Stimulated release of endothelin-converting enzyme is simultaneous with tissue-type plasminogen activator and decrease in coronary heart disease

OBJECTIVE: During the process of atherosclerosis the endothelium changes both structurally and functionally. We examined whether shedding of endothelin-converting enzyme (ECE), a metalloprotease responsible for endothelin production, is concomitant with tissue-type plasminogen activator (t-PA), and how atherosclerosis affects ECE release. DESIGN: Fourteen healthy volunteers and 24 patients with angiographically verified coronary heart disease (CHD) were investigated. ECE and t-PA releases were measured by a provocation test (20-min venous occlusion). RESULTS: Serum ECE activities were comparable in both groups before the venous occlusion test (in CHD patients 205 +/- 24 vs in healthy controls 204 +/- 40 pmol/ml/h, p = NS). However, delta-ECE (= the difference between, after, and before the venous occlusion test) was significantly lower in CHD patients than in controls (203 +/- 36 vs 338 +/- 43 pmol/ml/h, p = 0.02, respectively). Delta-t-PA was similar in both groups (22.3 +/- 4.4 vs 14.5 +/- 4.6 ng/ml, p = NS, respectively). Furthermore, t-PA and ECE values correlated in the CHD group in all pre-, post-venous occlusion test, and delta-venous occlusion test values (r = 0.56, p = 0.009; r = 0.62, p = 0.003; r = 0.54, p = 0.01, respectively). CONCLUSION: Vascular ECE release can be stimulated, and it is concomitant with t-PA release. A common location in endothelium may explain this simultaneous shedding. However, ECE levels do not rise in patients with CHD as markedly as in healthy patients. Atherosclerosis may explain reduced shedding of ECE.     

Effects of losartan on cardiovascular morbidity and mortality in patients with isolated systolic hypertension and left ventricular hypertrophy: a Losartan Intervention for Endpoint Reduction (LIFE) substudy

Context  Drug intervention in placebo-controlled trials has been beneficial in isolated systolic hypertension. Objective  To test the hypothesis that losartan improves outcome better than atenolol in patients with isolated systolic hypertension and electrocardiographically documented left ventricular hypertrophy (ECG-LVH). Design  Double-blind, randomized, parallel-group study conducted in 1995-2001. Setting and Participants  A total of 1326 men and women aged 55 through 80 years (mean, 70 years) with systolic blood pressure of 160 to 200 mm Hg and diastolic blood pressure of less than 90 mm Hg (mean, 174/83 mm Hg) and ECG-LVH, recruited from 945 outpatient settings in the Nordic countries, the United Kingdom, and the United States. Interventions  Patients were randomly assigned to receive once-daily losartan (n = 660) or atenolol (n = 666) with hydrochlorothiazide as the second agent in both arms, for a mean of 4.7 years. Main Outcome Measure  Composite end point of cardiovascular death, stroke, or myocardial infarction. Results  Blood pressure was reduced by 28/9 and 28/9 mm Hg in the losartan and atenolol arms. The main outcome was reduced by 25% with losartan compared with atenolol, 25.1 vs 35.4 events per 1000 patient-years (relative risk [RR], 0.75; 95% confidence interval [CI], 0.56-1.01; P = .06, adjusted for risk and degree of ECG-LVH; unadjusted RR, 0.71; 95% CI, 0.53-0.95; P = .02). Patients receiving losartan had reductions in the following without a difference in the incidence of myocardial infarction: cardiovascular mortality (8.7 vs 16.9 events per 1000 patient-years; RR, 0.54; 95% CI, 0.34-0.87; P = .01), nonfatal and fatal stroke (10.6 vs 18.9 events per 1000 patient-years; RR, 0.60; 95% CI, 0.38-0.92; P = .02), new-onset diabetes (12.6 vs 20.1 events per 1000 patient-years; RR, 0.62; 95% CI, 0.40-0.97; P = .04), and total mortality (21.2 vs 30.2 events per 1000 patient-years; RR, 0.72; 95% CI, 0.53-1.00; P = .046). Losartan decreased ECG-LVH more than atenolol (P<.001) and was better tolerated. Conclusion  These data suggest that losartan is superior to atenolol for treatment of patients with isolated systolic hypertension and ECG-LVH.      

Urinary cyclic AMP and vasopressin excretion in rat strains selected for their alcohol intake

Urinary excretion of adenosine 3′,5′-cyclic monophosphate (cAMP) and immunoreactive arginine vasopressin (AVP) were investigated after water loading and following ethanol loading in two rat strains selected for their voluntary ethanol intake. After ethanol loading ethanol preferring (AA) rats excreted more cAMP but less AVP than water preferring (ANA) rats. The results suggest that the strain difference in cAMP excretion is of renal origin and is not due to vasopressin or parathormone. Differences in the sympathetic nervous activity may be responsible for the difference in cAMP excretion.     

Soil exposure modifies the gut microbiota and supports immune tolerance in a mouse model

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Replacement of salt by a novel potassium- and magnesium-enriched salt alternative improves the cardiovascular effects of ramipril.

1. The influence of salt (sodium chloride; NaCl) (an additional 6% in the diet) and that of a novel sodium-reduced, potassium-, magnesium-, and L-lysine-enriched salt alternative on the cardiovascular effects of ramipril was studied in stroke-prone spontaneously hypertensive rats in a 6-week study. The intake of sodium chloride was adjusted to the same level by adding the salt alternative at a 1.75 times higher amount than regular salt. 2. Salt produced a marked rise in blood pressure and induced cardiac hypertrophy and significant mortality, while the salt alternative neither increased blood pressure nor caused any mortality and produced less cardiac hypertrophy than salt. 3. Ramipril treatment at a daily dose of 3 mg kg-1 normalized blood pressure and prevented the development of cardiac hypertrophy of rats on control diet. These effects of ramipril were blocked by the addition of salt but were only slightly attenuated by the addition of the salt alternative. The mortality in the salt group was prevented by ramipril. 4. Responses of mesenteric arterial rings in vitro were examined at the end of the study. Salt, but not the salt alternative, increased vascular contractile responses to noradrenaline. Ramipril treatment improved the arterial relaxation responses to acetylcholine and to sodium nitroprusside. The vascular relaxation enhancing effect of ramipril was blocked by salt but only slightly attenuated by the salt alternative. 5. Ramipril treatment did not significantly increase plasma renin activity in the presence or in the absence of salt supplementation. The salt alternative did not cause hyperkalaemia, either alone or in combination with ramipril treatment.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of donor source on renal allograft function in children on triple immunosuppression

Results of renal transplantation using cadaver donors (CAD)are usually inferior to those using living related donors (LRD).We have previously reported 100% 1-year CAD and LRD graft survivalusing adult cadaver donors and triple immunosuppression. Inthe present study glomerular and tubular function of 23 LRDand 22 CAD grafts (median ages 3.5 and 2.6 years) were comparedduring 3 years after transplantation. Glomerular filtrationrate (GFR) and renal plasma flow were lower in CAD grafts butremained stable in both groups. The mean GFRs were 87.3 and63.2 ml/min/l.73 m² at discharge and 82.8 and 72.5 ml/min/1.73m² at 36 months in LRD and CAD grafts respectively. No significantdifferences were found after 6 months. Tubular function wasgood in both groups. The only significant difference was inurate handling at 36 months (mean serum urate 396 µmol/lin CAD, 301 in LRD grafts, P<0.05). Cyclosporin nephrotoxicitymanifested as hyperkalae mia due to reduced distal potassiumsecretion and/or adrenal suppression. In conclusion, donor source had little effect on the developmentof progressive allograft dysfunction using adult CAD graftsand triple immunosuppression with CsA administered in threedaily doses to preschool children.     

Synthesis and maturation of type I and type III collagens in endometrial adenocarcinoma

OBJECTIVE: The structure and distribution of type I and type III collagens in the extracellular matrix of malignant endometrium was evaluated for their roles in the development and progression of this neoplasm. STUDY DESIGN: Collagen synthesis and deposition in endometrial adenocarcinomas was determined by immunohistochemical analysis of type I and type III procollagen and verified by computer-assisted morphometry and in situ hybridization. RESULTS: In the stroma of well-differentiated adenocarcinomas increased intracellular collagen synthesis was observed in fibroblastic cells as well as increased extracellular formation of newly synthesized type I and type III procollagen. Collagen maturation was also rapid. In moderately differentiated tumors, destruction and dissolution occurred around invading islets, concomitantly with decreased deposits of both collagens, despite increases in corresponding mRNAs. In poorly differentiated neoplasms, solid epithelial islets coexisted with sparse and distinctly collagen-positive stroma. Poorly differentiated neoplasms also contained tumor cells exhibiting intracellular collagen staining as well as in situ hybridization signals. In highly malignant papillary adenocarcinomas, the tumor cells induced distinctly increased collagen synthesis and deposition of newly synthesized collagen but not the mature cross-linked protein. CONCLUSIONS: In malignancy, compression of surrounding stroma and a fibroproliferative response with increased collagen synthesis and deposition may prevent tumor growth. In more advanced lesions, stromal dissolution may permit tumor spread and in highly malignant lesions an abnormal stroma may promote neoplasm progression.     

Transient vasopressin release and thirst in response to prolonged intracerebroventricular infusions of hypertonic mannitol in saline

In the conscious goat infusions of 0.4 M mannitol in 0.15 M NaCl into the lateral cerebral ventricle (40 or 100 min, 0.02 ml/min) caused slight, transient vasopressin release and temporary thirst, whereas infusions or pure, hypertonic (0.7 M) mannitol did not elicit thirst and inhibited the basic vasopressin release in the nonhydrated animal. In contrast, infusions of equiosmolal (0.35 M) NaCl induced persistent thirst and pronounced elevation of the plasma vasopressin concentration throughout the infusion period. The cerebrospinal fluid (CSF) osmolality was raised by the same order of magnitude (= 13%) after the mannitol/NaCl and the hypertonic NaCl infusions. The CSF Na+ concentration was elevated by greater than 10% at 5 min after hypertonic NaCl infusions, but it was reduced by approximately 10% at 5 min after the mannitol/NaCl infusions. There was no appreciable difference in the CSF K+ concentration after the infusions. The results are discussed with regard to the possible importance of CSF Na+-concentration as opposed to strict osmotic factors for the excitation of receptors involved in the control of water balance.