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J M Ledingham

Publications and source records attributed to J M Ledingham.

At least 19 recordsLinked to original sources
PubMed1997

Nitric oxide synthase inhibition with N omega-nitro-L-arginine methyl ester affects blood pressure and cardiovascular structure in the genetically hypertensive rat strain.

1. Inhibition of nitric oxide (NO) synthesis with the nitric oxide synthase (NOS) inhibitor N omega-nitro-L-arginine methyl ester (L-NAME) was used as a tool to investigate further a possible endothelial defect in the New Zealand genetically hypertensive (GH) rat strain compared with its normotensive (N) control strain. 2. N omega-nitro-L-arginine methyl ester was given to GH and N groups in their drinking water from age 7-10 weeks (10 mg/kg per day for week 1 and 2 and then 5 mg/kg per day for week 3). Tailcuff blood pressure (BP) was measured weekly and at the end of the experiment the mesentery was fixed by perfusion, second order branches of the mesenteric artery were embedded in Technovit and stained sections were used to quantify the structure of the mesenteric resistance arteries (MRA). The heart was removed and weighed for determination of left ventricular (LV) mass. 3. In GH rats, BP and LV mass were significantly raised by L-NAME, while in N rats L-NAME treatment significantly elevated BP, but had no effect on LV mass. 4. In GH rats, the media width was significantly increased by L-NAME treatment (P < 0.01); lumen diameter remained unchanged. Thus, the ratio of media width/lumen diameter (M/L) was significantly increased by exacerbation of the hypertrophic outward remodelling characteristic of the GH strain. There were no significant changes in the M/L ratio in L-NAME-treated N rats. 5. Thus, in the GH strain, cardiovascular structure is more sensitive to NOS inhibition than either its N control strain or (on evidence from the literature) the spontaneously hypertensive rat strain.

Animals↗
PubMed1995

Effect of felodipine on blood pressure, body sodium, plasma renin activity and plasma aldosterone in hypertensive and normotensive rats.

1. To explore its effect on blood pressure (BP) in relation to body sodium (Na), felodipine was given to New Zealand genetically hypertensive (GH) and normotensive (N) rats and to Japanese SHR and WKY rats, prepared for repeated measurements of body sodium (Na) by a whole body counting technique (22Na) using an Na-free pelleted diet and 22Na-NaCl fluid as the sole source of Na, with water also available. The drug was added to the food before pelleting pellets, 0.5 mg/g food. 2. Felodipine reduced BP in each strain; this effect was as great on normal Na intake as when on a zero Na intake. Felodipine caused an increase in plasma renin activity in each strain but the increase reached significant levels only in GH, SHR and WKY. Plasma aldosterone was decreased by treatment in GH and N and increased in SHR and WKY. 3. In rats on a zero Na intake (water sole drinking fluid), felodipine caused no fall in body Na (i.e. no natriuretic effect was detectable) except in WKY. When saline was freely available, felodipine tended to stimulate saline intake and was associated with an increase in body Na in all strains except SHR; body Na was high in SHR even in the absence of felodipine and did not increase further with felodipine treatment. Felodipine slightly speeded up the excretion of an Na load in rats on an ample NaCl intake (choice of 0.5% 22Na-NaCl and water) but this may have been due, in part, to the treated rats having taken, by choice, a greater intake of saline in the pre-load period. 4. In this study, felodipine reduced BP and stimulated PRA and salt appetite. Its effects on Na handling varied to some extent between the strains; there was no consistent natriuretic effect, but rather some evidence of Na retention.

Aldosterone↗
PubMed1995

Effect of felodipine treatment and withdrawal on blood pressure and cardiovascular structure in New Zealand genetically hypertensive rats.

1. Four groups of New Zealand genetically hypertensive (GH) rats were treated with felodipine as follows: (A) from ages 4-12 weeks; (B) 4-20 weeks; (C) 4-12 weeks then withdrawn from felodipine till age 20 weeks; and (D) 12-20 weeks. 2. Effects on blood pressure (BP), left ventricular (LV) weight and the structure of myograph-mounted mesenteric resistance arteries (MRA) were measured. 3. BP was about 170 mmHg in 4 week old GH rats and did not change substantially from this value in groups A and B but rose to over 230 mmHg in untreated controls. In rats of group D, started on felodipine at 12 weeks, BP fell rapidly and was 173 mmHg at 20 weeks. On withdrawal of felodipine at 12 weeks (group C) BP rose rapidly and exceeded control levels at 20 weeks. 4. LV mass was significantly lower (P < 0.001) in all groups (A, B and D) killed while on felodipine but rose to control levels in the rats taken off felodipine. 5. In the four treated groups there were no significant changes in MRA structure (lumen diameter, medial thickness, media/lumen ratio and volume of medial tissue) as measured on the myograph. 6. Felodipine induces substantial falls in BP in GH rats which are sufficient to prevent cardiac hypertrophy but do not alter MRA structure. Resistance artery structure in GH rats does not seem to relate to the level of hypertension, and may therefore not have a necessary role in the pathogenesis of this hypertensive strain.

Animals↗
PubMed1995

Long-term effects of treatment with enalapril on the structure of mesenteric resistance arteries in New Zealand genetically hypertensive rats.

1. New Zealand genetically hypertensive (GH) rats were treated with enalapril (20 mg/kg per day in drinking fluids) from age 4-10 weeks; one group (GHex-enal) was then taken off enalapril and followed for 6 more weeks to see if the drug-induced changes in blood pressure (BP) and structure of mesenteric resistance arteries (MRA) were long lasting once the enalapril was withdrawn. Control groups consisted of untreated GH and their normotensive (N) control strain. 2. Tail-cuff BP in GH treated rats fell significantly to N BP levels during treatment. On cessation of treatment BP rose rapidly. At age 16 weeks BP, although at a hypertensive level (mean +/- s.e.m., GHex-enal, 210.8 +/- 4.7 mmHg), was still significantly below the GH controls (230 +/- 6.9, P < 0.05), but above the N control group (137 +/- 3, P < 0.001). 3. Left ventricular (LV) mass in GH rats was reduced by enalapril to that in N rats; at the end of the subsequent period without treatment it was still significantly lower than the GH control group, but also significantly above the N group (GHex-enal, 255 +/- 6; GH 306 +/- 11; N 179 +/- 3, mg/100 g bodyweight). 4. The large changes in media, lumen and media/lumen ratio seen after 6 weeks of treatment were not sustained over the subsequent non-treatment period. However, values in the GHex-enal group at 16 weeks were closer to those in the N16 control group. 5. The persisting effects on smooth muscle (SM) cell density and SM fraction of the media contributed to an increase in SM cell volume which was significantly greater than the N16 group (P < 0.01). The number of layers of SM in the media was less than in the GH16 control group and not different from the N16 controls. 6. In GH rats the effect of ACEI on PB, LV mass and MRA structure is relatively longlasting once treatment is withdrawn.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1994

Remodelling of resistance arteries by treatment with enalapril in the New Zealand genetically hypertensive rat.

1. New Zealand genetically hypertensive (GH) rats were treated with enalapril from the age of 4 to 10 weeks and the effects of treatment on the structure of mesenteric resistance arteries (MRA) was measured by use of stereological analysis of stained sections and by myograph techniques. 2. Tail-cuff blood pressure (BP) was measured weekly and intra-arterial BP recorded just before MRA were either fixed by perfusion or mounted on a myograph. 3. Stereological techniques (Cavalieri and optical dissector) were used to determine media and lumen volume, fraction of smooth muscle (SM) within the media and SM cell density. For MRA mounted on the myograph, lumen diameter, media thickness, active tension and active pressure were recorded. 4. BP was significantly (P < 0.0001) lowered by enalapril throughout the experiment. Intraarterial BP and left ventricular (LV) mass were also significantly lower in the enalapril treated GH rats (P < 0.0001). 5. Stereological measurements showed that enalapril treatment significantly (P < 0.0001) reduced media volume by 50%, doubled lumen volume (P < 0.0001), reduced the fraction of SM in the media (P < 0.04), and had no effect on the number of SM cell layers or on SM cell density. 6. Myograph measurements showed a decrease in the ratio media thickness/lumen diameter which was accompanied by a decrease in maximum active tension and pressure development. 7. In the GH rat early treatment with enalapril causes a true loss of medial tissue that is not simply due to rearrangement of existing media around an enlarged lumen.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Stereological studies on mesenteric resistance artery structure in New Zealand genetically hypertensive and control rats.

1. Stereological methods were used to quantitate and compare the structure of mesenteric resistance arteries (MRA) in New Zealand genetically hypertensive (GH) rats aged 4, 10 and 16 weeks and their normotensive control strain (N). 2. Blood pressure (BP) (tail-cuff and intra-arterial) were recorded before the vessels were fixed by perfusion and embedded in Technovit Kulzer GmbH D-6393, Wehrheim, Germany). 3. Media and lumen volumes were measured on transverse sections (TS), by the Cavalieri method, and numbers of smooth muscle (SM) cells were estimated by the optical disector method. 4. There were no significant differences in lumen volume per unit vessel length between GH and age-matched N groups at any age. However, at 10 and 16 weeks volume in GH groups was 9-10% lower than their respective N groups. 5. Media volume per unit vessel length increased in GH rats at all ages. The media/lumen ratio also increased in GH at all ages. 6. Smooth muscle cell density (SM cell number per unit volume of media) decreased in GH rats at all ages, i.e. there was no evidence of hyperplasia. 7. Blood pressure (tail-cuff and intra-arterial) significantly increased in GH rats at 4 weeks of age and also at 10 and 16 weeks. 8. These results show that media volume is increased in GH early in life, is not due to hyperplasia, but may be due to hypertrophy of the SM cells, an increase in the amount of extracellular matrix or a combination of both.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Effects of cilazapril on the structure of mesenteric resistance arteries of New Zealand genetically hypertensive and normotensive control rats.

1. New Zealand genetically hypertensive (GH) rats and their normotensive controls (N) rats between the ages of 10 and 16 weeks were treated with cilazapril in the diet for 6 weeks. 2. Systolic blood pressure (SBP; tail-cuff) was measured weekly and intra-arterial blood pressure (BP) was measured at the end of the treatment period. 3. The effect of cilazapril on the structure of mesenteric resistance arteries (MRA) was evaluated by both stereological and myographic techniques. 4. Cilazapril lowered SBP significantly throughout the treatment period (16 weeks; GH with cilazapril 135 +/- 5 vs GH 216 +/- 9 mmHg, P < 0.001; N cilazapril 91 +/- 6 vs N 137 +/- 3 mmHg, P < 0.001); intra-arterial BP was also significantly lowered. 5. Bodyweight (BW) of treated GH rats was significantly lower than that of untreated GH at 16 weeks (P < 0.01; t-test); however, the weight of treated N rats was not significantly affected. Ventricular mass was reduced by cilazapril in GH and N rats (GH 259 +/- 10 vs 306 +/- 11, P < 0.001; N 171 +/- 3 vs 195 +/- 4 mg/100 g BW, P < 0.001). 6. Lumen volume of MRA was not significantly affected by cilazapril in either strain; media volume was reduced by 14% in both strains and the media/lumen ratio was significantly reduced. Vascular smooth muscle cell density significantly increased in cilazapril-treated GH rats.

Animals↗
PubMed1993

Cystic change in the head of the fibula in osteoarthritis.

We report eight patients with prominent cystic changes in the head of the fibula. Seven of these had osteoarthritis of the adjacent knee, and five had evidence of local deposition of calcium pyrophosphate dihydrate crystals. A radiographic survey of 470 knees in 254 patients with osteoarthritis suggested that such cysts are rare, but should be considered in the differential diagnosis of such changes before expensive or invasive investigations are performed.

Aged↗
PubMed1992

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↗
PubMed1991

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↗
PubMed1990

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↗
PubMed1990

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↗
PubMed1989

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↗
PubMed1989

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↗
PubMed1987

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↗
PubMed1986

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↗
PubMed1985

Jan Brod.

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Czechoslovakia↗