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Biomedical subjects

S L Skinner

Publications and source records attributed to S L Skinner.

At least 55 records · Page 3Linked to original sources
PubMed1987

Effects of angiotensins II and III on glomerulotubular balance in rats.

1. The role of angiotensin as a modulator of proximal glomerulotubular (GT) balance was investigated in anaesthetized rats by examining the relationship between glomerular filtration rate (GFR) and absolute proximal reabsorption (APR) during removal of endogenous angiotensin II (AII) and III (AIII) with enalaprilat (CEI) and then during their subsequent replacement by intravenous infusions. 2. Enalaprilat lowered mean arterial blood pressure (MABP) and increased renal blood flow (RBF), GFR, urine flow rate and sodium excretion. Filtration fraction (FF) was not altered. Absolute proximal reabsorption, derived from fractional lithium clearance, increased by only 48% of the change expected for 'perfect' GT balance. 3. Angiotensin II replacement corrected MABP, GFR and plasma renin level, but reduced RBF and increased FF; APR was decreased and GT balance was restored. Urine flow and sodium excretion remained above control values with AII. 4. Replacement with AIII did not correct the hypotension but completely reversed the renal and renin responses to enalaprilat and restored GT balance without affecting FF. 5. It was concluded that the relation between proximal reabsorption and GFR is considerably modified by the intrarenal angiotensin concentration. The findings are best explained by a direct stimulation of proximal tubular sodium transport by angiotensin at the concentrations existing in anaesthetized rats.

Absorption↗
PubMed1987

Potential functions of plasma prorenin; regional activation and tissue extraction.

The fate of circulating inactive prorenin was examined in patients and volunteers. Prorenin was activated either by acid-dialysis with warming at pH 3.3 or with trypsin. The results were similar but omission of warming reduced the value by 13%. In 6 volunteers, 20 min forearm venous occlusion raised regional total (T) and inactive (I) plasma renin concentration (PRC) by 51% and 48% without change of active (A) renin. During intense forearm exercise the ratio APRC: IPRC did not change in muscle or skin venous blood. Body anaerobic exercise increased APRC 3.7-fold without change in IPRC. These procedures activate plasminogen but are without effect on prorenin. In 18 patient with stable angina, TPRC was lower in coronary sinus than arterial blood (p less than 0.001) but APRC was not affected. A-V differences were not detected across the leg. Prorenin is apparently stable in the circulation but extracted by the heart.

Adult↗
PubMed1986

Extraction of plasma prorenin by human heart.

Arterial plasma prorenin underwent 58% extraction during one passage through the coronary circulation in eleven patients undergoing myocardial metabolic studies. Active renin and renin substrate were unaffected. Changes in renin and renin substrate concentrations were not detected across the enterohepatic, femoral, or renal vascular beds. This high degree of selective extraction of prorenin by the heart accounts for its proposed half-life. Prorenin could be a cardiotropic hormone.

Cardiac Catheterization↗
PubMed1986

Modulation of proximal tubular reabsorption by angiotensin II.

In shrinking-drop micropuncture studies in anaesthetized rats proximal tubular fluid reabsorption (JVa) decreased by 36% following intravenous infusion of enalapril. In a separate group of rats enalapril reduced fractional lithium clearance indicating decreased proximal fluid reabsorption. Following enalapril, GFR rose by 46% but absolute proximal reabsorption rose by 22% indicating 48% effectiveness of proximal glomerulo-tubular balance (GTB). Since renal blood flow and glomerular filtration rate (GFR) increased in parallel and arterial pressure fell, fluid uptake and proximal GTB were unlikely to have been decreased by peritubular physical forces. In anaesthetized rats proximal fluid reabsorption and proximal GTB are modulated by endogenous AII through direct stimulation of proximal tubular transport.

Angiotensin II↗
PubMed1983

Early functional and morphological changes in renal tubular necrosis due to p-aminophenol.

Functional and morphological changes developed rapidly in rats after the intravenous administration of the organic nephrotoxin p-aminophenol. Proximal intratubular pressure remained close to its mean control value of 14.9 +/- 0.9 mm Hg up to 40 min after injection of the nephrotoxin then rose rapidly over the following 50 min to a maximum of 38.7 +/- 7.4 mm Hg. Distal tubular pressure also rose in the same manner. Renal blood flow remained constant, but GFR fell to 11% of control values while fractional excretion of sodium and water rose 12 and five times, respectively. Morphological changes developed in parallel with the functional changes. They were widespread, varied in intensity from cell to cell, were more severe in the distal third of the proximal convoluted tubule and consisted of cytoplasmic swelling, reduced organelle concentration, reduction or loss of basal infoldings, widening of lateral intercellular spaces, extrusion of bubbles of cell sap into the tubular lumen; brush borders were preserved. No casts were present up to 90 min. Similar results were seen when p-aminophenol was added to the perfusate of the isolated perfused kidney. It is proposed that metabolic and morphological damage leads rapidly to both impairment of proximal tubular sodium reabsorption and increased flow resistance in the cortical collecting system. Both effects contribute to a rise in tubular pressures which oppose glomerular filtration.

Acute Kidney Injury↗
PubMed1982

Changes in active and inactive renin with haemodialysis.

Active (A) and inactive (I) plasma renin concentrations (PRC) were examined during haemodialysis in relation to blood pressure and body weight changes. Patients had either one (n = 15) or two (n = 51) remnant kidneys in situ, or were anephric (n = 4). 6 of the two remnant kidney patients had non-functioning renal allografts. Inactive renin was activated by acidification. Renin assay was by enzyme kinetic technique using sheep substrate and angiotensin I radioimmunoassay. Cryoactivation during handling was excluded. For the whole patient group the proportion of IPRC was inversely related to APRC in pre-dialysis plasma (p less than 0.001). APRC and IPRC did not change with heparinisation nor did activation of renin occur across the dialyser. Dialysis with up to 3 kg reduction in body weight did not consistently raise APRC or IPRC. Blood pressure was not significantly correlated with IPRC or APRC during dialysis. In all situations a high APRC was associated with a low IPRC:APRC ratio consistent with preferential secretion of the active form and/or consumption of the inactive renin zymogen.

Adolescent↗
PubMed1982

Biochemical and immunological characterization of ectopic tumoral renin.

Biochemical and immunological characteristics of renin secreted by two malignant renin-secreting tumors [pulmonary (PT) and paraovarian (POT)] were studied. They both contain inactive renin (IR), as renin activity of tumoral extracts was able to be increased after acid activation or trypsin treatment (10.1 to 20.8 Goldblatt units/g tissue for PT and 1.4 to 3.71 for POT). Renin activity after activation reached the value obtained by direct RIA of human renin (23 and 3.4, respectively), as both forms are recognized by renin antiserum. Both enzymatic activities could be completely inhibited by renin antiserum. Displacement curves for the two tumoral renins paralleled the MRC renin in the direct RIA. After chromatography on affigel blue, active renin was not bound to the gel, and inactive renin eluted only with 1 M NaCl. On pepstatin A Sepharose and CBL-pepstatin Sepharose (an N-modified-pepstatin), a separation of the two forms of pulmonary renin was obtained; inactive renin eluted with breakthrough proteins, whereas active renin was strongly bound to the gel. After this affinity chromatography, the molecular weights of inactive and active renin, determined on Ultrogel, were very close (46,000 and 42,500). We conclude that 1) ectopic renin in these cases in similar to the renal enzyme; 2) renin can be secreted in an inactive form, supporting the hypothesis of an inactive initial state of renin; and 3) molecular weight differences between the two forms are very slight.

Adenocarcinoma↗
PubMed1981

Activation of renin in an anaplastic pulmonary adenocarcinoma.

1. Biochemical characteristics of a renin-like enzyme secreted by a pulmonary adenocarcinoma have been studied. A very high renin content was revealed by both enzymatic (10.4 Goldblatt units/g of tissue) and direct radioimmunoassay of immunoreactive renin (23 Goldblatt units/g of tissue). 2. The higher value by direct radioimmunoassay suggested the presence of an inactive form of the enzyme. Indeed 40--100% activation occurred with treatment by trypsin or pepsin or prolonged dialysis at pH 7.4 with or without prior acid dialysis. This neutral activation was completely abolished by a serine proteinase inhibitor. 3. A large fraction of the renin in this tumour is inactive. In comparison with other prohormones produced in tumours the findings support strongly the proposition that renin passes through a proenzyme step in synthesis.

Adenocarcinoma↗
PubMed1978

The nature of inactive renin in human plasma and amniotic fluid.

1. The properties of inactive and active renin in human plasma and amniotic fluid were studied chromatographically. Activation was achieved at pH 3.3 with and without added pepsin. 2. Acid activation of renin was time- and temperature-dependent but was inhibited by dilution of the sample. The dilution effect was corrected by adding pepsin. Such characteristics indicate that activation at low pH is catalysed by intrinsic enzymes. 3. Separation and/or dilution of the activating enzyme during ion-exchange chromatography concealed the eluted position of inactive renin and reduced the amount recovered. Only after full activation of the eluted renin was achieved with added pepsin was a distinct peak of inactive renin exposed. 4. At pH 7.5 inactive renin carried a lower negative charge than the active enzyme. This charge difference was lost after activation. 5. No molecular-weight differences between active, inactive renin or the International Renin Standard were detected by gel filtration. No renin of larger molecular weight was present. 6. These findings will be helpful in purification studies of human inactive renin.

Amniotic Fluid↗
PubMed1977

Effect of hypertension on the in vitro incorporation of [1-14C]-oleate into phospholipid and cholesterol ester in the aortae of normal-fed and cholesterol-fed rabbits.

The effect of prior hypertension on the in vitro incorporation of [1-14C]-oleate into phospholipid and cholesterol ester in aortae from cholesterol-fed and normal fed rabbits was studied. Incorporation of [1-14C]-oleate into phospholipid was not increased in aortae from either hypertensive normal-fed or hypertensive cholesterol-fed rabbits when compared to the appropriate normotensive controls. In the normal-fed rabbits, incorporation of [1-14C]-oleate into cholesterol ester was increased by hypertension in all aortic regions. In cholesterol-fed rabbits cholesterol esterification was found to be proportional to the intimal cholesterol concentration, irrespective of the prior blood pressure or the particular aortic region studied. It is concluded that the increased lipid synthesis in atherosclerotic vessels from hypertensive rabbits is a consequence of the increased lipid accumulation produced by hypertension and not the result of hypertension directly stimulating arterial wall metabolism.

Animals↗
PubMed1977

Hypertension-accelerated atherogenesis in cholesterol-fed rabbits.

Entry of 125I-labelled low density lipoprotein ([125I]LDL) into the aortic intima was studied over 6 hours in normotenisve and hypertensive rabbits fed a 1% cholesterol diet for 9 and 4 weeks respectively. Studies were also made in hypertensive and normotensive cholesterol-fed rabbits in which blood pressure was reduced acutely with parenteral hydralazine. In all groups the entry of E1125I]LDL was greatest in the aortic arch and significantly less in both the descending thoracic and abdominal regions. Lipoprotein entry into the aorta of cholesterol-fed rabbits was increased some 10-fold over the corresponding value previously found in rabbits fed a normal diet [1]. This increase was due to increased vascular permeability as well as to increased plasma LDL concentration. The hypertensive cholesterol-fed rabbits did not show significantly greater entry of [125I]LDL than the normotensive cholesterol-fed rabbits. Comparison of the rate of LDL entry over 6 house and the quanitity of cholesterol accumulated in the aortic segments over the period of cholesterol feeding indicated that lipoprotein fractions other than LDL must contribute singificant amounts of cholesterol to the developing lesion. The finding that LDL entry paralledled accumulation during cholesterol feeding, together with the finding that acute reversal of hypertension did not reduce the entry of [125I] LDL suggest that mechanisms other than increased filtration of plasma low density lipoprotein contribute significantly to the accelerated development of atherosclerosis in hypertension.

Animals↗
PubMed1976

Incorporation in vitro of 14C-labelled acetate and 32P-labelled phosphate into lipid in thoracic aortae from hypertensive and nomotensive rabbits.

The effect of prior hypertension on lipid synthesis in the thoracic aortae of normal-fed and cholesterol-fed rabbits was studied in vitro using[1(-14)C] acetate and [32P] phosphate as lipid precursors. In normally fed rabbits, prior hypertension did not increase the incorporation of the labelled precursors into either phospholipid or neutral lipid. In cholesterol-fed rabbits, hypertension increased the incorporation of [32P] phosphate into phosphatidyl-choline and of [1(-14)C-acetate into cholesterol ester. The increased incorporation of [1(-14)C] acetate into cholesterol ester was accompanied by an increase in intimal total cholesterol concentration. For both normotensive and hypertensive cholesterol-fed rabbits there was a close correlation between cholesterol esterification and total cholesterol concentration of the thoracic intima. It is concluded that the increase in aortic lipid synthesis in hypertensive cholesterol-fed rabbits is secondary to the increased cholesterol accumulation induced by hypertension rather than to a direct stimulation of arterial wall lipid synthesis by hypertension per se.

Acetates↗
PubMed1976

Studies on renin release from isolated superfused glomeruli: effects of temperature, urea, ouabain and ethacrynic acid.

1. The effects of different energy substrates, of low temperature, of urea, and of ouabain and ethacrynic acid were studied on the rate of renin release from viable juxtaglomerular cells during superfusion of isolated rat glomeruli. 2. Neither lactate nor glutamate altered renin release rate from that observed using glucose as the sole energy substrate. Succinate 10 mM elevated release transiently but did not influence the release caused by reductions in osmolality through lowering sucrose concentration. 3. Peak renin release was more prolonged and returned more slowly to control following reductions in osmolality in phosphate-Ringer than in bicarbonate-Ringer. 4. At 37 degrees C, the peak of renin released induced by hypo-osmolality was smaller and delayed, and returned earlier to control than at 30 degrees C. Reduction in temperature from 30 to 4 degrees C resulted in a 32-fold increase in basal release rate. At 4 degrees C a 20 m-osmole/kg reduction in tonicity caused an additional 2-5-fold increase in release rate. 6. Increasing superfusate osmolality with urea did not affect basal renin release but 100 mM urea suppressed the releasing effect of a 15 mM reduction in NaCl concentration. 7. Ouabain (10(-4) M) caused a small (33 +/- 9%, P less than 0-025) transient increase in renin release. Ethacrynic acid (10(-3) M) provoked a progressive increase in release reaching 100 +/- 15% above control within 50 min. In the presence of both inhibitors the release provoked by hyposmolality was prolonged. 8. It is concluded that renin release in vitro is a function of actively regulated cell volume and it is proposed that a similar mechanism could underline both barorecptor and macula densa controls of renin secretion in vivo.

Animals↗
PubMed1976

Sensitivity of renin secretion to volume depletion in the anaesthetized dog: comparison between urinary drainage and slow haemorrhage.

1. An experimental technique utilizing 'denervation diuresis' from one kidney with measurement of renin release from the contralateral innervated kidney was developed to study the sensitivity of renin secretion to volume depletion. 2. With urine excretion, release of renin increased progressively from the innervated kidney. The increase was significant at a sodium deficit of 0-23 mole.kg-1. At a sodium deficit of 0-6 m-mole.kg-1 renin release had doubled. 3. Bilateral vagotomy did not alter this response. 4. Precise replacement of sodium loss with isotonic saline but without replacement of other urinary components returned renin release to control levels. 5. Slow haemorrhage causing a rate of volume and sodium loss equivalent to urinary drainage did not alter the rate of renin release. 6. With a single denervated kidney and contralateral nephrectomy, renin release fell progressively to minimal levels despite sodium deficits up to 2-6 m-mole.kg-1. 7. It is concluded that renin secretion is sensitive to at most a 0-5% change in body fluid volume and should be considered a primary response to volume depletion. The sensitivity of the response depends upon normal renal innervation but is not mediated via vascular volume receptors nor via receptors innervated by the vagus. 8. It is proposed that the extreme sensitivity of the renin-secreting system in these experiments results from the combination of volume depletion and slight hypotonicity of extracellular fluid acting on the renal afferent arteriole without the mediation of the macula densa,

Animals↗
PubMed1975

Measurement of renin concenration in human plasma using 125i-labelled sheep renin substrate.

Sheep renin substrate was prepared 28% pure, labelled with 125I and then diluted in concentrated unlabelled sheep substrate. Ten percent of the 125I-label was released as a small fragment on incubation with excess human renin. Adequate separation of the labelled fragment from the parent protein was accomplished with charcoal precipitation or gel filtration. Renin concentration in human plasma was assayed by incubating the 125I-labelled substrate with plasma under zero-order kinetic conditions. Renin was assayed in plasma that had been either acidified or untreated. The acidification procedure was employed to activate inactive renin which accounted for more than half of the total plasma renin concentration. The results of this radiochemical assay correlated closely with the results of bioassay. Specificity of the method was established with antirenin. The assay was sufficiently sensitive to measure suppressed plasma renin levels. The iodinated substrate was stable on storage at -10 degrees C over a six-month period. Because of its high affinity for human renin, ease of purification and stability of the iodinated product, sheep substrate provides a convenient means for routine determination of plasma renin concentration by radiochemical assay.

Angiotensin II↗