Objectives: Fibrosis is a classical feature of cardiac hypertrophy. To date changes within the basal lamina during normal and pathological cardiac growth have been poorly investigated. The goal of the present study was to determine if the expression of the muscle specific subunit of merosin (laminin a2 chain) together with that of fibronectin (FN) is modified in the diseased human heart. Laminin a2 chain expression was also investigated during physiological and pathological cardiac growth in the rat. Methods: In ten normal human hearts and ten hearts with idiopathic dilated cardiomyopathy (IDCM), the laminin-a2 and FN mRNA levels were quantified by slot-blot using total RNA and the protein distribution was analysed using an immunofluorescence approach. In Wistar rats, laminin a2 and FN mRNA expression was analyzed using RNase protection assay (RPA) and slot-blot assays. Results: The amount of laminin a2 mRNA did not vary in normal and pathological human hearts whereas it was significantly decreased in renovascular hypertensive rats (220%) P,0.05 versus normal tissue). The amount of fibronectin mRNA increased in IDMC patients (32, P,0.05 versus normal tissue), but was unchanged in hypertensive rats. A negative correlation was found between the cardiac laminin-a2 level and the age of the patients whatever the cardiac status. During postnatal development in the rat, a similar decrease in cardiac laminin-a2 level was observed between 3 and 30 weeks of age. Finally, the immunofluorescent approach failed to detect any alteration in laminin a2 distribution within the human myocardium. Conclusion: These data indicate that an imbalance between myocyte hypertrophy and the level of laminin-a2 might contribute to alterations in sarcolemmal properties, which occur during the development of cardiac hypertrophy and its transition to cardiac failure.
The synthesis and pharmacological activity of new potent nonpeptide non-tetrazole angiotensin II (AII) receptor antagonists are described. These compounds are 4-thioimidazole derivatives linked on N1 to a biphenylsulfonyl fragment by a methylene spacer. Different acidic sulfonamides such as sulfonylureas 12, sulfonylcarbamates 15, sulfonylamides 16, and sulfonylsulfonamides 17 have been investigated as replacements to the known potent tetrazole moiety at the 2'-biphenyl position. Their activity were evaluated by AII receptor binding assay as well as by in vivo (i.v. and po) assays such as inhibition of the AII-induced pressor response in pithed rats. Most of the synthesized sulfonyl derivatives showed nanomolar affinity for the AT1 receptor subtype. The N-propylsulfonylurea 12d and the ethyl sulfonylcarbamate 15b as representative members of this series exhibited high oral activity in the pithed rat model with ID50 values of 0.38 and 0.4 mg/kg, respectively. Structure-activity relationships on the imidazole ring linked to the methylbiphenyl N-propylsulfonylurea fragment demonstrated similar features to those found in the corresponding tetrazole series. For both class of compounds, the linear butyl chain in position 2 and a carboxylic acid in position 5 were important for high in vitro and in vivo activity. In most cases, replacement of the carboxylic acid was detrimental to in vivo activity while maintaining the in vitro binding affinity. Introduction of a methylthio group in position 4 was found to enhance oral activity compared to compounds with chloro or other alkylthio, (polyfluoroalkyl)thio, and arylthio groups. 2-Butyl-4-(methylthio)-1-[[2'- [[[(propylamino)carbonyl]amino[sulfonyl](1,1'-biphenyl)-4- yl]methyl]-1-H-imidazole-5-carboxylic acid (12d) as the most promising example of the series was synthesized as its dipotassium salt (50, HR 720). This compound 50 inhibited the specific binding of [125I]-AII to rat liver membranes with an IC50 value of 0.48 nM. In vivo, 50 dose-dependently inhibited the AII-induced pressor response in normotensive pithed rats (ID50 = 0.11 mg/kg i.v. and 0.7 mg/kg po). In addition, this compound produced a marked and long-lasting decrease in blood pressure in high renin animal models and proved to be superior to the corresponding tetrazole 45 as well as to DuP 753 or its active metabolite EXP 3174. Compound 50 has been selected for in-depth investigations and is currently undergoing phase II clinical trials.
After trandolapril treatment, the regression of VPB incidence not only is linked to hypertrophy and fibrosis, but additional causal factors also are involved including the myocardial phenotype and new calcium metabolism. Our model of Holter monitoring in conscious middle-aged SHR and multivariate data analysis might be useful in correlating myocardial structural modifications and ectopic activity.
SUMMARY1. The K+, Na+ and C1-fluxes from the oestrogen-stimulated rat uterine smooth muscle were measured using radioactive tracers.2. The cellular compartment contained a concentration of K+ of 173-6 mm which exchanged at a rate of 5.9 x 10-12 mol. cm-2. sec-1.3. Cl-exchanged at a rate of 6-9 x 1012 mol. cm-2. sec-1 from a cellular compartment having a concentration of 39-3 mm.4. The methods used for the evaluation of Na+ movements over-estimate both influx and efflux values. If an average value of flux of 9-2 x 10-12 mol.cm-2. sec-1 is considered we obtain, PNa /PK+ ratios of 2-4 (-42 mV) or 1-3 (-57 6 mV), which are too high and do not correspond to electrophysiological evidence.5. The relative permeabilities PC1-/IPK in the case of a membrane potential of -42-0 mV could be 0-8, or 1-3 in the case of a membrane potential of -57 6 mV.6. Both conductances GK+ and GCj1 seem to play an important role in determining membrane conductance.
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