Biomedical subjects

B Jackson

Publications and source records attributed to B Jackson.

At least 181 records · Page 10Linked to original sources

PubMed1988

Changes in the renin-angiotensin system, exchangeable body sodium, and plasma and atrial content of atrial natriuretic factor during evolution of chronic renal failure in the rat.

The remnant kidney model of progressive renal failure in the rat was used to assess the relationships between the renin-angiotensin system, exchangeable body sodium, and both plasma concentration and atrial content of atrial natriuretic factor (ANF) measured sequentially over 4 weeks. Following subtotal nephrectomy plasma creatinine (mumol/L) rose from 40 +/- 6 (sham) to 107 +/- 24 (P less than 0.05) at 1 week, and rose further to 124 +/- 20 (P less than 0.05) by 4 weeks. Plasma renin activity (nanograms of angiotensin I/mL/min) rose from 4.5 +/- 0.5 to 11.8 +/- 2.8 (P less than 0.05) at 1 week, but was suppressed by 4 weeks to 2.2 +/- 0.3 (P less than 0.001). Plasma angiotensin II (pg/mL) was 52 +/- 2 (sham), 117 +/- 20 at 1 week (P less than 0.05) and 51.3 at 4 weeks. Exchangeable sodium (mmol/kg) rose progressively from 43.2 +/- 5 (before surgery) to 48.6 +/- 0.9 at 1 week and 50.8 +/- 2.2 at 4 weeks. Plasma atrial natriuretic factor (ANF) (pg/mL) rose progressively from 114 +/- 6 (sham) to 248 +/- 31 (P less than 0.01) at 1 week and 456 +/- 78 at 4 weeks (P less than 0.01). Atrial ANF content fell as the plasma concentration rose. In the remnant kidney model of progressive renal failure there was a progressive increase in exchangeable body sodium and plasma atrial natriuretic factor, with reciprocal changes in atrial ANF content suggesting that ANF secretion rate was increased. Initially the renin-angiotensin system was stimulated, but later it was suppressed.

Animals↗

PubMed1988

The contribution of systemic hypertension to progression of chronic renal failure in the rat remnant kidney: effect of treatment with an angiotensin converting enzyme inhibitor or a calcium inhibitor.

In order to establish if pharmacological treatment of systemic hypertension modifies the course of progressive renal failure, we studied the effects of an angiotensin converting enzyme inhibitor and a calcium antagonist, on the renal structure and function in the remnant kidney model of chronic renal failure in the rat. Progressive renal failure was induced in adult female Sprague Dawley rats (SDR) by surgical removal of the right kidney, and segmental infarction of seven-eighths of the left kidney. Following subtotal nephrectomy, plasma creatinine rose from 65 +/- 16 mumol/l to 173 +/- 19 mumol/l (P less than 0.001) over a period of 6 weeks, systolic blood pressure (SBP) rose from 121 +/- 2 mmHg to 176 +/- 7 mmHg (P less than 0.001) and urinary protein excretion from 0.6 +/- 0.2 to 84 +/- 22 mg/24 h (P less than 0.001). Glomerular mesangial expansion was present after 2 weeks, then progressed, in association with the development of glomerular sclerosis, which became prominent after 6 weeks. Rats were treated with enalapril (5 mg/kg per day) or felodipine (30 mg/kg per day) from 1 week after subtotal nephrectomy, and their course compared with that of untreated rats. Systemic SBP decreased to a similar degree by both drug treatments. Six weeks after surgery, plasma creatinine concentration was lower in the enalapril-treated group (110 +/- 8 mumol/l, P less than 0.05) than in the felodipine-treated group (153 +/- 23 mumol/l). The latter group showed similar plasma creatinine concentrations to those of the untreated rats (173 +/- 19 mumol/l).(ABSTRACT TRUNCATED AT 250 WORDS)

Angiotensin-Converting Enzyme Inhibitors↗

PubMed1988

Chronic angiotensin converting enzyme inhibition in the two-kidney, one clip hypertensive rat.

Treatment with an angiotensin converting enzyme (ACE) inhibitor in renovascular hypertension produces acute effects on renal function; however, the long-term consequences of this are not known. We have studied the effect of chronic enalapril treatment on renal structure and function in the two-kidney, one clip model of renovascular hypertension in the rat. Four weeks after the left renal artery was clipped, the hypertensive rats were randomly allocated to treatment with enalapril, minoxidil or to no treatment. The drug dose was titrated for maximal hypotensive effect. After 4 months of treatment blood pressures were 129 +/- 3 mmHg (enalapril), 193 +/- 5 mmHg (minoxidil) and 220 +/- 4.8 mmHg (no treatment). Twelve months later survival was 84% (enalapril group), 48% (minoxidil group) and 15% (untreated group). Split kidney function (51Cr-EDTA clearance, ml/min) of the clipped kidneys was 0.0 (enalapril group), 0.26 +/- 0.23 (minoxidil group) and 0.74 +/- 0.13 (untreated group). The clipped kidney from enalapril-treated rats weighed 0.46 +/- 0.1 g, much less than in the minoxidil-treated group (1.2 +/- 0.07) or the untreated group (1.14 +/- 0.10). Enalapril treatment was withdrawn for 2 weeks in five rats, but the clipped kidney remained small and non-functional. Histological examination revealed marked interstitial fibrosis and tubular atrophy in clipped kidneys from both enalapril groups, in contrast to minor changes in the minoxidil-treated and the untreated groups. We conclude that chronic enalapril treatment of two-kidney, one clip hypertension in the rat improved survival and preserved total renal function, but was associated with irreversible fibrotic atrophy of the clipped kidney.

Angiotensin-Converting Enzyme Inhibitors↗

PubMed1988

Effects of perindopril on tissue angiotensin-converting enzyme activity demonstrated by quantitative in vitro autoradiography.

Inhibition of plasma angiotensin II generation does not fully explain the chronic hypotensive effects of angiotensin-converting enzyme (ACE) inhibitors. Therefore, the pattern of tissue ACE inhibition in rats was studied after oral administration of perindopril, a new ACE inhibitor. Tissue ACE was measured by quantitative in vitro autoradiography using [125I]-351A as a radioligand and compared with plasma ACE and the pressor response to intravenous (i.v.) angiotensin I. Following oral perindopril (1 mg/kg), plasma ACE activity was acutely reduced, but recovered over 24 h. The peak concentration of plasma perindoprilic acid, the active diacid of perindopril, occurred at 1 h, and the drug was undetectable by 24 h. The pressor response to i.v. angiotensin I was inhibited by 95% at 4 h and had not fully recovered by 24 h. Four hours after oral administration of perindopril, ACE was markedly inhibited in the proximal tubules of the kidney (24% control), lung parenchyma (10%), and aortic wall (18%) (p less than 0.01). At 24 h, ACE in these tissues had only partially recovered (32-63%). ACE was also identified in vascular endothelium of organs, including the lung, kidney, and testis; in these sites, vascular ACE showed a pattern of inhibition similar to that of aortic ACE. In contrast, ACE in testicular seminiferous tubules was unaffected by perindopril. These results demonstrate a prolonged effect of ACE inhibitors on tissue ACE that may better explain the time course of these drugs than the changes in plasma ACE or plasma levels of the drug.

Angiotensin I↗

PubMed1988

Near-total gastric necrosis caused by acute gastric dilatation.

Gastric dilatation caused by psychogenic polyphagia or bulimia may, under extreme circumstances, progress to total gastric necrosis. We have described a patient in whom acute abdominal symptoms and signs developed while he was receiving psychiatric treatment. Laparotomy showed massive gastric dilatation with near-total infarction. Total gastrectomy with cervical esophagostomy, feeding and decompressing jejunostomies, and wide drainage of the gastric bed were done. After staged reconstruction, recovery was uneventful.

Adult↗

PubMed1988

Lisinopril pharmacokinetics in chronic renal failure.

1. Lisinopril, a new orally active angiotensin converting enzyme inhibitor, was given to eight patients with stable chronic renal failure, in a dose of 5 mg 24 h-1 for 1 week. Creatinine clearance of the subjects ranged from 0.22 to 1.11 ml s-1. Lisinopril pharmacokinetics were studied over 8 days. 2. There was a close correlation between creatinine clearance and total 'area under the curve' over the 8 days of study (r = -0.88, P less than 0.05), and plateau lisinopril concentration and creatinine clearance (r = -0.77, P less than 0.05). 3. Serum angiotensin converting enzyme activity was inhibited in proportion to log serum lisinopril concentration (r = -0.99, P less than 0.001). Calculated IC50 was 47 ng lisinopril ml-1. from pooled data, with individual patients IC50 ranging from 20 to 70 ng lisinopril ml-1. 4. Creatinine clearance was unaltered by treatment. Serum potassium rose to over 5 mmol 1-1 in four patients, without adverse clinical effect.

Adult↗

PubMed1988

Alpha-smooth muscle actin is transiently expressed in embryonic rat cardiac and skeletal muscles.

Actin isoform expression may change during development, and in certain physiological, experimental and pathological situations. It is accepted that during sarcomeric (skeletal and cardiac) muscle development, the alpha-skeletal and alpha-cardiac isoforms of actin accumulate rapidly at the onset of muscle fibre formation, while there is a rapid fall in the expression of nonmuscle (beta and gamma) actin isoforms. Here we show that, before birth, both skeletal and myocardial cells express significant amounts of alpha-smooth muscle actin mRNA and protein. This expression is transient and disappears over the 1-7 days following birth. Our findings show that the program regulating actin isoform expression in sarcomeric muscle development is complex and that alpha-smooth muscle actin participates in this process.

Actins↗

PubMed1988

Relative inhibitory potency and plasma drug levels of angiotensin converting enzyme inhibitors in the rat.

1. 125I-351A, a tyrosyl derivative of the angiotensin converting enzyme (ACE) inhibitor lisinopril, was used as a radioligand, and radioinhibitor binding and displacement assays have been established. 2. The in vitro potency of a range of ACE inhibitors against rat ACE was determined using the radioinhibitor binding displacement assay. 3. The concentration of an ACE inhibitor needed to displace 50% of 125I-351A bound to rat ACE (ID50) was closely correlated with the concentration needed to inhibit 50% of ACE enzymatic activity (IC50). 4. Radioinhibitor binding displacement assay was used to measure the plasma concentrations of lisinopril, cilazapril and perindopril in rat plasma. 5. Plasma concentrations of lisinopril measured by radioimmunoassay were identical with that measured by radioinhibitor binding assays.

Angiotensin-Converting Enzyme Inhibitors↗

PubMed1988

Effect of enalapril treatment on progression of the nephrotoxic serum nephritis model of renal failure in the rat.

1. Nephrotoxic serum nephritis was induced immunologically in uninephrectomized Sprague-Dawley rats (n = 24). One-half were assigned randomly to treatment with enalapril (5 mg/kg per 24 h). 2. Untreated rats (n = 12) developed a progressive fall in creatinine clearance, a progressive rise in systolic blood pressure and marked proteinuria over a 6 week period. The mortality rate was 42% at 5 weeks and 66% at 6 weeks. 3. Enalapril-treated rats (n = 12) had no significant reduction in systolic blood pressure, and a similar reduction in creatinine clearance to that in untreated rats. Mortality was 50% at 5 weeks, and 92% at 6 weeks. 4. Proteinuria but not the blood pressure rise was significantly reduced by enalapril treatment. 5. Converting enzyme inhibitors may have a specific role in the treatment of nephritic diseases.

Animals↗

PubMed1988

Effect of glycaemic control on glomerular filtration rate in the streptozotocin diabetic rat.

1. Diabetes was induced in 32 adult Wistar-Kyoto rats with streptozotocin (60 mg/kg). Fourteen rats remained untreated, 10 received insulin three times per week, and eight received insulin daily. Fourteen non-diabetic rats served as controls. 2. Exchangeable sodium and plasma volume were elevated in the untreated diabetic rats. Treatment normalized these parameters. 3. Glomerular filtration rate (GFR) was elevated in the untreated diabetic group and the group receiving insulin three times per week compared with the control group. Daily insulin treatment restored GFR towards control values. 4. Plasma atrial natriuretic factor was similar in untreated diabetic rats and non-diabetic rats.

Animals↗

PubMed1988

Lack of cross sensitivity between captopril and enalapril.

Oral inhibitors of angiotensin converting enzyme (ACE) now have an established place in the treatment of hypertension and heart failure. Captopril, the first of these agents, was initially used in high doses and was associated with adverse effects including proteinuria, skin rash and taste disturbance. We report 11 patients who developed side effects during captopril therapy (proteinuria two, rash four, taste disturbance four and taste disturbance with rash one) who were subsequently treated with enalapril, a second generation angiotensin converting enzyme inhibitor. Proteinuria did not recur in either patient, skin rash resolved in all five cases and taste disturbance resolved in four of five during enalapril therapy. We conclude that the side effects of proteinuria, skin rash and taste disturbance are consequences of captopril idiosyncrasy rather than inhibition of the angiotensin converting enzyme. The reported incidence of these side effects with the current recommended dosage of captopril is low.

Captopril↗

PubMed1988

Differential angiotensin-converting enzyme inhibition in brain after oral administration of perindopril demonstrated by quantitative in vitro autoradiography.

To help elucidate potential sites for the central actions of a new angiotensin-converting enzyme (ACE) inhibitor, perindopril, ACE levels were measured in the brain of Sprague-Dawley rats by quantitative in vitro autoradiography after administration of the drug. Following acute oral administration of 1 mg/kg perindopril, ACE in the two circumventricular organs, the subfornical organ and organum vasculosum of the lamina terminalis, was markedly inhibited and had only partially recovered after 24 h. The ACE inhibition in the circumventricular organs did not correlate with the inhibition of ACE in plasma but with that of pressor response to intravenous angiotensin I. No or little change in ACE was observed in other brain structures which are rich in the enzyme, including the choroid plexus and basal ganglia. However, large doses of perindopril (up to 16 mg/kg) did progressively inhibit ACE in all brain structures measured, including the basal ganglia. These findings fit with the deficient blood-brain barrier known to occur in the circumventricular organs. These regions are rich in ACE and angiotensin II receptors and exhibit physiological responses to angiotensin II with effects on fluid, electrolyte, and blood pressure homeostasis. Combined with current observations, the circumventricular organs are potential targets for the centrally mediated actions of ACE inhibitors.

Angiotensin I↗

PubMed1988

Inhibition of tissue angiotensin converting enzyme. Quantitation by autoradiography.

Inhibition of angiotensin converting enzyme (ACE) in serum and tissues of rats was studied after administration of lisinopril, an ACE inhibitor. Tissue ACE was assessed by quantitative in vitro autoradiography using the ACE inhibitor [125I]351A, as a ligand, and serum ACE was measured by a fluorimetric method. Following oral administration of lisinopril (10 mg/kg), serum ACE activity was acutely reduced but recovered gradually over 24 hours. Four hours after lisinopril administration, ACE activity was markedly inhibited in kidney (11% of control level), adrenal (8%), duodenum (8%), and lung (33%; p less than 0.05). In contrast, ACE in testis was little altered by lisinopril (96%). In brain, ACE activity was markedly reduced 4 hours after lisinopril administration in the circumventricular organs, including the subfornical organ (16-22%) and organum vasculosum of the lamina terminalis (7%; p less than 0.05). In other areas of the brain, including the choroid plexus and caudate putamen, ACE activity was unchanged. Twenty-four hours after administration, ACE activity in peripheral tissues and the circumventricular organs of the brain had only partially recovered toward control levels, as it was still below 50% of control activity levels. These results establish that lisinopril has differential effects on inhibiting ACE in different tissues and suggest that the prolonged tissue ACE inhibition after a single oral dose of lisinopril may reflect targets involved in the hypotensive action of ACE inhibitors.

Adrenal Glands↗

PubMed1988

Characterization of angiotensin converting enzyme (ACE) in the testis and assessment of the in vivo effects of the ACE inhibitor perindopril.

Angiotensin converting enzyme (ACE) was characterized by radioligand studies utilizing the potent ACE inhibitor 351A, a derivative of lisinopril. Ligand binding characteristics were similar for ACE derived from testis, lung, and kidney, despite known differences in structure between ACe from these sources. This observation suggests that the ACE active enzymatic site is similar in different tissues. The effect of the orally active ACE inhibitor perindopril was studied ex vivo in tissues of the rat after oral gavage. Radioligand bound to tissue ACE was reduced after perindopril treatment, in tissue homogenates of lung and kidney, but not testis. Autoradiographs of radioligand binding to tissue sections obtained ex vivo after oral perindopril showed inhibition of ACE in the aorta, lung, and kidney, but did not reveal any inhibition of ACE in the testis. ACE in small vessels of the testis was inhibited as in the aorta, while at the same time testicular ACE was unaffected. ACE in rat testis appears to have a similar enzymatic binding site to ACE from the lung and kidney. Perindopril inhibited ACE in the lung and kidney but did not affect ACE in the testis, suggesting the drug is limited in testicular penetration by the blood-testis barrier. This may explain the lack of any reports of adverse effects of ACE inhibitors on testicular function.

Angiotensin-Converting Enzyme Inhibitors↗

PubMed1988

Inhibition of tissue angiotensin converting enzyme by perindopril: in vivo assessment in the rat using radioinhibitor binding displacement.

Changes in angiotensin converting enzyme (ACE) derived from plasma, lung, aorta, brain, kidney and testis were measured in rats treated with perindopril. Angiotensin converting enzyme was measured by a radio inhibitor binding method using 125I351A. Rats were gavage fed perindopril (1, 4 and 8 mg/kg) and changes followed over 48 hr. Plasma and kidney ACE were both affected acutely with reduction of 125I351A binding to less than 5% of that in control animals 1 and 2 hr after gavage. Ligand binding to ACE in plasma and kidney returned to control levels after 24 hr. Ligand binding to ACE in lung, aorta and brain also was displaced after perindopril treatment. Changes were of a lesser degree than in plasma or kidney. Maximal effect was 1 to 4 hr after treatment and persisted through 24 hr postgavage. Ligand binding to ACE from testis was little altered over the time period of study. In a dose varying study rats were gavage fed perindopril (0-32 mg/kg) and tissues were studied 4 hr later. Ligand binding to plasma and kidney ACE was displaced by 50% at a dose of 1 mg/kg or less, whereas a dose of 16 to 32 mg/kg was required for a similar effect on ACE in lung, aorta and brain. ACE in testis was only affected to a small degree at a dose of 32 mg/kg. ACE is tissues was inhibited differentially after oral treatment with perindopril. Although differing in bioavailability, bioactivation of the drug or different binding properties of the enzyme could all account for the results, the most likely explanation is that there is variation in tissue penetration of the drug.

Angiotensin-Converting Enzyme Inhibitors↗

PubMed1988

Inhibition of angiotensin converting enzyme (ACE) in plasma and tissues: studies ex vivo after administration of ACE inhibitors.

Two methods of radio-inhibitor binding to tissue membrane homogenates and in vitro autoradiography have been used for ex vivo studies on the inhibition of tissue angiotensin converting enzyme (ACE) following acute and chronic administration of ACE inhibitors. Tissue ACE is differentially inhibited in time and degree in different tissues of the rat. Plasma and kidney ACE are inhibited completely at low doses whereas lung and aorta are only inhibited by 60-70%, even after very high does of ACE inhibitors. In the brain only those structures outside the blood-brain barrier are inhibited at low doses but at high doses perindopril appears able to cross the blood-brain barrier. Similarly, testicular ACE is not inhibited and appears to be protected by a blood-testis barrier. Preliminary results suggest that after chronic administration there is also a variable pattern of induction and inhibition of ACE in different tissues. By relating the degree of tissue inhibition to physiological responses it may be possible to determine the role of local renin-angiotensin systems in regional haemodynamics and in the hypotensive action of ACE inhibitors. Further, the techniques of radioligand inhibitor binding and in vitro autoradiography can be extended to other important cardiovascular enzymes (renin and kallikrein) when suitable high affinity specific inhibitors become available.

Angiotensin-Converting Enzyme Inhibitors↗

PubMed1988

Effects of perindopril on angiotensin converting enzyme in tissues of the rat.

Perindopril, an orally active angiotensin converting enzyme (ACE) inhibitor, was fed by gavage to male Sprague-Dawley rats. The effect on tissue ACE was measured ex vivo by quantitation of binding of the specific radioligand 125I-3511A to ACE in tissue homogenates. In an acute time-course study perindopril (1, 4 or 8 mg/kg) inhibited plasma ACE activity by more than 90% in 1 h but no inhibition remained after 24 h. Kidney ACE was affected to a similar degree and followed a similar time-course of inhibition to plasma ACE. In contrast, ACE was inhibited to a lesser degree in lung and aorta homogenates, with maximum effect 4-8 h postgavage, and with inhibition persisting 48 h following the dose. In testis homogenates, ACE remained unaltered following the administration of perindopril at all three doses. Therefore we conclude that plasma ACE inhibition does not parallel tissue effects, and that drug penetration into the testis appears to be limited.

Angiotensin-Converting Enzyme Inhibitors↗

PubMed1988

Diabetic nephropathy in the rat: differing renal effects of an angiotensin converting enzyme inhibitor and a calcium inhibitor.

The renal functional alterations that occurred in streptozotocin-induced diabetes in uninephrectomized rats were studied over a three-month period. Diabetic animals had elevated systemic systolic blood pressure, creatinine clearance and urinary protein excretion. After three months, systolic blood pressure was 131 +/- 2 mmHg, creatinine clearance was 1.52 +/- 0.06 ml/min and urinary protein excretion 70.8 +/- 17.9 mg/24 h. Non-diabetic control rats had a systolic blood pressure of 117 +/- 3 mmHg (p less than 0.001), creatinine clearance of 1.15 +/- 0.05 ml/min (p less than 0.001), and protein excretion of 8.22 +/- 0.2 mg/24 h (p less than 0.001). Diabetic rats were treated with enalapril or verapamil, 5 mg.kg-1.day-1 which reduced systolic blood pressure to 108 +/- 3 mmHg (p less than 0.001) and 114 +/- 2 mmHg (p less than 0.001) respectively. Treatment with enalapril reduced the degree of proteinuria at three months (36.4 +/- 3.0 mg/24 h, p less than 0.05). Protein excretion rate in verapamil treated rats was 57.7 +/- 10.1 mg/24 h at three months, similar to that of untreated diabetic rats. Filtration fraction of untreated diabetic rats was 0.40 +/- 0.04. Treatment with enalapril lowered filtration fraction (0.26 +/- 0.02, p less than 0.01) whilst verapamil had no significant effect (0.37 +/- 0.02). The differing effects of enalapril and verapamil on renal function occurred despite similar degrees of hypotension, and may reflect the different intrarenal haemodynamic effects of these drugs.

Animals↗