Biomedical subjects

D Heudes

Publications and source records attributed to D Heudes.

At least 55 records · Page 3Linked to original sources

PubMed1995

Morphometric detection of incipient glomerular lesions in diabetic nephropathy in rats. Protective effects of ACE inhibition.

BACKGROUND: Glomerulosclerosis is the main renal lesion complicating diabetes in humans and in experimental models. Angiotensin I-converting enzyme (ACE) inhibitors are effective in preventing the development of diabetic nephropathy. Incipient glomerular lesions were explored in streptozotocin-diabetic rats at a stage when glomerulosclerosis was not yet established. The modulation of such early glomerular lesions by a new ACE inhibitor (Trandolapril (T) at high or low doses was assessed. EXPERIMENTAL DESIGN: Five groups of rats were designed as follows: (a) nondiabetic control rats, (b) diabetic rats, (c) diabetic rats treated with 0.1 mg/kg/day of T, (d) diabetic rats treated with 1 mg/kg/day of T, and (e) nondiabetic rats treated with 1 mg/kg/day of T. The rats were killed at 1, 3, and 6 months after the beginning of the treatment. The kidneys were studied using a powerful morphometric technique at optical microscopic level with an image analyzer to measure the following glomerular parameters to assess the development of incipient glomerular lesions: (a) total glomerular surface area, (b) glomerular tuft surface area, (c) mesangial surface area, (d) ratio of the mesangial surface area to the glomerular tuft surface area, and (e) mean thickness of the Bowman's capsule. In parallel, albuminuria was measured. RESULTS: The results showed the development of glomerular hypertrophy in parallel with the increase in glomerular mesangial domain and in albuminuria with diabetes. They also demonstrated that ACE inhibitor given at a high dose is significantly effective in reducing glomerular hypertrophy and the expansion of the mesangial domain. ACE inhibitor given at a low dose tended to reduce glomerular hypertrophy and the expansion of the mesangial domain. Furthermore, ACE inhibitor at both doses completely abolished the albuminuria increase, maintaining the levels of albuminuria within the range of young nondiabetic rats. CONCLUSIONS: Using morphometric image analysis, incipient glomerular changes can be detected before glomerulosclerosis is patent in experimental diabetes. Moreover, they can be easily and reliably quantified by this technique, allowing comparison among experimental groups. These changes can be prevented by ACE inhibition.

Angiotensin-Converting Enzyme Inhibitors↗

PubMed1995

[Early matrix and cellular modifications in a hypertension model induced in rats (Goldblatt model). Quantitative and morphometric study].

In the two-kidney one-clip hypertensive Goldblatt model of nephrosclerosis, the aim of this study was to detect, during the first twenty-eight days of high blood pressure, interstitial and periarterial (interlobular arterial and arteriolar) kidney changes. Morphometric analysis for type I collagen, in situ hybridization for type I and IV collagen mRNAs and immunohistochemistry for inflammatory cells were used to quantify and localize the following lesions: 1) A very early increase of collagen I proteins and mRNAs soon as the first 3 days and an important influx of inflammatory cells (macrophages and T-helper lymphocytes) were observed concomitantly. Then, these phenomenons decrease until the end of the experiment. 2) The interstitium reacts in the same way but with a lower intensity and with a time shifting. The main interstitial changes were seen after the second week of hypertension. 3) A same periarterial collagen I increase was measured during the first 3 days of hypertension in both clipped kidney and unclipped kidney. This hypertension-independent manifestation in the clipped kidney does not increase in later times of hypertension as it does in the unclipped kidney. A possible explanation is given by the angiotensin II concentration higher in the clipped kidney than in the unclipped kidney, and by direct angiotensin II effects as growth factor. 4) Periarterial fibrosis and macrophages or T-helper lymphocytes infiltration were co-localized. The intensity of both phenomenons is well correlated. These facts suggest that inflammatory cell infiltration and interstitial fibrosis are strongly and early linked.

Animals↗

PubMed1994

Calcium blockade versus ACE inhibition in clipped and unclipped kidneys of 2K-1C rats.

ACE inhibitors have been shown to worsen the kidney damage occurring distal to a renal artery stenosis. To determine if this effect was due to the decrease of arterial pressure or to an inhibition of the formation of angiotensin, we compared the effects of equihypotensive doses of an angiotensin converting enzyme inhibitor (enalapril) and a long-acting calcium antagonist (Ro 40-5967) in 2K-1C rats. The rats were treated for five weeks with either enalapril, Ro 40-5967, or were left untreated. A group of sham operated rats was used as control. At the end of the five-week treatment period, proteinuria, plasma urea and creatinine were measured and quantitative morphometry of the clipped and unclipped kidneys was performed. Ro 40-5967, despite an absence of inhibition of the renin-angiotensin system, worsened the lesions of the clipped kidney to the same extent as enalapril. In contrast, the effects of both drugs on the unclipped kidney were different. Ro 40-5967, and not enalapril, increased the weight and the glomerular surface area of the unclipped kidney. Ro 40-5967 did not change the glomerulosclerosis index, which was improved by enalapril. In contrast with enalapril, Ro 40-5967 decreased plasma urea and creatinine concentrations. Only enalapril decreased proteinuria which originated from the unclipped kidney as shown by nephrectomy experiments. We conclude that during ACE inhibition the fall in renal perfusion pressure seems to be the main determinant of the renal damage distal to a renal artery stenosis, independently of a blockade of the renin-angiotensin system.(ABSTRACT TRUNCATED AT 250 WORDS)

Angiotensin-Converting Enzyme Inhibitors↗

PubMed1994

Increased SMC proliferation after endothelial injury in hyperinsulinemic obese Zucker rats.

The long-term effect of long-lasting hyperinsulinemia on aortic smooth muscle cell (SMC) proliferation after endothelial injury was investigated using the obese Zucker rat model, which is characterized especially by early spontaneous development of hyperinsulinemia and insulin resistance. SMC proliferation was provoked by the passage of an embolectomy catheter with a tightly inflated balloon and was assessed by measuring the incorporation of [3H]thymidine in the DNA of intima-media layers. Compared with controls, the SMC mitotic activity was not significantly increased from day 2 to day 7 after injury, but from day 14 to day 30 after endothelial denudation, SMC proliferation was significantly less decreased in obese than in lean rats [on day 14, DNA synthesis = 107 +/- 18 counts.min-1.micrograms DNA-1 in lean and 345 +/- 44 counts.min-1.micrograms DNA-1 in obese rats (P = 0.003); and on day 30, DNA synthesis = 74 +/- 18 counts.min-1.micrograms DNA-1 in lean and 133 +/- 19 counts.min-1.micrograms DNA-1 in obese rats (P = 0.0055)]. As a result, the intima-media DNA content was higher in obese than in lean rats on day 14 and even more so on day 30, suggesting a higher amount of SMCs in the intima-media. Moreover, on day 30, the aortic thickening, as measured by a histomorphometric technique, was much higher in obese than in lean rats. This difference was entirely due to an increase in SMC content of the intima, mainly resulting from a dramatic increment in the number of nuclei and nuclear number density.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1994

Effect of chronic ANG I-converting enzyme inhibition on aging processes. I. Kidney structure and function.

The effect of angiotensin I-converting enzyme inhibition (ACEI) on the age-related changes in the kidney structure and function was investigated in rodents. Normotensive male Wistar (WAG)/Rij rats were treated with perindopril from the age of 6 mo to the day of killing at 12, 24, or 30 mo. Mean blood pressure, constant from 6 to 30 mo, was reduced by 19 mmHg in treated animals. With age, the major functional modifications were a decrease in glomerular filtration rate and in renal blood flow, a rise in intrarenal vascular resistance (IVR), a reduced tubular reabsorption of salts, and a progressive increase in proteinuria. ACEI significantly reduced IVR and proteinuria. From a structural point of view, the glomeruli showed 1) an increase in size, 2) a decrease in capillary surface, 3) a diffuse thickening of the glomerular basement membrane, 4) an expansion of the mesangial matrix, and 5) an accumulation of albumin droplets in podocytes inducing 6) a dispersed focal and segmental glomerulosclerosis which, at 30 mo, affected < 2% of glomeruli. Of these six age-related structural changes, ACEI delayed the appearance of the three latter changes.

Aging↗

PubMed1994

Effect of chronic ANG I-converting enzyme inhibition on aging processes. II. Large arteries.

The consequences of hypertension and aging on cardiovascular structure and function are reputed to be similar, suggesting that blood pressure plays a role in the aging process. However, the exact relationship between aging, blood pressure, and the arterial structure-function relationship has not been demonstrated. To test the effects of aging, renin-angiotensin system, and pressure on the arterial wall, 20 normotensive male WAG/Rij rats were killed at 6, 12, 24, and 30 mo of age and compared with similar groups treated with an angiotensin (ANG)-converting enzyme inhibitor (ACEI), perindopril. Arterial function was determined by a systemic hemodynamic study and by in situ measurement of carotid compliance. Arterial wall structure was determined by histomorphometric and biochemical methods. Aging did not significantly modify blood pressure, but ACE inhibition decreased blood pressure significantly from 6 to 30 mo. Plasma renin activity decreased with age and increased with ACEI. Plasma atrial natriuretic factor increased with age and was significantly decreased with ACEI. Absolute and relative left ventricular weight increased with age, and ACEI delayed these increases. Arterial wall stiffness increased with age, as shown by a significant decrease in systemic and local arterial compliance and by an increase in aortic characteristic impedance. The increase in carotid wall compliance after poisoning of smooth muscle contractile function (KCN) was greater in young (6- and 12-mo old) than in old (24- and 30-mo old) rats. Chronic ACEI treatment increased basal carotid compliance values slightly and did not change KCN carotid compliance. The aortic and carotid luminal size increased regularly with age. Aging was associated without any change in absolute elastin content. In contrast, collagen content increased with aging. Aging was also associated with an increase in medial thickness. Medial thickening was mainly due to smooth muscle hypertrophy. Aging was associated with intimal proliferation, which became progressively thicker and collagen rich. ACEI treatment did not prevent aortic lumen enlargement but significantly postponed the increase in medial and intimal thickening. Biochemical determinations of the aortic wall components confirmed the morphometric data. In conclusion, the age-dependent large artery enlargement and stiffening were observed both in normotensive rats and in those rats whose blood pressure was lowered by ACEI. This suggests that aging and blood pressure affect arterial wall structure and function by different mechanisms.

Aging↗

PubMed1994

Effects of heparinoids on the sclerotic reaction of rat thoracic aorta to injury: comparison between standard and low-molecular-weight heparins in vitro and in vivo.

To assess further the influence of heparinoids on arterial sclerosis, we compared the effects of standard heparin and of a low-molecular-weight (low-mol-wt) heparin (CY 216) in vitro on proliferation of cultured arterial smooth muscle cells (SMC) from rat aorta and in vivo on the sclerotic response of rat thoracic aorta to injury with a balloon catheter (SMC proliferation and deposition of elastin and collagen in the intima-media, using biochemical and histomorphologic techniques). Both heparinoids decreased replication of SMC in vitro in a similar dose-dependent manner. In vivo, heparin treatment [continuous intravenous (i.v.) administration, 60 IU/h/kg body weight (0.35 mg/h/kg)] inhibited all aspects of the aortic reaction for < or = 28 days after injury: synthesis of DNA (early peak of thymidine incorporation into DNA on D3.5); accumulation of DNA, collagen and elastin on D14 and D28; intimal thickening on D14. An equivalent treatment with CY 216 [60 antiactivated factor X (Xa) IU/h/kg (0.71 mg/h/kg)] exerted similar though less intense effects on the reaction of intima-media, as assessed biochemically, but reduced formation of neointima in a proportion nearly identical to that of heparin. In some respects, which appear to be related mainly to the fibrotic reaction of aortic media to injury, heparin tended to be a slightly more potent antisclerotic agent than CY 216 although, owing to pharmacokinetic differences, CY 216 had stronger plasma anti-Xa activity than heparin.

Animals↗

PubMed1994

Preeclampsia associated focal and segmental glomerulosclerosis and glomerular hypertrophy: a morphometric analysis.

Renal biopsies from hypertensive pregnant women performed 8 to 10 days postpartum were processed by morphometric analysis. We allocated the 74 patients into four groups according to the respective forms of pregnancy hypertension, i.e. preeclampsia and gestational hypertension. Groups I and II included preeclamptic women, with (group I) or without (group II) de novo FSGS. Groups III and IV included biopsies of women with isolated gestational hypertension, appeared during the third trimester (group III) or earlier (group IV). The control group included 17 biopsies from age-matched nonpregnant women presenting with isolated hematuria. Glomerular lesions of typical preeclampsia were seen in all the biopsies of groups I and II, and in some of women with gestational hypertension of groups III and IV. Our morphometric analysis of these renal biopsies showed a progressive increase in glomerular size from early gestational hypertension, gestational hypertension of the 3rd trimester, isolated preeclampsia, and finally preeclamptic nephropathy associated with FSGS. The largest glomeruli were seen in preeclamptic women with severe hypertension and histologic lesions of preeclampsia with FSGS. Thus, both systemic hypertension and glomerular hypertrophy seem necessary to induce FSGS in this type of pathology.

Adult↗

PubMed1994

Colocalization of myocardial fibrosis and inflammatory cells in rats.

BACKGROUND: Left ventricular overload and aging lead to an increase in fibrosis in the rat cardiac interstitium. The relationship between fibrosis, fibroblast activity, and inflammatory cell infiltration, was explored in spontaneously hypertensive rats (SHR) and Wistar controls. EXPERIMENTAL DESIGN: The left ventricle of three groups of eight SHR and eight Wistar controls hearts were sectioned for light microscopy, immunohistochemistry, and in situ hybridization with a cDNA probe encoding the murine alpha 1 chain of type I collagen. Fibrosis was measured morphometrically. Monoclonal antibodies directed against Ia antigen, CD8+ cytotoxic, CD4+ helper lymphocytes and monocyte/macrophages were used to localize and quantify the inflammatory cells. RESULTS: In 2-month-old rats, with nearly normal interstitial cardiac tissue, fibroblasts expressing collagen mRNA were located around coronary vessels. The areas of fibrosis and interstitial cellular infiltration were more extensive in 22-month-old rats than in 12-month-old rats and greater in SHR than in Wistar. Fibroblasts expressing collagen mRNA were mainly found at the border between fibrosis and myocytic cells, and were always colocalized with lymphocytes and macrophages. The interstitial areas of fibrosis and collagen I expressing fibroblasts had the same pattern of infiltrating cells in normotensive rats than in SHR. Fibrosis and the density of macrophages and CD4+ lymphocytes were correlated. CONCLUSIONS: Thus, fibroblast activity could be closely related to the presence of lymphocytes and macrophages in the myocardium of spontaneously hypertensive and aged rats.

Aging↗

PubMed1993

Effects of Ro 40-5967, a new calcium antagonist, and enalapril on cardiac remodeling in renal hypertensive rats.

The goal of the present study was to compare the effects of an angiotensin-converting enzyme (ACE) inhibitor (enalapril) and a long-acting calcium antagonist (Ro 40-5967) on cardiac remodeling secondary to renovascular hypertension. For this purpose, two kidney-one clip (2K-1C) hypertensive rats, 6 weeks after renal artery clipping, were either untreated or treated for 5 weeks with equihypotensive doses of enalapril (3 mg/kg/day) and Ro 40-5967 (30 mg/kg/day). At the end of the treatment period, cardiac weight, maximum coronary blood flow ([MCBF], measured in isolated perfused hearts), and interstitial and perivascular collagen volume fraction (measured by morphometry) were evaluated in all rats. Both drugs similarly decreased arterial blood pressure (ABP) for 24 h. Enalapril was more effective than Ro 40-5967 in inducing regression of cardiac hypertrophy. MCBF was decreased in untreated hypertensive rats and was increased to the same extent by both treatments, although not normalized. Interstitial cardiac collagen content after 11 weeks of hypertension was not increased in untreated hypertensive rats. In contrast, the collagen volume fraction measured in the perivascular area was increased in untreated hypertensive rats and this increase was not significantly suppressed by either enalapril or Ro 40-5967. These results show that cardiac hypertrophy, decrease in MCBF and increase in myocardial collagen content, do not evolve in parallel in 2K-1C hypertensive rats. Two antihypertensive treatments, enalapril and Ro 40-5967, increased MCBF to the same extent but had different effects on cardiac hypertrophy despite having equal antihypertensive efficacy.

Animals↗

PubMed1993

Effects of diltiazem on netilmicin-induced nephrotoxicity in rabbits.

Aminoglycoside nephrotoxicity remains a common clinical problem and is the major cause of acute toxic renal failure in hospitalized patients. In recent studies, calcium channel blockers gave controversial results in the prevention of acute ischemic or toxic renal failure. The aims of the study were (i) to describe a rabbit model of mild renal failure (50% reduction in glomerular filtration rate with a mean value of 1.78 +/- 0.46 ml/kg/min) induced by netilmicin given intramuscularly at 20 mg/kg of body weight every 8 h for 5 days, (ii) to investigate the protective effect of diltiazem given at a therapeutic dose (1 mg/kg given intramuscularly every 8 h for 5 days), and (iii) to investigate the mechanisms of this protection through evaluation of function tests, optic histology, and glomerular morphometry. Animals treated with netilmicin and diltiazem exhibited an unchanged glomerular filtration rate compared with controls (3.39 +/- 0.58 versus 3.68 +/- 0.78 ml/kg/min, respectively). This protective effect was not associated with any change in systemic or renal hemodynamics (i.e., no change in renal plasma flow) or changes in the pharmacokinetics of netilmicin, as assessed by fractional excretion and cortical uptake. Netilmicin-induced tubular toxicity was unchanged by diltiazem. Our results suggest that (i) netilmicin exhibits a toxic effect at both the glomerular and the tubular levels, (ii) diltiazem, a calcium channel blocker, when given at low therapeutic doses, is able to prevent the aminoglycoside-induced renal failure through a potential glomerular mechanism. The precise mechanisms of the protection remain to be elucidated. These results deserve clinical evaluation in high-risk patients.

Aldosterone↗

PubMed1993

Evidence for in vivo carotid and femoral wall thickening in human hypertension. Groupe de Prévention Cardio-vasculaire en Médecine du Travail.

Little is known of the in vivo structural changes of large arteries in uncomplicated hypertension. Therefore, we measured the intima-media thickness and lumen diameter of common carotid and femoral arteries by a computerized ultrasonographic technique in 25 normotensive and 25 never treated hypertensive men of similar age (from 25 to 72 years). The intraobserver variability of carotid and femoral wall thicknesses was 4.3% and 5.6%, respectively. Moreover, an in vitro study of 13 human arterial segments removed at autopsy demonstrated a strong correlation (r = .989, P < .001) between computerized ultrasonic and histological intima-media thickness measurements. Compared with control subjects, hypertensive patients had similar arterial diameters but higher carotid and femoral intima-media thicknesses (P < .001) as well as higher ratios of carotid and femoral intima-media thickness to lumen (P < .001, P < .01). The carotid thickness was correlated with age in control subjects (r = .48, P < .05) but not in hypertensive patients. The femoral thickness was correlated with age both in control subjects (r = .55, P < .01) and in hypertensive patients (r = .46, P < .05). Thus, carotid and femoral arterial walls of hypertensive patients were thickened. This thickening was not due to age, although aging also thickened both vessels in control subjects and the femoral artery only in hypertensive patients. Such a wall thickening associated with a normal diameter provides direct evidence of vascular growth and represents a new target to monitor noninvasively in vivo for large artery changes in human hypertension.

Adult↗

PubMed1993

Continuous versus intermittent angiotensin converting enzyme inhibition in renal hypertensive rats.

Converting enzyme inhibitors impair renal function of the kidney beyond a stenosis of the renal artery in humans and induce histological lesions in the clipped kidney of renal hypertensive rats. In two-kidney, one clip hypertensive rats, we compared the time course and magnitude of the biochemical effects of angiotensin converting enzyme inhibition on the plasma renin-angiotensin system, cardiac hypertrophy, renal lesions, and 24-hour blood pressure decrease induced by either intermittent angiotensin converting enzyme inhibition administration (benazepril PO, 10 mg/kg once a day, n = 93) or continuous administration (benazeprilat, 3 mg/kg per day via osmotic pumps, n = 92). Control rats (n = 91) received the drug vehicle intermittently or continuously. Mortality was significantly reduced by both intermittent (n = 3/93) and continuous (n = 3/92) inhibition compared with controls (n = 18/91) (P < .001). Changes in the plasma renin-angiotensin system and blood pressure were parallel. A continuous suppression of the activity of the plasma renin-angiotensin system was associated with a 24-hour decrease in blood pressure with continuous inhibition, whereas intermittent inhibition induced a similar fall in blood pressure only for the first hours after gavage.(ABSTRACT TRUNCATED AT 250 WORDS)

Angiotensin II↗

PubMed1993

Towards an objective prognostic index of acute graft-versus-host disease.

Acute graft-versus-host disease (AGVHD) is one of the major complications of allogenic non-T-depleted HLA-compatible bone marrow transplantation. It is not yet possible to predict the clinical evolution of the disease at the time of its first manifestation. Twenty patients who initiated the disease with only moderate skin involvement were selected consecutively among those followed between January 1985 and December 1988 in the Bone Marrow Transplantation Unit, Saint Louis Hospital, Paris. A skin biopsy was performed at the onset of the AGVHD for each patient. For each biopsy, one 5-microns thick section was fixed by Bouin's solution, stained with hematoxylin and eosin and studied by image analysis at a final calibration of 7.6 pixels/microns. Ten patients did not exceed grade I (low risk group) and ten developed a more severe grade (high risk group) in the evolution of the disease. The mean and coefficients of variation, skewness and kurtosis of dimension-, form- and texture-related parameters of the nuclei of lymphocytes infiltrating the skin were investigated for their ability to discriminate between the high and low risk groups. The best discrimination was obtained using texture-related variables. An index containing 5 texture-related variables gave the maximum separation between the two groups, with a 100% correct classification. Our results represent a learning-step towards the development of a prognostic index of AGVHD.

Acute Disease↗

PubMed1992

Beneficial effects of trandolapril on experimentally induced congestive heart failure in rats.

Angiotensin-converting enzyme (ACE) inhibitors have been shown to prolong life expectancy in patients with congestive heart failure. In order to determine the relative contributions of the different factors involved in this beneficial effect, we investigated in an experimental model of postinfarction cardiac insufficiency in the rat over a 9-12-month period (1) the kinetics of the development of the hemodynamic, biologic, and morphologic alterations that accompany heart failure, and (2) the kinetics of the effects of a new, long-acting ACE inhibitor, trandolapril. Following induction of infarction, systolic blood pressure, left ventricular dP/dt, and end-diastolic pressure were immediately decreased, decreased, and increased, respectively, and these modifications persisted throughout the study. Cardiac index, on the other hand, was only initially and transiently decreased. Cardiac remodeling (left ventricular dilation, myocardial hypertrophy, and fibrosis) occurred as early as 7 days after infarction and worsened throughout the study. Plasma atrial natriuretic factor (ANF) and urinary cyclic guanosine monophosphate (cGMP) were also increased. In this model, a 1-year oral treatment with trandolapril resulted in early hemodynamic and biologic beneficial effects (reductions in pre- and afterload, increase in cardiac index, and decrease in plasma ANF), and in a delayed reversal of the infarction-induced cardiac morphologic alterations. Hence, the trandolapril-induced increase in survival rate is due initially to the drug's hemodynamic effects and over the long-term to both its hemodynamic and cardiac morphologic (limitation of remodeling) effects.

Angiotensin-Converting Enzyme Inhibitors↗

PubMed1992

Long-term treatment with trandolapril opposes cardiac remodeling and prolongs survival after myocardial infarction in rats.

Long-term treatment with angiotensin I converting enzyme inhibitors (ACEIs) prolongs survival in rats developing congestive heart failure after myocardial infarction (MI). In this experimental model, we investigated at regular intervals the effects of a 1-year oral treatment with trandolapril, a new ACEI, on (a) survival rate and duration and (b) hemodynamic, biological, and cardiac and vascular histomorphological parameters. Control MI rats and sham-operated trandolapril-treated and control rats were simultaneously studied. In MI rats, trandolapril significantly increased the survival rate and duration, increasing the life expectancy by approximately 6 months. It also significantly decreased the arterial blood pressure and increased diuresis. These effects occurred as soon as the treatment was started and persisted throughout the study. Trandolapril significantly limited the development of myocardial hypertrophy, decreasing the heart weight and left ventricular hypertrophic area and increasing the left ventricular myocyte nuclear density, but these effects, starting after 3-6 months, were delayed compared to the hemodynamic ones. Finally, trandolapril limited the development of myocardial (both subendocardial and subepicardial) and aortic fibrosis. It is concluded that the early pre- and afterload effects of trandolapril are initially responsible for its beneficial action on survival, whereas later the drug's antihypertrophic and antifibrotic properties together with persistent hemodynamic effects account for the prolonged survival improvement.

Angiotensin-Converting Enzyme Inhibitors↗

PubMed1991

Effect of ramipril, an inhibitor of angiotensin converting enzyme, on the response of rat thoracic aorta to injury with a balloon catheter.

We have studied the effect of ramipril (10 mg/kg daily by gastric gavage) on the development of neointima 2 and 14 days after injury to rat aorta with a balloon catheter. In treated animals, there was no significant inhibition of the early mitotic reaction after injury (synthesis of DNA, as reflected by aortic thymidine incorporation on the second day): the mean (95% confidence interval) was 3,553 (892) in the control group vs. 2,853 disintegrations/min/micrograms of DNA (555) in the treated group, 2 p greater than 0.15. However, ramipril decreased the amount of neointima formed 14 days after injury, as characterized by (a) a highly significant decrease of the intima to intima + media areas ratio [21.1 (2.4) vs. 13.7% (2.2), 2 p less than 10(-4]); (b) a significant decrease of intima-media wet weight [35.4 (1.0) vs. 30.9 mg (0.9), 2p less than 0.005]; and (c) without any significant effect on intima-media DNA content [96.3 (7.9) vs. 91.7 micrograms (5.7), 2p greater than 0.3]. These observations suggest that angiotensin converting enzyme inhibitors may not act mainly through an inhibition of smooth muscle cell proliferation. Other effects, such as inhibition of migration, hypertrophy, and matrix synthesis, should also be considered.

Angiotensin-Converting Enzyme Inhibitors↗

PubMed1991

Effects of fasting and refeeding on the proliferative response of rat aorta to injury.

To explore the interplay between the mitotic activity of arterial smooth muscle cells and the variations of plasma glucose and insulin concentrations, we have studied over 14 days the response of thoracic aorta to injury with a balloon catheter in rats submitted to fasting and refeeding. Animals were fasted from the day before until the third day after injury. The proliferative reaction of intima-media was assessed 2, 3.5, 4, 6, 8, and 14 days after injury, comparing freely fed with fasted-refed rats. Fasting decreased plasma glucose and insulin concentrations and DNA synthesis by intima-media, whereas refeeding increased these three variables transiently. The DNA content of intima-media at any time during the response to injury and the intimal thickening on day 14 were not influenced by the sequence of fasting and refeeding, which suggests that the early decrease in DNA synthesis induced by fasting had been compensated for by the later increase in DNA synthesis induced by refeeding. In conclusion, besides hormonal influences (such as insulin), metabolic influences (such as the availability of energetic fuels) are likely to act on the proliferative response of arteries to injury.

Animals↗