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J D Firth

Publications and source records attributed to J D Firth.

54 records · Page 3Linked to original sources
PubMed1992

Organ distribution of the three rat endothelin messenger RNAs and the effects of ischemia on renal gene expression.

To determine the organ distribution of production of the three endothelin (ET) isopeptides, we have developed three ribonuclease protection assays specific for the messenger RNAs (mRNAs) of rat ETs 1, 2, and 3.12 organs from adult Sprague-Dawley rats were examined: heart, lung, liver, spleen, kidney, stomach, small intestine, large intestine, testis, muscle, salivary gland, and brain. The mRNA for ET1 was five times more abundant in the lung than in any other organ studied, moderate expression was seen in the large intestine, and lower levels of mRNA were detected in each of the other organs examined. ET2 was expressed at high level in both large and small intestine and at low level in stomach, muscle, and heart, but ET2 mRNA could not be detected elsewhere. ET3 mRNA was found in all organs, particularly in small intestine, lung, kidney, and large intestine. Because of reports suggesting that ETs might be involved in the hypoperfusion and hypofiltration observed in postischemic kidneys, we have also studied levels of mRNA in kidneys that had previously been subjected to 25 or 45 min of clamping of the renal pedicle. At 6 h after 45 min of ischemia, ET1 mRNA increased to a peak of 421 +/- 69% (mean +/- SEM, n = 3) of that in a standard renal RNA preparation. By contrast, ET3 mRNA decreased in the postischemic organ, falling to a value of 19 +/- 2% of standard at the same time point. The effects of ischemia on ET1 and ET3 mRNAs were long-lasting, with elevation of ET1 and depression of ET3 persisting for days. ET2 mRNA remained undetectable throughout. These findings (a) support a role for ET1 in postischemic renal vascular phenomena and (b) demonstrate a situation in which the expression of ET isoforms is clearly subject to differential regulation.

Animals↗
PubMed1991

Renal sodium retention in the nephrotic syndrome.

Where do the experiments on rat kidneys exposed to puromycin leave us in attempting to evaluate further the pathophysiology of oedema in human nephrotic syndrome? They cannot be considered conclusive. The arguments favouring an intrinsic abnormality in the kidney as a major factor in sodium retention, rather than this being a secondary response to humoral and neural influences stimulated by changes in actual or perceived plasma volume, would be strengthened by experiments using another animal model of the nephrotic syndrome. But taken together with the longstanding clinical observations demonstrating the absence of any correlation between plasma oncotic pressure and diuresis or sodium retention, the work particularly of Dorhout-Mees and his colleagues on plasma volume, the frequent failure of infusions of salt-free albumin to induce natriuresis, and the profound resistance to intensive diuretic therapy in many nephrotics, the evidence for an important, probably predominant, role of intrinsic renal retention of sodium is strong. This is not to negate the importance of Starling forces in determining the distribution of the retained salt and water, nor to suggest that, on occasion at least, hypovolaemia, relative or absolute, may contribute to sodium retention. Certainly hypotensive shock due to hypovolemia in nephrotic patients untreated by diuretics has been observed often enough, particularly in children, and the risk of over-enthusiastic diuretic treatment resulting in tubular necrosis in the course of management of minimal change disease, is well recognised. An important role for leakage of plasma from the vascular compartment in the initiation of the oedema of the nephrotic state is certainly likely, but to consider this the major continuing mechanism is really not tenable.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Impaired natriuretic response to atrial natriuretic peptide in the isolated kidney of rats with experimental cirrhosis.

1. Sodium retention in cirrhosis may be partly attributable to resistance to a putative circulating natriuretic factor. In cirrhosis, plasma concentrations of atrial natriuretic peptide are often increased in the presence of sodium retention. 2. In order to determine whether the kidney of cirrhotic animals may be insensitive to atrial natriuretic peptide, isolated perfused kidneys from six cirrhotic and five control rats were exposed to increasing concentrations of atrial natriuretic peptide. Cirrhosis had been induced by carbon tetrachloride administration. 3. Excretion in vivo of a 2 mmol sodium load, administered by gavage, was impaired in cirrhotic animal for up to 4 h as compared with control animals (4.2 +/- 1.9 vs 34.9 +/- 13.4% P less than 0.05). 4. During perfusion at 110 mmHg in the absence of atrial natriuretic peptide, sodium excretion by isolated kidneys of cirrhotic animals tended to be lower than in control animals, but the difference was not significant (4.93 +/- 1.01 vs 8.41 +/- 1.48 mumol min-1 g-1 kidney weight, P = 0.09). There was a smaller increase in urinary sodium excretion by the kidneys of cirrhotic rats compared with control rats in the presence of atrial natriuretic peptide at 10, 50 and 200 pmol/l (respectively: 0.06 +/- 0.08 vs 1.29 +/- 0.35 mumol/min-1 g-1 kidney weight, P less than 0.02; 0.49 +/- 0.08 vs 1.82 +/- 0.42 mumol min-1 g-1 kidney weight, P less than 0.03; 1.42 +/- 0.16 vs 3.23 +/- 0.73 mumol min-1 g-1 kidney weight, P less than 0.05), but not at 1000 pmol/l.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Effect of endothelin on the function of the isolated perfused working rat heart.

1. The effect of endothelin on the performance of the isolated perfused working rat heart has been examined. 2. A low concentration of endothelin (60 pmol/l) produced a gradual but sustained increase in cardiac output; coronary vascular resistance was unaffected. 3. A high concentration of endothelin (600 pmol/l) produced a rapid increase in cardiac output, followed by a marked fall in cardiac output as progressive, severe coronary vasoconstriction developed. 4. The coronary vasoconstriction induced by endothelin (600 pmol/l) was partially blocked by nicardipine (0.5 mumol/l). 5. In the presence of either nicardipine (0.5 mumol/l) or verapamil (0.2 mumol/l), the increment in cardiac output induced by endothelin (600 pmol/l) was greater than that induced by the addition of the same concentration of endothelin to hearts which had not been exposed to calcium-entry blockers. 6. The effect of endothelin on myocardial contractility has a different time course, concentration dependence and response to calcium-entry blockade than the effect on the coronary vasculature. This suggests that different mechanisms are involved in the generation of the myocardial and vascular responses to endothelin.

Animals↗
PubMed1990

Effect of natriuretic agents, vasoactive agents and of the inhibition of metabolism on sodium handling in the isolated perfused kidney of the nephrotic rat.

1. The kidney taken from a rat rendered nephrotic by exposure to puromycin aminonucleoside retains sodium abnormally when perfused in isolation and has an abnormally low vascular resistance (J. D. Firth et al., Clin. Sci. 1989; 76, 387-95). In this study the relation of oxygen consumption to sodium reabsorption has been examined in the isolated nephrotic organ, which has also been exposed to a variety of natriuretic agents and to the effect of inhibition of metabolism by cooling, in an attempt to discern the transport process, or processes, responsible for abnormal tubular handling of sodium. In addition, the effects of three endogenous vasoconstrictors, noradrenaline, angiotensin II and endothelin, on the function of the isolated nephrotic kidney have been examined. 2. The ratio of mol of sodium reabsorbed by the tubules of the isolated nephrotic kidney to mol of oxygen consumed was reduced in comparison with the control kidney (means +/- SEM): 9.22 +/- 0.97 versus 15.43 +/- 1.55 (P less than 0.002). 3. In the presence of ouabain (1 mmol/l), acetazolamide (1 mmol/l), frusemide (200 mumol/l), the combination of these three agents together, hydroflumethiazide (100 mumol/l), benzamil (100 nmol/l) or atrial natriuretic peptide (1000 pmol/l), a lesser increment in sodium excretion was induced in the isolated nephrotic kidney than in the control kidney and the nephrotic organ continued to excrete less sodium in both absolute and fractional terms. 4. This suggests that enhanced tubular sodium reabsorption in the isolated nephrotic kidney does not depend upon abnormally increased activity of the Na+/K(+)-adenosine triphosphatase, bicarbonate-dependent sodium transport, Na+/K+/2Cl- co-transport, electrically neutral proportionate reabsorption of sodium and chloride (distal tubule), epithelial sodium channel (distal tubule) or atrial natriuretic peptide-sensitive sodium transport processes. 5. When isolated nephrotic kidneys and normal kidneys were cooled to 8-10 degrees C the handling of sodium became virtually identical in the two groups. On re-warming to 37 degrees C, the original differences in sodium handling between nephrotic and control kidneys were restored. This implies that the mechanism responsible for the abnormal tendency to retain sodium is temperature-sensitive; as yet it remains otherwise undefined. 6. The sensitivity of the renal vessels to noradrenaline, angiotension II and endothelin, as judged by the percentage reduction in perfusate flow rate produced by a given concentration of any of these agents, was not substantially altered in the nephrotic kidney compared with the control kidney. Increase in vascular tone was not associated with amelioration of the tendency of the isolated nephrotic organ to retain sodium. Increasing concentrations of angiotensin II caused the filtration rate to increase in the nephrotic kidney. This effect was unexpected: in the control preparation, as anticipated, angiotensin II caused the filtration rate to decrease.

Acetazolamide↗
PubMed1990

Effect of polycations on the function of the isolated perfused rat kidney.

1. In minimal change nephrotic syndrome the occurrence of heavy proteinuria can be explained on the basis of a reduction in charge selectivity of the glomerular filtration barrier, and it has been proposed that this might be caused by the neutralization of anionic groups by a circulating polycationic factor. 2. The effects of two polycations, protamine and poly-L-lysine, on the function of the isolated perfused rat kidney have been examined. 3. Poly-L-lysine polymers of relatively high molecular weight (8800 and 17,800) induced heavy proteinuria, while simultaneously causing a marked increase in renal vascular resistance and a fall in filtration rate. Protamine (approximate molecular weight 7000) at relatively high concentration induced modest proteinuria in the absence of effects on vascular resistance or filtration rate. 4. A poly-L-lysine polymer of lower molecular weight (3800) did not induce proteinuria. Protamine at a concentration of 40 micrograms/ml and below did not affect protein excretion either. Both provoked substantial natriuresis. This appeared to be largely due to an effect on the tubular handling of sodium since the filtration rate remained steady while fractional sodium excretion rose markedly. 5. The natriuretic effect of protamine was blocked by heparin, but not by indomethacin or verapamil, suggesting that the mechanism of natriuresis did not depend upon either prostaglandin production or entry of calcium through verapamil-sensitive channels.

Animals↗
PubMed1989

Sodium and lithium handling in the isolated hypertensive rat kidney.

1. Isolated kidneys taken from spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto rats (WKY) were perfused over a range of perfusion pressures. 2. Lithium clearance was used as an index of proximal tubule sodium handling. 3. When the perfusate contained an oncotic agent (albumin, 6.7 g/dl) the SHR kidneys performed differently from the WKY kidneys with a reduction in inulin clearance, sodium excretion, fractional sodium excretion and fractional lithium excretion [at 105 mmHg (14 kPa) perfusion pressure, SHR 6.0 +/- 1.1% vs WKY 12.6 +/- 2.4% (mean +/- SEM); at 150 mmHg (20 kPa), SHR 17.1 +/- 1.6% vs WKY 27.0 +/- 2.3%]. Calculated indices of distal tubular function showed no major differences between SHR and WKY. 4. When kidneys were perfused without oncotic agent in the perfusate the differences between SHR and WKY in tubular handling of sodium and lithium were largely abolished. 5. These findings are consistent with the hypothesis that increased sodium reabsorption occurs in the proximal tubules of the kidneys of SHR and suggest that this is an intrinsic property of the kidney, not immediately dependent on neural or humoral factors. Increased sodium reabsorption in the proximal tubule may contribute significantly to the existence of hypertension in the SHR.

Animals↗
PubMed1989

Abnormal sodium handling occurs in the isolated perfused kidney of the nephrotic rat.

1. In order to examine the handling of sodium by the nephrotic kidney when separated from the immediate influences of renal nerves and humoral factors, kidneys were taken from nephrotic rats (puromycin aminonucleoside) and studied over a range of perfusion pressures using the isolated perfused kidney technique. 2. When perfused with medium containing 6.7 g/dl albumin, the nephrotic kidneys performed differently from controls with a reduction in sodium excretion at all pressures [(mean +/- SEM) 1.14 +/- 0.43 vs 4.20 +/- 0.69 mumol/min at 105 mmHg (14 kPa); 6.32 +/- 1.56 vs 44.60 +/- 5.30 mumol/min at 150 mmHg (20 kPa)]. Renal vascular resistance, inulin clearance, fractional sodium excretion and fractional lithium excretion were also reduced. 3. When kidneys were perfused without oncotic agent these differences between nephrotic and control kidneys remained. Perfusion with medium containing 10 g/dl albumin, designed to prevent glomerular filtration, abolished the difference in vascular resistance between the two groups. Captopril had no effect on the sodium retention or vascular resistance of nephrotic kidneys. 4. It was concluded that (a) the isolated nephrotic kidney demonstrates increased avidity for sodium, (b) the abnormality of sodium handling is not dependent on the presence of altered oncotic forces, and (c) the alteration in vascular resistance is conditional upon glomerular filtration.

Animals↗
PubMed1989

Sodium handling in the isolated perfused kidney of the cirrhotic rat.

1. In cirrhosis the kidney tends to retain salt and water abnormally. Two theories have been proposed to account for this: the 'underfilling' theory, in which sodium retention is thought to occur secondary to perceived underfilling of the circulation, and the 'overflow' theory, in which sodium retention is considered to be due to a primary renal defect. 2. Using the model of cirrhosis produced by carbon tetrachloride administration in the rat, the ability of the kidney to excrete sodium has been examined in vivo and during isolated perfusion. 3. Cirrhotic animals demonstrated a reduced ability to excrete an acute sodium load: 6 h after 2 mmol of sodium was given by gavage, 27.5 +/- 10.5% had been excreted by the cirrhotic rats and 62.5 +/- 7.0% by control rats (P less than 0.025). 4. In contrast, during isolated perfusion, kidneys from cirrhotic animals excreted the same amount of sodium as control animals over a range of perfusion pressures from 90 to 150 mmHg (12 to 20 kPa). 5. The data are consistent with the view that in cirrhosis the kidney retains sodium in response to immediate external factors.

Animals↗
PubMed1989

Sodium excretion during elevation of renal venous pressure: modulation by dDAVP.

Studies were performed to determine the effects of elevation of renal venous pressure on sodium excretion by the isolated perfused rat kidney in the presence and absence of a specific V2-receptor agonist, 1-des-amino-8-D-arginine vasopressin (dDAVP), at a concentration (1 ng/ml) expected to have maximal antidiuretic activity but minor vasopressor action. In either the presence or absence of dDAVP, increments in venous pressure led to falls in perfusate flow rate and glomerular filtration rate, which became significant at an imposed pressure greater than or equal to 18.75 mmHg. In the absence of dDAVP, absolute sodium excretion fell as venous pressure increased, and there was a negative correlation between fractional sodium excretion (FENa) and renal venous pressure (RVP) within each experiment and when all data points were combined: FENa = 3.46-0.072RVP (r = -0.608, P less than 0.01). In contrast, in the presence of dDAVP, absolute sodium excretion was unchanged, and in four of five experiments FENa rose as venous pressure increased (in one it remained unchanged). Linear regression analysis of all data points showed a positive correlation between FENa and RVP: FENa = 1.27 + 0.127RVP (r = 0.392, P less than 0.05). The slopes of the two regression lines were significantly different (P less than 0.001). It is postulated that this effect of dDAVP may be mediated via changes in the distal tubular pressure response to elevation of RVP. Such an effect of vasopressin could explain the observation that the response to renal vein constriction in vivo is dependent on volume status.

Animals↗
PubMed1988

Endothelin: an important factor in acute renal failure?

Very low concentrations of the vasoconstrictor peptide endothelin cause intense long-lasting renal vasoconstriction. In the isolated perfused rat kidney, the concentration of endothelin required to reduce blood-flow by 50% is 200 pmol/l, compared with 1000 pmol/l angiotensin II (previously the most potent known vasoconstrictor). Whereas angiotensin II has little effect on the glomerular filtration rate (GFR), a rise in endothelin from 100 to 800 pmol/l reduces GFR by 90%. Endothelin is probably present in the circulation at low concentrations in vivo; events associated clinically with acute renal failure would tend to increase this concentration. Endothelin may be a mediator in the pathogenesis of acute renal failure.

Acute Kidney Injury↗
PubMed1988

Raised venous pressure: a direct cause of renal sodium retention in oedema?

Contemporary theories of oedema formation are often based on the idea that "effective" blood volume is reduced, and that sodium retention and oedema are a result of the kidney responding, as in haemorrhage, to a perception by receptors in the circulation that blood volume is inadequate. This idea has enhanced understanding of the pathophysiology of such conditions as cardiac failure and cirrhosis, but has obscured the fact that blood volume is almost always increased in oedematous states. Evidence is presented that an increase in renal venous pressure can cause sodium retention by a direct action on the kidney: a rise in venous pressure could thereby initiate a vicious circle by causing sodium retention, expansion of plasma volume, and further increase in venous pressure. This sequence of events may be crucial in the pathophysiology of cor pulmonale, and an exacerbating factor in other oedematous states.

Animals↗
PubMed1988

Low concentrations of ANP cause pressure-dependent natriuresis in the isolated kidney.

The effect of alteration in renal perfusion pressure on the response of the isolated perfused rat kidney to concentrations of alpha-human atrial natriuretic peptide (ANP) within the pathophysiological range has been examined. At a perfusion pressure of 90 mmHg ANP concentrations of 50, 200, and 1,000 pmol/l were without effect on any parameter tested. At a perfusion pressure of 130 mmHg 50 pmol/l ANP produced an increase of 3.13 +/- 0.68 mumol/min in sodium excretion (UNa V), compared with a fall of 0.33 +/- 1.04 mumol/min in controls (P less than 0.02); fractional excretion of sodium (FENa) rose by 1.45 +/- 0.36% vs. -0.12 +/- 0.47% (P less than 0.05); glomerular filtration rate (GFR) was unchanged. At 200 and 1,000 pmol/l larger changes in UNa V and FENa were seen; only at 1,000 pmol/l was a significant effect on GFR observed. In contrast, frusemide (furosemide) at concentrations of 10 and 100 mumol/l was natriuretic at both 90 and 130 mmHg, with lesser absolute but greater proportional changes being seen at the lower pressure. It was concluded 1) the response of the isolated kidney to ANP is critically dependent on perfusion pressure, 2) at elevated levels of perfusion pressure the isolated kidney can respond to levels of ANP within the upper physiological and pathophysiological range.

Animals↗
PubMedDate not supplied

Exogenous phospholipase C stimulates epithelial cell migration and integrin expression in vitro.

Phospholipase C secreted by bacterial pathogens has been identified as a virulence factor in several human diseases and has been implicated in impeding wound healing. The role of phospholipase C in the intracellular signal control of epithelial growth was studied in normal human skin keratinocytes cultured in conditions simulating aspects of wound healing. Bacillus cereus phospholipase C decreased cell-cell contact and increased cell migration resulting in disruption of the advancing epithelial sheet. Phospholipase C-induced migration was blocked by inhibitor of the phosphoinositol signal transduction pathway neomycin sulfate and protein kinase C inhibitor RO-31-8220. Induced migration was associated with elevated levels of matrix metalloproteinase-9 which, when blocked by tissue inhibitor of metalloproteinase-1, was accompanied by a loss of migration. Adhesion studies showed that phospholipase C treatment enhanced cell binding to fibronectin, vitronectin and collagen IV. Immunostained phospholipase C-stimulated cells cultured on fibronectin showed enhanced expression and relocation of the integrin subunits alpha(v), alpha5 and beta1. Confocal microscopy showed that phospholipase C-induced levels of integrin subunit beta1 were predominantly deposited on the basal surface of the cell apparently in focal contacts and associated with actin stress fibers. These results indicate that exogenous phospholipase C signaling from a bacterial source may play an important role in perturbing normal reepithelialization via altered expression of integrins and matrix metalloproteinase-9.

Bacillus cereus↗