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Biomedical subjects

J Bernheim

Publications and source records attributed to J Bernheim.

At least 19 recordsLinked to original sources
PubMed2006

High incidence of BRCA1-2 germline mutations, previous breast cancer and familial cancer history in Jewish patients with uterine serous papillary carcinoma.

OBJECTIVE: To test the carrier status of the three germline founder mutations in Jewish patients with uterine serous papillary carcinoma (USPC) and to evaluate its association to their personal and familial cancer records. METHODS: Retrospective analysis of histologically confirmed USPC Jewish patients diagnosed between April 1, 1997 and December 31, 2003. All cases were genetically tested for the three BRCA1-2 founder germline mutations (185delAG and 5382insC in BRCA1 and 6174delT in BRCA2). The analysis was performed on genomic DNA extracted from whole blood or paraffin embedded normal tissue of these patients, employing PCR amplification of target sequences and differential digestion with restriction enzymes. The carrier frequency was compared to the known population frequency of these mutations. RESULTS: The study group comprised 22 Jewish patients with USPC diagnosed within this timeframe. The mean age was 71.8 years (range 56-79). FIGO surgical stage distribution revealed 59% at stages III-IV. Seven USPC patients (32%) with a previous diagnosis of breast cancer were identified. Familial cancer history was recorded in 23% of the patients (four with breast cancer and one with ovarian cancer). DNA analysis revealed six BRCA1-2 germline mutation carriers (27%) as follows: three with BRCA2-6174delT, two with BRCA1-185delAG, and one with BRCA1-5382insC mutation. Three of the carriers had a previous diagnosis of breast cancer. Four carriers had familial cancer history in first-degree relative (three with breast cancer and one with ovarian cancer). CONCLUSIONS: The high rate of BRCA germline mutations in USPC patients observed in the present study, coupled with the strong personal and familial cancer history as well as the histological and clinical resemblance to the ovarian cancer, may indicate that USPC is a part or an expression of the hereditary breast-ovarian cancer syndrome. This option may have implications in our clinical recommendations for non-affected BRCA1-2 carriers.

Aged↗
PubMed2006

Somatostatin treatment attenuates proteinuria and prevents weight loss in NZB/W F1 mice.

Somatostatin, a naturally occurring neuropeptide, is an immunomodulator which inhibits humoral and cell mediated immunity as well as secretion of proinflammatory cytokines. The objective of this study was to examine the effects of a somatostatin analogue on the severity of glomerulonephritis in the female NZB/W F1 murine model of systemic lupus erythematosus (SLE). Twenty female NZB/W F1 mice were treated at 23 weeks of age with 10 mg/kg of the somatostatin analogue Sandostatin- LAR, IM every four weeks. Ten control mice received IM injection of vehicle. Mice were assessed at four-week intervals for weight change, proteinuria, anti-DNA antibodies and splenocyte cytokine profile. The mice were sacrificed at age 34.5 weeks. Kidneys were collected and evaluated by light and immunofluorescence (IF) microscopy. Spleens were collected and splenocyte intracellular cytokines were measured by FACS analysis. In the treatment group significantly less proteinuria was observed four weeks after the second somatostatin analogue injection (dipstik scale: +2.07 +/- 0.95 versus. +3.5 +/- 1.08, P = 0.0002). The treated mice did not lose weight while the control group lost weight over time (P = 0.016). No differences were noted between the groups in anti-DNA antibody titres, cytokine profile or the severity of lupus nephritis as assessed by light and IF microscopy. Somatostatin analogue treatment attenuated proteinuria and prevented weight loss in NZB/W F1 mice, suggesting a possible beneficial effect on renal parameters and systemic manifestations of the disease. Further studies will be needed to assess the value of somatostatin analogue treatment in lupus nephritis, utilizing higher doses, at different stages of the disease, for longer periods.

Animals↗
PubMed2003

Early endothelial dysfunction following renal mass reduction in rats.

BACKGROUND: Endothelial dysfunction has been previously described in severely hypertensive rats with renal mass reduction (RMR) receiving large dietary Na loads. Because hypertension and Na loading reduce endothelium-dependent vasodilation, the effect of renal failure per se is unclear. METHODS: Responses to acetylcholine in noradrenaline-contracted isolated perfused mesenteric arteries were studied. Vessels were obtained from RMR rats kept on a normal diet, 3 and 10 days after surgery, and the results were compared with those from sham-operated rats (SN). The role of three putative mediators of endothelium-dependent vasodilation was assessed using: L-NAME (10(-4) mol L(-1)); indomethacin (INDO, 10(-5) mol L(-1)); and a mixture of charybdotoxin and apamin (C/A, both 10(-7) mol L(-1)), inhibitors of Ca-activated K-channels to mediate the effects of endothelium-derived hyperpolarizing factor (EDHF). RESULTS: Response to acetylcholine but not that to nitroprusside (endothelium-independent) was decreased in RMR. L-NAME reduced further acetylcholine relaxations in SN but not in RMR. By contrary, INDO decreased acetylcholine vasodilation in RMR but had no effect in SN. C/A had similar effects in the SN and RMR rats. The levels of 6-keto prostaglandin F1alpha were elevated in the urine of the RMR rats and were perfusate from the RMR vessels. CONCLUSION: Endothelial dysfunction occurs early after RMR, even when systolic blood pressure is only minimally elevated and Na intake is normal. This alteration may be because of decreased availability of nitric oxide, partially compensated by increased prostacyclin production.

6-Ketoprostaglandin F1 alpha↗
PubMed2003

Suppressive effect of aspirin on aberrant crypt foci in patients with colorectal cancer.

BACKGROUND: and aims: Aspirin and other non-steroidal anti-inflammatory drugs have been shown to reduce the risk of colorectal cancer (CRC). Animal models have shown that aspirin is also effective in reducing the density of aberrant crypt foci (ACF). The aim of the study was to evaluate the effect of chronic administration of aspirin on the distribution pattern and histological characteristics of ACF in patients with CRC. METHODS: Our study compared the distribution patterns and histomorphological characteristics of ACF between a group of CRC patients treated with low dose aspirin (n=59) and a control group without aspirin (n=135). ACF were visualised on methylene blue stained macroscopically normal mucosa, microdissected, and serially cut. RESULTS: ACF were found in 75.8% of mucosal samples from the control group and in 36% of mucosal samples from the aspirin treated group, indicating a 47% decline in prevalence of ACF in colonic samples of patients treated with aspirin. A significant reduction from 92.5% to 40% (p<0.0001) was found in distal large bowel samples containing one or more ACF. Similarly, the aspirin treated group showed a reduction in ACF density of 64% and 82%, respectively, in both proximal and distal parts of the colon, indicating a significant reduction in ACF/cm(2) in distal colon samples (p<0.01). The aspirin treated group displayed a 52% reduction in dysplastic ACF although this difference was not statistically significant. CONCLUSIONS: Our study has provided evidence of the effective chemopreventive action of low dose aspirin on ACF in humans.

Adult↗
PubMed2003

Selecting stent grafts for the endovascular treatment of abdominal aortic aneurysms.

Minimally invasive endovascular techniques for the treatment of abdominal aortic aneurysms (AAA) have significantly reduced the morbidity of these procedures as compared with standard surgical repair. In addition, patients with extensive comorbid medical illnesses in whom standard operative repair is contra-indicated, may be successfully treated using endovascular means. A variety of endovascular stent grafts are currently being used clinically for endovascular AAA repair. The characteristics of these stent grafts vary significantly. In selecting the specific stent graft to be used for endovascular AAA repair, these specific characteristics must be considered particularly with regard to the individual patient's anatomic and physiologic characteristics. In addition, the indications for use of endovascular grafts as compared to standard open surgery have not yet been fully defined. Endovascular stent grafts in current use have limitations and their use must be tempered accordingly, until their long-term effectiveness is more completely evaluated. This article describes the general principles of use for endovascular devices for the repair of AAA. It details the features and results for the devices in current use and highlights the factors that influence the selection of specific stent graft types.

Aortic Aneurysm, Abdominal↗
PubMed2002

Immunoreactivity of p53, Ki-67, and c-erbB-2 in phyllodes tumors of the breast in correlation with clinical and morphologic features.

BACKGROUND AND OBJECTIVES: Phyllodes tumor (PT) is a biphasic tumor with unpredictable behavior. Our study aimed to evaluate clinicopathologic factors and biomarkers that may be helpful in predicting the outcome of these tumors. METHODS: We evaluated immunoreactivity of p53, c-erbB-2, and Ki-67 in 23 PT treated over a 10-year period. The proliferative activity in PT and expression of p53 and c-erbB-2 were correlated with clinicopathologic features of the tumors and patients' outcome. RESULTS: Positive stromal p53 immunoreactivity was found in PT with atypia, infiltrative borders, high cellularity, as well as in PT that displayed higher then average proliferation index, although none of these parameters reached statistical significance. There was a good correlation between proliferative stromal cell activity expressed Ki-67-labeling index and the malignant features of the tumors. Primary tumors that recurred displayed high proliferative activity. Three of four recurrent tumors showed a progression toward higher malignant phenotype with concomitant increase in proliferative stromal cell activity. c-erbB-2-positive tumors had no particular histologic features or association with either p53 positivity or higher proliferative indices. CONCLUSIONS: p53 expression tends to be more frequent in PT with higher malignant potential but did not predict recurrence. Incompletely excised tumors that recurred displayed high proliferative activity in their primary tumors. Progression toward more malignant phenotype in the recurrent PT was accompanied with increase in stromal cell proliferative activity, suggesting the presence of biological continuity between benign, borderline, and malignant PT.

Adolescent↗
PubMed2001

Risk factors of endometrial polyps resected from postmenopausal patients with breast carcinoma treated with tamoxifen.

BACKGROUND: Endometrial polyps are the most common endometrial pathology described in association with postmenopausal tamoxifen exposure. Up to 3% of these polyps may show malignant changes. However, to the authors' knowledge no one has described any risk factor for the development of this pathology in postmenopausal patients with breast carcinoma treated with tamoxifen. OBJECTIVE. The objective of this study was to evaluate whether risk factors can be identified for the development of endometrial polyps in postmenopausal patients with breast carcinoma treated with tamoxifen. METHODS: The authors reviewed the medical records of 54 postmenopausal patients with breast carcinoma in whom endometrial polyps were resected by hysteroscopy after at least 6 months of tamoxifen treatment (Group I). Demographic characteristics, health habits, risk factors for endometrial carcinoma, and clinical factors related to the primary breast disease were examined. The results were compared with those obtained from 210 similar patients in whom hysteroscopy did not reveal any endometrial pathology (Group II). RESULTS: Age at menopause was significantly older, duration of breast disease was significantly longer, and body weight was significantly heavier among Group I patients compared with Group II patients (P = 0.0162, P = 0.0026, and P = 0.0364, respectively). Endometrial thickness, measured by transvaginal ultrasonography, was significantly thicker in Group I patients (16.3 +/- 7.2 mm) compared with that detected in Group II patients (11.8 +/- 6.3; P = 0.0001). CONCLUSIONS: Various factors, such as older age at menopause, longer duration of breast disease, heavier weight, and thicker endometrium may contribute to the prediction of increased risk of development of endometrial polyps in postmenopausal patients with breast carcinoma treated with tamoxifen.

Antineoplastic Agents, Hormonal↗
PubMed2001

In vitro effect of advanced glycation end-products on human polymorphonuclear superoxide production.

BACKGROUND: Advanced glycation end-products (AGEs) are elevated in the sera of diabetic patients. The latter are prone to severe bacterial infections. Advanced glycation end-products have been shown to modulate immune competent cell activities. In this study we examined the in vitro effect of advanced glycation end-products on superoxide anion generation by human polymorphonuclear leukocytes. MATERIALS AND METHODS: Advanced glycation end-products were prepared by incubation of bovine serum albumin (BSA) with glucose for 90 days. Superoxide production was measured as the superoxide dismutase-inhibitable reduction of ferricytochrome c. The effect of advanced glycation end-products on superoxide production was evaluated in both baseline (nonstimulated) and stimulated (by either formyl-methionyl-leucyl-phenylalanine, or phorbol-myristate-acetate) polymorphonuclear leukocytes. RESULTS: The baseline superoxide production of polymorphonuclear leukocytes was significantly increased by advanced glycation end-products in a dose-dependent manner. In contrast, in stimulated polymorphonuclear leukocytes advanced glycation end-products significantly inhibited superoxide production, again in a dose-dependent manner. This inhibitory effect of advanced glycation end-products was observed after dialyzing AGE-BSA, thereby eliminating the possible influence of reactive carbohydrates. No modification of superoxide production was seen with BSA and only a mild inhibitory effect of glucose at high concentrations. CONCLUSIONS: Advanced glycation end-products depress superoxide production by stimulated polymorphonuclear leukocytes. As superoxide plays an essential role in bactericidal activity, this polymorphonuclear leukocyte dysfunction may be a contributory factor to the increased prevalence and severity of bacterial infection seen in diabetic patients.

Dose-Response Relationship, Drug↗
PubMed2001

Primary serous papillary carcinoma of the peritoneum: CT findings.

AIM: To describe the computed tomography (CT) findings of primary serous papillary carcinoma of the peritoneum. MATERIAL AND METHODS: The clinical data and imaging studies of 36 women aged 37-85 years with primary papillary serous carcinoma of the peritoneum were retrospectively evaluated. Twenty-seven patients presented with general abdominal complaints; all had elevated levels of CA-125. Thirty-two women were post-menopausal, four had had bilateral salpingo-oophorectomy. RESULTS: The most common findings on pre-operative abdominal CT, performed in 30 patients, were a variable amount of ascites (n = 29), omental involvement (n = 28), irregular parietal peritoneum thickening (n = 22) and mural thickening of the sigmoid colon (n = 10). Thoracic findings included enlarged cardiophrenic nodes (n = 15) and pleural effusion (n = 11). Six patients had unilateral or bilateral adnexal masses of soft tissue density, which proved to be surface serous papillary carcinoma. CONCLUSION: Diffuse peritoneal disease on CT in patients with normal-sized ovaries or following bilateral salpingo-oophorectomy, with elevated level of serum CA-125, but without an identifiable primary tumour, should suggest the diagnosis of primary serous papillary carcinoma of the peritoneum. Associated adnexal masses or focal bowel wall thickening may be seen, representing surface involvement by this tumour.

Adult↗
PubMed2001

Evaluation of putative molecular biomarkers in abdominal and retroperitoneal leiomyosarcomas.

AIMS: Leiomyosarcomas (LMS) are diverse tumours with different biological behaviour. To evaluate the biological nature of intraabdominal and retroperitoneal leiomyosarcomas we retrospectively examined the immunoreactivity of p53, bcl-2 and proliferative activity expressed as Ki-67-labelling index in 43 tumours. METHODS: Immunohistochemical staining was performed using a peroxidase-streptavidin method on paraffin-embedded sections using specific anti- p53, anti- bcl-2 and anti Ki-67 monoclonal antibodies. RESULTS: Of 43 tumours, seven were located in the stomach, 11 in the small or large bowel, 12 in the uterus, 11 in the retroperitoneum and two cases in the urinary bladder. Five-year disease-free survival was 46.5%. Twenty-three patients (53.4%) died of the disease. Positive immunoreactivity for p53 and bcl-2 was found in 18 (41.9%) and 26 patients (60.5%), respectively. Positive Ki-67 staining was observed in eight patients (18.6%). Proliferative indices were higher in LMS with high mitotic activity (P=0.004) and high grade (P=0.009). All Ki-67 positive LMS were intermediate or high-grade tumours. Ki-67-labelling index showed inverse relationship to bcl-2 expression. A trend towards higher survival and expression of bcl-2, p53 or Ki-67 was found. CONCLUSIONS: Our results demonstrate that p53 and bcl-2 are expressed in a substantial number of intraabdominal and retroperitoneal leiomyosarcomas. In our study, the expression of these biomarkers did not predict patient outcome. Higher Ki-67 labelling indices were found in more biologically aggressive leiomyosarcomas.

Abdominal Neoplasms↗
PubMed2001

Successful intraperitoneal nutrition in rabbits with short-bowel syndrome.

The efficacy of intraperitoneal alimentation as a means of nutritional support for various degrees of short-bowel syndrome was studied, using the rabbit model. Twenty-eight rabbits were divided into 5 groups. Group I had a sham operation; Groups II, III and IV had 50 %, 75 % and 90 % small-bowel resections (SBR), respectively; Group V had a 90 % SBR with intraperitoneal nutrition. All the rabbits received a regular diet and tap water post-operatively. The rabbits in Group V received intraperitoneal alimentation (IPA) by way of a peritoneal catheter inserted at the time of surgery. The nutrition consisted of 10 % dextrose with 5.5 % amino acids. This provided 30 - 35 kcal/kg of additional energy per day. All the rabbits within Group IV (90 % resection without IP nutrition) died within 2 to 5 weeks. IP nutrition enabled body weight to be maintained and prevented the death of all rabbits with 90 % small-bowel resection.

Animals↗
PubMed2001

The prognostic value of DNA ploidy in small renal cell carcinoma.

The objective was to study the prognostic value of Deoxyribonucleic Acid (DNA) ploidy status in small renal cell carcinomas (RCC). The nuclear DNA content of renal cell carcinoma tissues from patients who underwent radical or partial nephrectomy has been analyzed by flow cytometry. The results of the DNA ploidy have been correlated to the size of tumors and disease progression. Of the 50 patients with RCC studied, 8 (16%) progressed. Tumors with non-diploid DNA patterns were found in 24 (48%) of the 50 patients and in 4 of the 8 patients who progressed. Overall the median tumor size in our series was 50 mm. A tumor diameter of 50 mm or less was measured in 26 patients (group I) and above 50 mm in 24 (group II). Non-diploid DNA patterns were found in 11 (42.3%) and 13 (54.2%) patients in groups I and II, respectively. This difference between the groups was not significant. Only one patient in group I (3.8%) developed metastatic disease and died 72 months after the operation. In group II, 7 patients (29.2%) presented tumor progression and 5 died of metastatic disease. The survival probability in group I was 95% at 5 and 8 years (95% CI 70% to 99%) and for group II 94% at 5 years (95% CI 67%-99%) and 67% at 8 years (95% CI 39%-83%). DNA ploidy is an inaccurate predictor of tumor behavior in patients with RCC, even in small tumors. Tumor size is a more significant predictor of outcome.

Adult↗
PubMed2001

The effects of an ACE inhibitor and a calcium antagonist on the progression of renal disease: the Nephros Study.

BACKGROUND: The renoprotective effect of ACE inhibition in chronic renal disease is well established but the studies on effects of calcium antagonists on progression of renal disease and on proteinuria have given varying results. METHODS: We conducted an open long-term randomized prospective multi-centre study comparing the combination of ramipril and felodipine ER (F) with either drug alone in non-diabetic renal disease. Included were patients with uncontrolled hypertension (diastolic blood pressure (DBP)) > or =95 mmHg on treatment with a diuretic and a beta-blocker. Fifty-one patients received the combination of R and F, 54 patients R, and 53 patients F. The treatment goal was a DBP <90 mmHg and a similar BP reduction in the three groups. Mean doses at the last visit were 5+5, 10 and 9 mg, respectively, after a mean treatment time of nearly 2 years. The progression of renal impairment was studied by serial measurements of serum creatinine, iohexol clearance, and albuminuria. RESULTS: The reduction in supine systolic (S) BP and DBP expressed as median values were -19.0/-14.5,-14.3/-15.0 and -13.5/-13.3 mmHg in the R+F, R, and F groups, respectively. There was no significant difference between the groups. When correction for the acute drug effect was performed the R+F group had a slower progression rate of the renal disease (loss of glomerular filtration rate (GFR) ml/min/year) compared with the F group (P<0.05) but not to the R group (P>0.20). There was a rise in albuminuria after 2 years in the F group (P<0.05), but no significant change was found in the other groups. CONCLUSIONS: In patients with non-diabetic renal disease the combination of an ACE inhibitor and a calcium antagonist in reduced doses used in addition to baseline therapy with beta-blockers and diuretics, tended to cause a better BP reduction as each drug per se. The R+F treatment also caused a slower progression of the renal disease compared with F alone. The combination treatment seems to afford better BP control and appears to be a favourable therapeutic option in patients with renal disease and hypertension.

Adult↗
PubMed2001

Low molecular weight heparin reduces proteinuria and modulates glomerular TNF-alpha production in the early phase of adriamycin nephropathy.

BACKGROUND/AIM: Heparin has been shown to be renoprotective in a number of experimental nephropathies. The inflammatory component in the early phase of Adriamycin (ADR) induced nephropathy has been established. A microdose of low molecular weight heparin (Fragmin; F) has been noted to exert immunomodulatory effects independent of its anticoagulant activity. We assessed the effects of microdoses of F on daily proteinuria and glomerular production of tumor necrosis factor alpha (TNF-alpha) and prostaglandins 8 and 15 days after induction of ADR nephropathy. METHODS: Following intravenous injection of ADR (7 mg/kg) to Wistar rats weighing 200 +/- 20 g, F 20 microg/day/rat s.c. was administered for 8 and 15 days (groups F8 and F15). The respective control groups (C8 and C15) received normal saline subcutaneously. Proteinuria, serum albumin, and creatinine clearance were evaluated on days 8 and 15. The production of TNF-alpha and prostaglandins from glomerular supernatants was measured by radioimmunoassay on days 8 and 15. RESULTS: F significantly reduced proteinuria (mg/day) on day 8: 13.6 +/- 1.2 in F8 versus 40.3 +/- 2.7 in C8 (p = 0.008). The glomerular production of TNF-alpha (pi/ml) was significantly lower on day 8 in rats treated with F: 356 +/- 33 in F8 versus 764 +/- 81 in C8 (p = 0.006). A decrease in the prostaglandin E2/thromboxane B2 ratio was noted in the F group between 8 and 15 days (1.1 in F8 vs. 0.9 in F15, p = 0.005) which principally reflects an increase of thromboxane B2. The antiproteinuric effect of F shown after 8 days was no longer present after 15 days (354 +/- 91 mg/day in F15 vs. 499 +/- 69 mg/day in C15, p = 0.33). The same trend was seen for the glomerular production of TNF-alpha. Light microscopy and immunohistochemistry for interstitial and glomerular macrophages were negative. CONCLUSION: The lowering effect of microdoses of F on the proteinuria seen during the early phase of ADR nephropathy may be mediated by a decreased production of glomerular TNF-alpha, supporting the anti-inflammatory action of low molecular weight heparin.

Animals↗
PubMed2001

Effect of methyldopa on renal function in rats with L-NAME-induced hypertension in pregnancy.

BACKGROUND: Pregnancy-induced hypertension is characterized by an increased sympathetic activity and probably by a decreased synthesis/activity of nitric oxide. The aim of the present study is to evaluate whether the beneficial action of the sympathetic antagonist methyldopa (a first-choice hypotensive agent in the treatment of PIH) may be associated to changes in nitric-oxide synthesis. METHODS: Forty pregnant Wistar rats received L-NAME (NO synthase inhibitor, 9-10 mg/kg/day) from mid-pregnancy (day 11) through to term. Some rats were treated with daltroban (TxA receptor antagonist, 60 mg/kg/day), diltiazem (calcium channel blocker, 30 mg/kg/day), methyldopa (central adrenergic antagonist, 400 mg/kg/day) or L-arginine (260 mg/kg/day) from mid-pregnancy. The effect of the different treatments on systolic blood pressure (SBP), creatinine clearance (CCR), urine protein excretion (UP) and urinary nitrate excretion (UNO(3), representing urine NO metabolite) were evaluated and the results compared with those found in normal pregnancy. Normal pregnant rats receiving similar treatment were used as controls. RESULTS: In normal pregnant (P) rats, SBP values decreased from 94 +/- 2 to 83 +/- 3 mm Hg at the end of pregnancy (p < 0.01) and CCR augmented significantly. Drug treatment had no significant effect. In NAME-treated rats, at the same period, the SBP augmented from 92 +/- 1 to 129 +/- 1.8 mm Hg (p < 0.01). At the end of pregnancy, NAME rats had significantly lower CCR values and higher UP excretion when compared with P rats. UNO(3) increased significantly in P and in P rats treated with methyldopa. As expected, in NAME rats UNO(3) excretion was significantly reduced. Treatment with methyldopa normalized SBP, improved CCR and proteinuria and was associated with an increase in UNO(3). Similar results were obtained with L-arginine treatment. Diltiazem lowered SBP significantly but had no effect on renal function or UNO(3) and daltroban had no effect. CONCLUSION: The increased UNO(3) found in NAME rats treated with methyldopa suggests that the vasoconstriction secondary to chronic NO inhibition may be partially related to an increased sympathetic activity. The efficient action of the sympathetic antagonist methyldopa may be due not only to its antihypertensive effects but also by its stimulating effect on NO synthesis leading also to an improvement of renal function.

Animals↗
PubMed2001

Chronic exogenous hyperinsulinaemia-induced hypertension in pregnant rats: effect of chronic treatment with l-arginine.

Recent studies have shown that maternal hyperinsulinaemia is a risk factor for the development of hypertension in pregnancy. Experimentally, pregnant rats with chronic exogenously induced hyperinsulinaemia (P-INS rats) have increased blood pressure at the end of gestation. This is associated with a blunted elevation of the excretion of the urinary metabolites of nitrate (UNO(x)). In the present study, we aimed to evaluate the mechanism(s) of the increase in blood pressure in this model. Four groups were studied: normal pregnant rats (P rats), P-INS rats, P-INS rats treated with L-arginine (2 g/l in the drinking water) (L-ARG rats) and hyperinsulinaemic virgin rats (V-INS rats). Systolic blood pressure (SBP), UNO(x) excretion (on ingestion of a controlled low-nitrate diet), urine noradrenaline (norepinephrine) and plasma endothelin levels were evaluated. Rats were killed on day 22 of pregnancy. Five P-INS rats were not killed at this time, in order to measure SBP 30 and 60 days after delivery. Fetal number and fetal body weight were evaluated. At the end of pregnancy, a 10+/-3% increase in SBP was found in P-INS rats, contrasting with a fall of -15+/-4% in P rats (P<0.01). In the L-ARG group at the end of pregnancy, SBP values had fallen by -14+/-2%, to values comparable with those of P rats. The increase in UNO(x) excretion was 175+/-38% in P rats, 106+/-12% in L-ARG rats and 41+/-8% in P-INS rats (P<0.01 compared with P and L-ARG groups). No differences were found in the urinary excretion of noradrenaline or in the plasma levels of endothelin-1 between the pregnant groups. Fetal number was similar in all groups, but fetal body weight was lower for P-INS rats compared with P and L-ARG rats. Thus the blood pressure response to L-arginine strongly suggests that a decrease in NO availability may be the main pathogenic mechanism involved in the development of hypertension in this model.

Animals↗