before and after infusion of purified bovine parathyroid extract (PTE). Glomerular filtration rate and blood bicarbonate concentrations were kept constant throughout the experiments. A significant increase in fractional bicarbonate excretion was observed following PTE infusion in both the volume-contracted (8.67 +/- 3.25 to 14.70 +/- 3.63%, P less than 0.010) and the volume-expanded state (22.80 +/- 3.04 to 37.26 +/- 3.38%, P less than 0.050). It is concluded that PTE decreases reabsorption of bicarbonate independent of the volume state of the animal.

Alkalosis↗
PubMed1975

Distal site of action of parathyroid hormone on phosphate reabsorption.

The sites of inhibited phosphate transport following administration of bovine parathyroid hormone (bPTH) to thyroparathyroidectomized (TPTX) dogs were investigated. Phosphate reabsorption by the proximal and distal nephron was studied using recollection micropuncture, stop-flow methodology, and electron-probe microanalysis. Following bPTH, delivery of phosphate from the proximal tubule increased from 26 to 37% of the filtered load, P less than .01. Fractional phosphate excretion increased from 2.3 +/- 1.5 to 21.4 +/- 2.3%, P less than .001. The increased delivery of phosphate at the point of micropuncture in the proximal tubule accounted for approximately half of the phosphaturia. In six TPTX dogs, which were saline loaded, similiar increases in phosphate delivery from the proximal tubule from 27 +/- 1 to 36 +/- 2% of the filtered load resulted in a strikingly smaller phosphaturia, 5.1 +/- 1 to 9.8 +/- 2.4%, NS. In stop-flow experiments, phosphate concentratin ratios were slightly increased in the proximal nephron and markedly increased in the distal nephron following bPTH. It is concluded that parathyroid hormone markedly decreases phosphate transport in the distal nephron.

Aminohippuric Acids↗