Amyloid arthropathy complicating myelomatosis: successful treatment with radiosynovectomy.
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Amyloidosis↗
Biomedical subjects
J M Ledingham
Publications and source records attributed to J M Ledingham.
Effect of enalapril on body sodium and handling of a sodium chloride load in hypertensive and normotensive rats.
1. The effect of enalapril on handling of an Na load and on body Na during 96 h of zero Na intake was measured in hypertensive rats (GH and SHR) and their normotensive controls (N and WKY) by a whole body counting method. 2. Enalapril treatment led to a greater fall in body Na in the first 24 h after the Na load (as expected from the known effect of ACE inhibition on aldosterone production) and thus to a slightly faster excretion of an amount equivalent to the load. 3. Enalapril-treated rats were unable to maintain body Na on a zero Na intake. This was also expected from the known effect on aldosterone production, though other mechanisms are not excluded. The effect was more marked in the SHR and WKY than in GH and N but there was no significant difference in this effect between the hypertensives and their respective control strains.
Animals↗
Sodium retention and volume expansion as mechanisms.
After nephrectomy, the level of arterial pressure is determined by the permitted degree of fluid volume expansion. With kidneys present, the fundamental requirement for fluid volume homeostasis is met by maintaining the balance between sodium and water intake and output. When one-kidney, one-clip (1-K,1-C) hypertension develops on a free diet, early sodium retention occurs with transient increase in extracellular (ECFV) and plasma (PV) volumes, which may persist into the chronic stage. In sodium deprivation, hypertension is not inhibited and ECFV and PV are not significantly raised. Thus, when sodium is available, sodium retention may contribute to the hypertensive mechanism, but when unavailable, other mechanisms must be largely, if not wholly, responsible. When hypertension is reversed by unclipping, the immediate fall in blood pressure is attributable to reduction first in cardiac output and second in peripheral resistance, accompanied by diuresis and contraction of PV: but if external fluid balance is maintained, cardiac output and blood pressure still fall, although at a slower rate, indicating that factors other than volume are implicated. In the development of hypertension, the hemodynamic changes are the reverse of those on unclipping, with transient increase in cardiac output associated with increased myocardial contractility and decreased venous capacity which, when coupled with fluid retention, raise mean circulatory filling pressure. In conclusion, the kidney possesses many mechanisms for raising pressure and reestablishing sodium homeostasis including not only sodium retention, but also release of pressor hormones, renin and possibly others, enhanced afferent sympathetic activity and suppression of the release of medullary hypotensive factors.
Animals↗
Surfeit and deficit of sodium: evidence from studies of body sodium in rats.
The concept of a basal level of body sodium (Strauss' state 'between surfeit and deficit') was studied by means of body sodium measurements in rats on different sodium intakes, in some cases after diuretic pretreatment. At a certain level of body sodium, when sodium intake was just enough to allow for body growth, a sodium chloride load (followed by a zero sodium intake) was excreted more or less quantitatively in 24-48 h. In rats pretreated with an ample sodium intake, the load was excreted more quickly and some additional sodium was also excreted. In rats pretreated with diuretic and a zero sodium diet, body sodium was very low and a sodium chloride load was retained to an extent that was more or less appropriate to the deficit. In a subsidiary part of the study, rats pretreated with a low sodium intake and frusemide and continuing on frusemide during and after the load, excreted a sodium chloride load at much the same rate as rats given a load following pretreatment with a very low sodium diet alone (i.e. not given a diuretic); after excreting the load they were able to maintain a stable (though reduced) level of body sodium in spite of cessation of sodium intake. Rats pretreated with hydrochlorothiazide, and continuing on this drug during and after the load, had a continued loss of sodium after cessation of sodium intake. The results are discussed in the light of the Strauss concept and appear to confirm it. Basal body sodium is, by inference, identified as the level at which delivery of sodium to the distal tubule exactly equals distal sodium reabsorption.
Animals↗
Salt appetite, body sodium, handling of a NaCl load, renin, and aldosterone in genetically and spontaneously hypertensive rats.
Salt appetite, body sodium, handling of a NaCl load, plasma renin activity (PRA), and plasma aldosterone concentration (PAC) were compared in New Zealand genetically hypertensive (GH) and Japanese spontaneously hypertensive rats (SHRs) and their respective normotensive controls [normal Wistar (N) and Wistar-Kyoto (WKY) rats]. Salt appetite was increased in SHRs compared with GH, N, and WKY rats when rats were on salt-free chow and given a choice of distilled water and NaCl solution. Body sodium, measured by whole body counting, was higher in SHRs than in the other strains but did not differ among GH, N, and WKY rats. The rate of excretion of a NaCl load was not increased in GH rats and was slightly increased in SHRs only when on a very low NaCl intake. PRA and PAC (radioimmunoassay) were lower in SHRs than in GH, N, and WKY rats. PAC had a significant negative correlation with body sodium across the four strains. There is no evidence of any abnormality in sodium regulation in GH rats. However, the SHRs have an increased salt appetite and an increased body sodium even when sodium intake is limited; PRA and PAC appear to have responded appropriately to the increased body sodium.
Aldosterone↗
Effect of enalapril on handling of a sodium chloride load by genetically hypertensive and normotensive rats.
1. Enalapril was given in the drinking water (300 mg/L) for 4.5 days to normotensive (N) and genetically hypertensive (GH) rats on zero sodium intake. An intraperitoneal NaCl load was given 12 h after enalapril was started. 2. Enalapril did not increase the maximum rate of sodium excretion, but caused the rats to excrete more than the load in the first 24 h and then to have a slow fall in body sodium while on a sodium-free diet. 3. In terms of the Strauss et al. (1958) concept of body sodium, enalapril appears to lower the basal level. However, in addition it causes a slow leak of sodium which becomes apparent when sodium intake is very low.
Animals↗
Autoregulation in hypertension: a review.
The hypothesis examined here is that autoregulation of peripheral flow is the dominant factor in initiating and maintaining the rise in peripheral resistance in hypertension. Vascular smooth muscle possesses myogenic activity, which is dependent upon wall tension and thus upon intravascular pressure, but the activity is modulated by metabolic factors which are flow-dependent. Autoregulation of flow by the microvessels is considered to be a reflection of the wider concept of autoregulation of tissue or cellular oxygen tension through the control of oxygen delivery and extraction in relation to oxygen consumption. Indirect evidence for the hypothesis, involving the measurement of oxygen delivery and consumption both in the whole body and in defined regions in various forms of hypertension, is discussed. Individual and species differences in the type of response of the microvessels to changes in oxygen tension and in the dependence/independence of oxygen consumption on flow may account for some of the discrepant observations. Specific criticisms of the hypothesis are discussed and it is concluded that the balance of indirect evidence supports the hypothesis. Lastly, if autoregulation is indeed involved in development of hypertension, it constitutes only a part of a complex pathogenic mechanism, whose major role is to maintain sodium and water balance in the body.
Animals↗
Handling of a sodium load by rats on a low sodium intake and frusemide.
1. Groups of rats (n = 9-10 per group) were given a medium sodium (Na) diet or a low Na diet or a low Na diet plus low or high dose frusemide in order to have their body Na in a state of surplus or deficit or neither. 2. Body Na was measured by a 22Na whole body counting method involving Na-free chow and the drinking fluid as the only source of Na (22Na-labelled NaCl). Intraperitoneal NaCl (same specific activity) loads were given and their excretion was measured by repeated measurements of body Na over the next 48 h. 3. Rats in surplus excreted more than the load; those in neither surplus nor deficit excreted more or less exactly the load (allowing for growth); those with a small deficit retained enough Na to make up most of the deficit; those with a deficit that was larger than the load retained approximately the whole load. 4. The results support the Strauss-Hollenberg concept that there is a basal body Na above which Na is excreted and below which any available Na is retained.
Animals↗
Body sodium in rats: response to DOCA, adrenalectomy, changes in salt intake, and a salt load.
Body Na was studied by an isotope method in rats on Na-free diet plus a choice of H2O and 0.5% or 0.1% NaCl. Two groups (1 on 0.5%, 1 on 0.1% NaCl) had Silastic deoxycorticosterone acetate (DOCA) implants, two similar groups were sham operated, and a fifth group (on 0.5% NaCl) underwent adrenalectomy (ADX). Saline consumption increased in DOCA-treated and ADX rats. Body Na was increased by DOCA and by drinking 0.5% NaCl compared with 0.1% NaCl. Body Na after intraperitoneal NaCl loading (which raised body Na 8-10%) and withdrawal of NaCl drinking fluids was analyzed by use of the model y = Ae-a(t-d) + Be-bt, where y is body Na at time t and d is delay before fast rate constant a is established; d was greater on the lower Na intake. Rate constant a was not reduced by chronic DOCA treatment. Coefficient B of the slow exponential, representing the basal level to which body Na falls on zero Na intake, and equivalent to Hollenberg's "set-point," was higher in DOCA-treated rats. This analysis makes use of Hollenberg's set-point concept, but the findings suggest that the set-point is related to mineralocorticoid activity and is thus presumably variable.
Adrenalectomy↗
Effects of DOCA and salt intake on body sodium, fluid intake, blood pressure and excretion of a sodium load in rats.
Body sodium was measured repeatedly by a whole-body counting method (22Na) in control and deoxycorticosterone acetate (DOCA)-treated Wistar rats taking a sodium-free pelleted diet and drinking a choice of H2O and either 0.5% NaCl or 0.1% NaCl (n = 11 per group, four groups). Body sodium was higher in DOCA-treated than in control rats and higher in rats on 0.5% NaCl than in those on 0.1% NaCl. These differences persisted even when all sodium intake was stopped. An intraperitoneal NaCl load was excreted at least as rapidly by the DOCA-treated as by the control rats. Commencement of excretion was slower in the rats on 0.1% NaCl than in those on 0.5% NaCl. It is concluded that DOCA raises the basal level of body sodium but does not slow down the excretion of sodium in the body in excess of the basal level.
Animals↗
Effect of isometric exercise on the renal excretion of sodium and potassium in mild hypertension.
1. Basal levels of pulse rate, blood pressure and rates of sodium and potassium excretion were observed in eight white male patients with mild hypertension and eight age-, sex- and colour-matched controls during an initial rest period of 90 min and then for 5 h after a 1 h period of isometric exercise involving all four limbs in rotation. The studies were repeated on another day with the subjects resting instead of exercising for 1 h. 2. Changes in systolic pressure after exercise were similar in the hypertensive and control groups, whereas the rise in diastolic pressure was higher and the rise in pulse rate lower after exercise in the hypertensive group compared with the control group. 3. The changes in the rate of salt excretion were significantly different in the two groups, the hypertensive group retaining proportionately more sodium and potassium over several hours.
Adult↗
Long-term measurement of total exchangable sodium in one- and two-kidney Golblatt rats.
Total exchangeable sodium (Nae) was measured by wholebody counting of 22Na in 1- and 2-kidney Goldblatt rats before, and for 12 weeks after, renal artery clipping. In 1-kidney Goldblatt rats, Nae relative to body weight increased immediately after the clipping procedure and then fell though not to normal levels; from the 10th to the 12th week it again rose rapidly, probably secondary to vascular damage. In 2-kidney Goldblatt rats, Nae relative to body weight increased immediately after the clipping procedure but by the 5th day it was back to normal and remained normal thereafter. Consideration of the values for absolute Nae (i.e. expressed in mmol per rat) casts some doubt on the reality of the sodium 'retention', except in the 1-kidney Goldblatt rats in the later stages of their hypertension. Immediately after surgery temporary loss of weight (presumably mainly affecting fat stores and muscle) probably accounts for much of the rise in Nae relative to body weight.
Animals↗
Meningitis in Whipple's disease.
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Humans↗
The effect of dietary sodium intake on the blood pressure and cardiac output responses to angiotensin II in unanaesthetized rats.
1. Dose-response curves for the pressor activity of angiotensin II have been determined in unanaesthetized rats receiving diets containing 2-5% (w/w) or 0-007% (w/w) sodium and administered in various sequences. 2. Dose-response curves were shifted to the left in rats on a high-, compared with a low-, sodium intake. This response was maintained for 7 days on changing from high to low sodium. 3. There was no difference in the relation between the fall of cardiac output and the rise of blood pressure in any of the experimental groups. 4. Dose-response curves for peripheral resistance showed the same directional change as seen for the pressor response in rats on high- and low-sodium diets. Since depression of cardiac output was proportional to the pressure rise, the absolute change in peripheral resistance was greater than the blood pressure response. The proportional changes were similar. 5. It is concluded that alterations in the pressor response to angiotensin caused by changes in sodium loading are attributable to changes in peripheral resistance and not to changes in the cardiac output response to the acute rise in blood pressure.
Angiotensin II↗
The role of the kidney in hypertension.
The role of the kidney in hypertension is reviewed in terms of sodium and water homeostasis, of the secretion of renin inappropriate to the state of sodium and water balance and of other renal humoral factors which might be implicated in the hypertensive process. Fundamental to the long-term maintenance of hypertension is an alteration in the relationship between renal perfusion pressure and the excretion of sodium and water. This alteration may be brought about as a result of renal structural damage, sympathetically mediated renal vasoconstriction or the action of renal or extrarenal hormones which modulate sodium and water excretion. When renin is secreted in excess of the prevailing level of sodium and water balance, the generated angiotensin contributes to the hypertension directly through peripheral and renal vasoconstriction. The level of blood pressure in two hypertensive patients with chronic renal failure was found to be highly correlated with the level of plasma renin activity as this was lowered by the administration of a beta-blocking drug. In rats deprived of sodium, renal artery constriction and contralateral nephrectomy was followed by hypertension without any elevation of plasma angiotensin and with a minimal expansion of plasma volume unaccompanied by expansion of extracellular fluid volume. The possible role of this small volume change and of other possible factors in producing hypertension is discussed. Studies in the nephrectomised rat confirmed eariler reports that renal medullayr auto-explants inhibited renoprival hypertension, but neither the identity nor mode of action of the medullary hypotensive factor were further clarified.
Angiotensin II↗
The influence of sodium intake on the pressor response to angiotensin II in the unanaesthetized rat.
1. Dose-response curves for the pressor activity of angiotensin II have been determined in unanaesthetized rats receiving diets containing 2-5% (w/w) or 0-007% (w/w) sodium; the different diets were administered in various sequences. 2. In comparison with those from rats receiving a low sodium diet, the dose-response curves were displaced to the left on the high sodium diet, indicating a greater response to angiotensin, and this displacement persisted for a period of approximately 7 days after the diet was changed from high to low sodium. The dose-response curve subsequently shifted to the right when the low sodium diet was maintained for longer. 3. There was a negative correlation between the slope of the dose-response curve and the basal blood pressure in all groups; the correlation was significant in three out of the five different treatment groups. 4. Basal blood pressures were significantly raised in rats on the high sodium diet for 7 days. 5. A number of possible mechanisms have been considered to explain both the parallel shift of the dose-response curve and alteration in its slope. It is concluded that the observed findings are compatible with an action of sodium-loading on the sensitivity of the smooth muscle cell to angiotensin, on the resting of the renin-angiotensin system, on the rate of inactivation of angiotensin and on a change in initial length of the muscle fibre.
Angiotensin II↗
Experimental renal hypertension.
The study of hypertension resulting from procedures devised to modify renal function in diverse ways has been pursued intensively in the past forty years and has contributed greatly to the understanding of hypertensive processes in man. Such procedures have included partial or complete removal of renal tissue, interference with the renal circulation and the administration of sodium and hormones promoting the tubular reabsorption of sodium. From all these studies, certain basic conclusions can be drawn. The fundamental mechanism involved in all forms of renal hypertension appears to be an alternation in the relationship between renal perfusion pressure and sodium and water excretion. The probable way in which this fundamental mechanism operates is outlined. The kidney itself is susceptible to the effects of hypertension and changes take place within it which then contribute a renal element to the hypertension whatever its primary cause.
Acute Disease↗