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D G Shirley

Publications and source records attributed to D G Shirley.

At least 19 recordsLinked to original sources
PubMed1995

A micropuncture study of renal tubular lithium reabsorption in sodium-depleted rats.

1. The marked reduction in fractional lithium excretion (FELi) which accompanies chronic sodium depletion was investigated using free-flow micropuncture in anaesthetized rats which had been maintained in a sodium-depleted state for 8-10 days. 2. Compared with previous values in sodium-replete rats, sodium depletion was associated with small reductions in total and superficial nephron glomerular filtration rate and enhanced fractional reabsorption of water, sodium and lithium in the proximal convoluted tubule. 3. In untreated (sodium-depleted) rats, fractional deliveries of lithium (FDLi) to the late proximal convoluted tubule, early distal tubule and late distal tubule were 0.41 +/- 0.02, 0.20 +/- 0.01 and 0.18 +/- 0.02 (means +/- S.E.M.), respectively. Fractional lithium excretion (0.08 +/- 0.01) was significantly lower than late distal FDLi (P < 0.001). 4. Treatment with amiloride did not affect segmental lithium handling up to the late distal tubule. Frusemide had no effect on lithium reabsorption in the proximal convoluted tubule, but early distal FDLi (0.30 +/- 0.01) was raised compared with the untreated group (P < 0.001). Both diuretics eliminated the difference between late distal FDLi and FELi, respective values being 0.17 +/- 0.02 and 0.15 +/- 0.01 (amiloride-treated rats) and 0.31 +/- 0.02 and 0.34 +/- 0.02 (frusemide-treated rats). 5. These data indicate that part of the reduction in FELi in chronic sodium depletion is due to enhanced fractional fluid (and lithium) reabsorption in the proximal convoluted tubule. In addition, however, they provide direct evidence for amiloride-sensitive lithium reabsorption in the collecting ducts.(ABSTRACT TRUNCATED AT 250 WORDS)

Absorption↗
PubMed1995

A micropuncture study of the renal response to haemorrhage in rats: assessment of the role of vasopressin.

The acute effects of haemorrhage (15 ml (kg body wt)-1) on renal function at whole-kidney and single-nephron levels were studied in Inactin-anaesthetized rats. In order to assess the role of vasopressin in mediating the haemodynamic effects, responses in untreated Long-Evans rats were compared with those in Brattleboro rats (which lack circulating vasopressin) and in Long-Evans rats treated with a V1 receptor antagonist. In time-control animals, there were no significant changes in mean arterial pressure (MAP), excretion rates, glomerular filtration rate (GFR), superficial-nephron GFR (SNGFR) or fluid reabsorption in the superficial proximal tubules during the course of the experiment. Following haemorrhage, the immediate reduction in MAP was followed in each group by partial recovery for 30 min; thereafter, MAP was stable. In untreated Long-Evans rats, haemorrhage was followed by a 26% reduction in GFR (P < 0.001, measured 60-150 min post-haemorrhage) and a larger reduction (45%, P < 0.001) in SNGFR, so that the SNGFR/GFR ratio fell significantly ((27.9 +/- 1.9) x 10(-6), control period; (20.2 +/- 2.2) x 10(-6) post-haemorrhage, P < 0.01). Slightly greater reductions in GFR and SNGFR were seen in Brattleboro rats and V1 antagonist-treated Long-Evans rats, which corresponded to slightly greater haemorrhage-induced reductions in blood pressure in these groups; the falls in the SNGFR/GFR ratio were similar to that in untreated Long-Evans rats. In all three groups of bled rats, fractional reabsorption by the proximal convoluted tubule increased slightly 30-60 min after haemorrhage, but during the subsequent period (60-150 min) returned to values indistinguishable from those during the control period. The results suggest that the renal haemodynamic changes that follow moderate haemorrhage include a preferential reduction in the GFR of superficial nephrons. Vasopressin appears to play no role in this response. Increases in fractional reabsorption in the proximal tubules are seen only during the immediate post-haemorrhage period.

Absorption↗
PubMed1994

The effect of chronic sodium depletion on renal function in conscious rats.

In order to investigate the effect of chronic sodium depletion on renal proximal tubular reabsorption, studies were performed in conscious, unrestrained Brattleboro rats. Since these animals lack circulating vasopressin, fractional water reabsorption in the distal nephron can be assumed to be constant and changes in urine flow rate should therefore reflect changes in end-proximal fluid delivery. Sodium depletion was induced by placing rats on a low-sodium diet (4 mmol Na (kg dry wt)-1) and administering frusemide (40 mg (kg body wt)-1) by gavage on the first 2 days. Extracellular volume, measured after 7-9 days, was reduced by 19% (P < 0.02) as compared with that of rats maintained on a control diet. Urine flow rate, measured during days 4-7 of the low-sodium diet, was significantly lower than that of control rats (142 +/- 8 vs. 168 +/- 5 ml day-1, P < 0.01). Since renal papillary interstitial fluid osmolality was found to be reduced in the sodium-depleted rats (693 +/- 38 vs. 812 +/- 36 mosmol (kg H2O)-1, P < 0.05), it is unlikely that water reabsorption from sites beyond the proximal tubule had increased. The observed reduction in urine flow rate therefore strongly suggests a reduction in end-proximal fluid delivery. In the second part of the study, a single group of Brattleboro rats was used, in which osmotic minipumps were implanted in the peritoneal cavity for continuous infusion of [14C]inulin. After recovery from the operation, the rats were maintained on a control diet for 6 days (pre-control period), then subjected to sodium depletion (low-sodium diet for 6 days, frusemide administration on the first 2 days), and finally returned to the control diet for 6 days, with access to 0.46 M NaCl solution on the first 2 days, in order to restore sodium balance (post-control period). On the final 2 days of each phase, urine flow rate and [14C]inulin clearance (= glomerular filtration rate, GFR) were measured. Urine flow rates during the pre-control, sodium depletion and post-control periods were 169 +/- 7, 132 +/- 8 (P < 0.001) and 176 +/- 8 microliters min-1, respectively; corresponding values for fractional water excretion were 7.0 +/- 0.3, 6.0 +/- 0.5 (P < 0.01) and 7.4 +/- 0.4%. Only a small reduction GFR, of borderline statistical significance, was observed during sodium depletion.(ABSTRACT TRUNCATED AT 250 WORDS)

Absorption↗
PubMed1994

Lithium reabsorption in perfused loops of Henle: effects of perfusion rate and bumetanide.

The contribution of the loop segments to lithium reabsorption in sodium-replete, anesthetized Sprague-Dawley rats was examined by perfusing superficial loops of Henle between late proximal convolutions and early distal tubules. Preliminary experiments in which lithium was initially present only inside or outside the perfused loop confirmed substantial permeability of one or more of the loop segments to lithium. In subsequent experiments, in which lithium was infused intravenously and included in the perfusate so that the perfusate-to-plasma lithium concentration ratio was close to that found in late proximal tubules during lithium clearance studies, lithium reabsorption was inversely related to the perfusion rate: values for fractional lithium reabsorption (FRLi) at perfusion rates of 10, 20, and 30 nl/min were 58 +/- 3, 17 +/- 2, and 2 +/- 2%, respectively. Bumetanide (10(-6) M) markedly inhibited FRLi but also reduced water reabsorption, suggesting an effect on the pars recta at this dose; 10(-7) M bumetanide, which was without effect on water reabsorption, had only a small effect on FRLi at a perfusion rate of 10 nl/min but reduced FRLi by approximately 70% at 20 nl/min. We argue that the remarkable flow dependency of lithium reabsorption, together with its bumetanide sensitivity, provides evidence for significant voltage-driven lithium reabsorption in the thick ascending limb of Henle.

Absorption↗
PubMed1992

A micropuncture study of renal lithium reabsorption: effects of amiloride and furosemide.

The validity of the lithium clearance technique as a measure of end-proximal fluid delivery was assessed using micropuncture in sodium-replete, Inactin-anesthetized Sprague-Dawley rats. Three groups of animals were used: controls, amiloride treated, and furosemide treated. Diuretic-induced salt and water losses were replaced. Fractional lithium excretion (FELi) was 0.23 +/- 0.01, 0.24 +/- 0.02, and 0.40 +/- 0.03 in the control, amiloride, and furosemide groups, respectively. In each group, the tubular fluid-to-plasma lithium concentration ratio at the end of the proximal convoluted tubule (PCT) was significantly greater than unity (control, 1.16 +/- 0.03; amiloride, 1.16 +/- 0.02; furosemide, 1.17 +/- 0.02). In the control group, fractional lithium delivery (FDLi) at the late PCT was 0.50 +/- 0.02, while FDLi at the early distal tubule was 0.25 +/- 0.01; the latter did not differ significantly from FDLi at the late distal tubule or from FELi. Values in amiloride-treated rats were almost identical. Furosemide had no effect on FDLi at the late PCT, but raised that at the early distal tubule to 0.37 +/- 0.03. We conclude that 1) lithium reabsorption in the PCT lags slightly behind that of water, 2) substantial furosemide-sensitive lithium reabsorption occurs beyond the PCT, and 3) no significant lithium reabsorption occurs in nephron segments beyond the loop. These findings call into question the use of lithium clearance as a quantitative measure of end-proximal fluid delivery in sodium-replete animals.

Absorption↗
PubMed1991

Acute and chronic changes in renal function following unilateral nephrectomy.

Free-flow micropuncture was used to assess proximal and distal tubular function in rats immediately (2 to 5 hours), five days and 30 days after uninephrectomy (UN); results were compared with those in sham-operated littermates. Excretion rates of water, sodium and potassium were approximately doubled in the remaining kidney of UN rats. Two to five hours after UN there were small increases in glomerular filtration rate (GFR) and single nephron GFR which at this stage were not accompanied by an increase in absolute proximal reabsorption; that is, fractional proximal reabsorption fell. After five days, GFR and single nephron GFR had increased further; at this stage absolute proximal reabsorption was also significantly elevated. After 30 days, kidney weight, GFR, single nephron GFR and absolute proximal reabsorption had all increased by approximately 40%, and glomerulotubular balance in the proximal tubule had been fully restored. Data derived from distal tubular collections indicated that at every stage after UN: (a) fluid delivery to both early and late distal puncture sites was increased; (b) in contrast, there was no increase in sodium delivery to the late distal tubule, suggesting that the natriuresis resulted from reduced sodium reabsorption beyond the distal tubule and/or increased delivery of sodium from deep nephrons; and (c) there was a marked increase in potassium secretion into the accessible portion of the distal tubule which was more than adequate to explain the observed kaliuresis.

Animals↗
PubMed1991

How important are suppression of aldosterone and stimulation of atrial natriuretic peptide secretion in the natriuretic response to an acute sodium load in man?

1. Aldosterone is suppressed by sodium loading. We studied the contribution of this decrease in plasma aldosterone to the natriuresis after acute sodium loading in healthy volunteers. 2. Two litres of saline [0.9% (w/v) NaCl] were infused during the second hour of a 6 h infusion of aldosterone (3 pmol min-1 kg-1) or placebo in eight healthy young men. On the placebo day, plasma aldosterone decreased by 30 min after the start of saline infusion and remained suppressed. During aldosterone infusion, plasma aldosterone was maintained at around 400 pmol/l. 3. Urinary sodium excretion, lithium clearance and plasma atrial natriuretic peptide increased and plasma renin activity decreased after saline infusion, whether or not aldosterone was infused. However, from 60 to 240 min after saline infusion, natriuresis was significantly less during aldosterone infusion than on the placebo day. In addition, saline loading led to a progressive increase in the ratio of sodium clearance to lithium clearance, used as an index of the fractional distal tubular rejection of sodium, and in the ratio of urinary sodium to potassium. These increases were prevented by the infusion of aldosterone. 4. This study suggests that there are differences in the mechanisms determining the early and the later responses to an acute sodium load. Suppression of aldosterone may explain much of the later increase in natriuresis after saline infusion. In addition, the results are consistent with a role for atrial natriuretic peptide in the immediate increase in sodium excretion after saline loading.

Adult↗
PubMed1991

Effect of a single test dose of lithium carbonate on sodium and potassium excretion in man.

1. The possible natriuretic and kaliuretic effects of a single dose of lithium, as used in lithium clearance studies, were investigated in 15 healthy subjects on fixed sodium (100 mmol/24 h) and potassium (70 mmol/24 h) intakes. Lithium carbonate (300 mg or 600 mg) or placebo tablets were administered, double-blind and in random order, midway through a 48 h urine collection (divided into six 8 h periods), at 23.00 hours. 2. During the three 24 h periods which preceded the administration of lithium or placebo (control days), rates of sodium and potassium excretion followed normal circadian patterns, but no differences in excretion rates between the 3 control days were observed. Placebo tablets did not affect excretion rates. 3. After the 300 mg dose of lithium carbonate, 24 h sodium excretion increased by approximately 17 mmol (P less than 0.05); almost all of the natriuretic effect occurred during the first two 8 h periods. No effect on potassium excretion was observed. 4. After the 600 mg dose of lithium carbonate, 24 h sodium excretion increased by approximately 48 mmol (P less than 0.001) and 24 h potassium excretion increased by approximately 19 mmol (P less than 0.01). These effects were confined to the first two 8 h periods and thus occurred before and during the usual lithium clearance period. 5. Plasma renin activity, measured in 10 subjects, increased after the 600 mg dose of lithium carbonate (P less than 0.005), but plasma concentrations of aldosterone and atrial natriuretic peptide were not significantly affected. Neither the 300 mg dose of lithium carbonate nor the placebo tablets affected hormone levels.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1991

The renal vascular response to mild and severe haemorrhage in the anaesthetized rat.

1. In order to document the characteristics of the renal vascular response to blood losses of varying severity, Inactin-anaesthetized rats were subjected to a haemorrhage of 5, 10, 15 or 20 ml (kg body weight)-1, while a fifth group (control rats) remained unbled. Radioactive microspheres (diameter 10 microns) were used to determine cardiac output, total renal blood flow and the distribution of blood flow within the kidneys; measurements were made before and 5-120 min after haemorrhage. 2. In control animals none of the variables studied changed significantly during the experimental period. 3. Immediately after haemorrhage there were reductions in arterial pressure and cardiac output which were roughly proportional to the severity of haemorrhage. Arterial pressure recovered to some extent during the next 30 min, then stabilized; cardiac output recovered only slightly. 4. Total renal blood flow fell to an extent dependent on the degree of haemorrhage, with no evidence of subsequent recovery. The approximate reductions in renal blood flow were 2% (n.s.), 15%, 30% and 50% after bleeds of 5, 10, 15 and 20 ml kg-1, respectively. Renal vascular resistance increased consistently only in the groups bled 15 and 20 ml kg-1. When renal blood flow was expressed as a fraction of cardiac output, it increased during the period immediately after haemorrhage, indicating some degree of 'protection' of the renal circulation in the face of hypotension. 5. Measurements of intrarenal blood flow indicated a significantly reduced flow to the superficial cortex after every degree of haemorrhage. Inner cortical flow was less affected and fell significantly only in the groups bled 15 and 20 ml kg-1; blood flow to the mid-cortex was intermediate.

Anesthesia↗
PubMed1991

Effect of frusemide on lithium clearance and proximal tubular reabsorption in anaesthetized rats.

1. In order to investigate the lithiuretic effect of frusemide, simultaneous measurements of fractional lithium excretion (FELi) and fractional fluid delivery to the end of the proximal convoluted tubules were made in Inactin-anaesthetized rats, first during a control period, then during intravenous infusion of frusemide at either 0.8 or 8.0 mg kg-1 h-1. Fluid balance was maintained by infusion of NaCl-KCl solution adjusted to match urinary excretion rates; measurements were made after urine flow had stabilized. 2. In time-control animals, which did not receive frusemide, no significant changes were observed in either FELi or fractional fluid delivery to the end of the proximal convoluted tubules (determined as the plasma/tubular fluid inulin concentration ratio, P/TFIn). 3. In animals given the high dose of frusemide, FELi increased from 0.22 +/- 0.02 (mean +/- S.E.M.) during the control period to 0.45 +/- 0.03 during frusemide infusion (P less than 0.001); this was accompanied by a modest increase in P/TFIn, from 0.43 +/- 0.02 to 0.51 +/- 0.02 (P less than 0.01). 4. In animals given the lower dose of frusemide, FELi increased from 0.21 +/- 0.01 to 0.37 +/- 0.01 (P less than 0.001). In this group, however, there was no discernible change in P/TFIn (0.43 +/- 0.02 vs. 0.44 +/- 0.01, not significant). 5. These results suggest that under control conditions a significant component of lithium reabsorption may occur beyond the proximal tubule, most likely in the loop of Henle.

Absorption↗
PubMed1990

Renal function in normal and potassium-depleted rats before and after preparation for micropuncture experimentation.

Renal function was examined in unrestrained conscious rats maintained on either a control diet or a low-potassium diet, then re-examined in the same animals after thiobutabarbital (Inactin) anaesthesia and preparation for micropuncture studies. In conscious rats, insulin clearance (CIn) was not significantly different in the two groups (control 1012 +/- 43, low-K 904 +/- 58 microliters/min per 100g body wt; mean +/- SE), but lithium clearance (CLi; used as an estimate of end-proximal fluid delivery) and fractional lithium excretion (FELi) were substantially reduced in the low-K group (CLi: 246 +/- 11 vs 126 +/- 8 microliters/min per 100g body wt, P less than 0.001; FELi: 0.245 +/- 0.009 vs 0.143 +/- 0.008, P less than 0.001). Following anaesthesia and preparation for micropuncture, there were significant reductions in urine flow rate and sodium excretion in the control group, but not in the low-K rats. Potassium excretion increased in both groups, but values in the potassium-depleted animals remained extremely low. In neither group of rats was preparation for micropuncture associated with significant changes in CIn, CLi or FELi. Thus, differences in tubular function between control and potassium-depleted rats were still apparent. The results suggest that preparation for micropuncture disturbs the function of the distal nephron, but that rates of glomerular filtration and proximal tubular reabsorption remain similar to values in conscious animals.

Anesthesia↗
PubMed1990

Analysis of the relation between lithium clearance and sodium clearance in rats.

In rats on a normal or high sodium intake, lithium clearance (CLi) is thought to approximate fluid delivery to the end of the proximal tubule (Vprox), whereas in rats on a very low sodium intake CLi is lower than Vprox owing to significant reabsorption of lithium in the distal nephron. This paper examines the relation between CLi and sodium clearance (CNa) in animals adapted to a range of dietary sodium contents (5-300 mmol/kg). Measurements were performed in conscious, unoperated rats with hereditary diabetes insipidus, in which changes in urine flow rate (V) can be used as an index of changes in Vprox; stimulation of distal lithium reabsorption was identified by comparing changes in CLi with the corresponding changes in V. CLi exhibited a curved, positive relation with CNa, with considerable scatter and a sharp decrease of CLi at low values of CNa. Further analysis indicated that this relationship consisted of three elements: (i) an almost unaltered Vprox in response to variations in dietary sodium: taken alone, this would result in a horizontal regression of CLi on CNa. (ii) Distal reabsorption of lithium in rats on very low sodium intakes, bending the curve towards low CLi values at low values of CNa. (iii) Intra-individual variations in Vprox, causing covariation of CLi and CNa; the slopes of the regression lines linking the two depended on the level of sodium intake, but all the regression lines intercepted the CLi axis at a similar (low) value of CLi, making a major contribution to the curved shape of the relationship. It is concluded that observations of greatly reduced values of CLi at low values of CNa cannot be taken as unequivocal evidence, per se, of distal reabsorption of lithium. Nor should measured values of CLi be corrected for differences in CNa.

Absorption↗
PubMed1990

The influence of posture on renal tubular function in man.

The acute effects of changes in posture on renal function were investigated in healthy volunteers. Proximal tubular function was assessed using two methods simultaneously: lithium clearance and urine flow rate during maximal water diuresis. Changing from the standing to the supine posture was associated with significant increases in urine flow rate and in the clearances of sodium, potassium, creatinine and lithium (p less than 0.01 in each case). Increases in fractional water excretion and fractional lithium excretion (using creatinine clearance as an estimate of glomerular filtration rate) were also observed (p less than 0.01). The increases in lithium clearance and urine flow rate, both absolute and fractional, were significantly correlated. These findings suggest that the acute increase in sodium excretion following assumption of the supine posture results largely from an increase in end-proximal fluid delivery, due partly to an increase in glomerular filtration and partly to a decrease in fractional reabsorption in the proximal tubule. The results also provide circumstantial support for the use of lithium clearance as a marker of end-proximal delivery in man.

Adult↗
PubMed1990

Unreliability of lithium clearance as a marker of proximal tubular function during haemorrhagic hypotension in the rat.

Fractional lithium excretion (FELi) was measured before and after hypotensive haemorrhage (15 ml (kg body wt)-1) in anaesthetized Brattleboro rats; simultaneously, micropuncture collections were made from late proximal convoluted tubules. Micropuncture data indicated that fractional reabsorption in the proximal convoluted tubules was not affected significantly by haemorrhage, whereas FELi fell from 0.25 +/- 0.02 (mean +/- S.E.M.; control period) to 0.03 +/- 0.01. In time-control animals, no significant change in either variable was observed. These results suggest that lithium clearance is an unreliable marker of proximal tubular function during haemorrhagic hypotension.

Animals↗
PubMed1990

Atrial natriuretic peptide--cyclic GMP coupling and urinary sodium excretion during acute volume expansion in man.

The present study examines hormonal and renal responses to acute volume expansion in normal man, with particular emphasis on the atrial natriuretic peptide (ANP)--cyclic GMP coupling. Two liters of isotonic saline were infused into eight normotensive male subjects over a 1-h period. Plasma and urinary measurements were made before, during, and up to 300 min after the start of the saline infusion. With the initial increase in urinary sodium excretion there were increases in plasma ANP and plasma cyclic GMP, which reached maximum levels at 15 min after the end of the saline infusion. Urinary cyclic GMP increased gradually during saline infusion up to approximately 60 min after the end of the infusion. Plasma ANP and plasma and urinary cyclic GMP excretion gradually declined thereafter. By contrast, urinary sodium excretion remained elevated up to the end of the observation period. The saline infusion was associated with marked reductions in plasma renin activity and aldosterone, which persisted up to the end of the study. These results suggest a coupling between the increases in plasma ANP, the production of cyclic GMP, and urinary sodium excretion, in particular during the initial renal response to acute volume expansion. However, other mechanisms including the suppression of the renin--angiotensin--aldosterone system may become increasingly important in the later natriuretic response to acute volume expansion.

Adult↗
PubMed1990

Lack of effect of dietary potassium on renal lithium clearance in man.

The effects of alterations in dietary potassium (40, 80 and 160 mmol day-1) on endocrine status and on renal lithium clearance were assessed in 10 healthy subjects on a fixed sodium intake; measurements were made on the fifth day of each dietary regimen. Plasma aldosterone concentration was found to increase with potassium intake, whereas plasma renin activity and the plasma concentration of atrial natriuretic peptide did not change significantly. Neither absolute lithium clearance nor fractional lithium excretion was affected measurably by changes in dietary potassium, suggesting that provided the potassium intake remains within the normal range it is unnecessary to control this factor during lithium clearance studies in man.

Adult↗
PubMed1989

Is renal lithium clearance altered in essential hypertension?

In order to assess whether enhanced fractional sodium reabsorption in the proximal tubule might contribute to the development of essential hypertension, we examined the relationship between arterial blood pressure and lithium clearance (CLi; used as an estimate of end-proximal fluid delivery) or fractional lithium excretion [FELi; measured using the clearances of creatinine and 51Cr ethylenediamine tetraacetic acid (EDTA) as estimates of glomerular filtration rate] in normal young males (n = 32) and in patients with essential hypertension (n = 44). In neither group was there evidence of a negative correlation between blood pressure and CLi or FELi. Mean values for CLi and FELi in a subgroup of hypertensive patients (n = 20) were almost identical to those in 20 normotensives matched for age, sex and race. These results provide no support for suggestions that a defect in proximal tubular sodium handling is an important factor in the development and/or maintenance of essential hypertension.

Adult↗