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Biomedical subjects

J S Silvestre

Publications and source records attributed to J S Silvestre.

At least 19 recordsLinked to original sources
PubMed2006

[Diabetes and peripheral arterial occlusive disease: therapeutic potential and pro-angiogenic strategies].

Cardiovascular complications are the leading cause of morbidity and mortality in patients with diabetes mellitus; up to 80% of deaths in patients with diabetes are closely associated with vascular disease. The ability of the organism to form a collateral network of blood vessels constitutes an important response to vascular occlusive disease and determines to a large part the clinical consequences and severity of tissue ischemia. The development of new vessels is significantly reduced in diabetic patients with coronary or peripheral artery disease. This probably contributes to the severe course of limb ischemia in diabetic patients, in which peripheral artery disease often results in foot ulceration and lower extremity amputation. Diabetic retinopathy remains one of the major causes of acquired blindness in developed nations. This is true despite the development of laser treatment, which can prevent blindness in the majority of those who develop macular edema or proliferative diabetic retinopathy. The hallmark of diabetic retinopathy is the lack of microvessels in the macula, leading to hypoxia, associated with peripheral retinal neovascularization that may ultimately cause severe vitreous cavity bleeding and/or retinal detachment. The factors that stimulate retinal blood vessel growth have not been fully defined, but there is accumulating evidence that the renin-angiotensin-bradykinin system may be involved in a number of retinal vascular disorders, including retinopathy of prematurity and proliferative diabetic retinopathy. Only a few studies have specifically evaluated the effect of diabetes on angiogenesis in ischemic vascular disease and in the retina. Moreover, the mechanisms by which diabetes could both limit the formation of new blood vessels in most organs and simultaneously induce proliferative diabetic retinopathy remain largely undefined. In the present review, we aimed to briefly describe the main molecular mechanisms involved in the ischemia-induced angiogenesis, and their alterations in diabetes. Possible therapeutic strategies to restore angiogenesis in diabetic patients are also listed.

Arterial Occlusive Diseases↗
PubMed2006

Pleiotropic effects of statins and related pharmacological experimental approaches.

Statins, the most widely prescribed cholesterol-lowering drugs, are considered to be first-line therapeutics for the prevention of coronary heart disease and atherosclerosis. Statins act by inhibiting the enzyme 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase, the rate-limiting enzyme in endogenous cholesterol biosynthesis, which catalyzes the reduction of HMG-CoA to mevalonic acid. Inhibition of this enzyme has proven to be effective for lowering plasma total cholesterol, low-density lipoprotein-cholesterol, and triglyceride levels in humans and can therefore be useful to treat atherosclerotic and dyslipidemic disorders. However, the clinical benefits of statins appear to extend beyond their lipid-lowering effects. Besides reducing cholesterol biosynthesis, inhibition of mevalonate by statins also leads to a reduction in the synthesis of important intermediates, such as the isoprenoids farnesyl pyrophosphate and geranylgeranyl pyrophosphate. These intermediates are involved in the posttranslational prenylation of several proteins (e.g., Ras, Rho, Rac) that modulate a variety of cellular processes including cellular signaling, differentiation, and proliferation. Given the central role of these isoprenylated proteins in endothelial function, atherosclerotic plaque stability, platelet activity, coagulation, oxidation, and inflammatory and immunologic responses, it could be anticipated that these compounds may exert multiple beneficial effects in a broad spectrum of disorders including cardiovascular disease, osteoporosis, Alzheimer's disease and related vascular dementia, viral and bacterial infection, etc. This article summarizes these cholesterol-lowering-independent effects of statins, termed "pleiotropic effects", and the underlying mechanisms, as well as the preclinical experimental approaches that would be useful to evaluate the effects of statins.

Animals↗
PubMed2005

Research on adverse drug events. I. Muscarinic M3 receptor binding affinity could predict the risk of antipsychotics to induce type 2 diabetes.

Antipsychotics are associated with a wide range of adverse effects, several of which may represent a serious health risk to patients. There is an increased concern about metabolic disturbances associated with antipsychotics, including weight gain, dyslipidemia, hyperglycemia, and type 2 diabetes. However, little is known about the mechanisms underlying antipsychotic-induced metabolic disturbances and, in particular, those related to the induction of abnormal glucose metabolism and diabetes. The present article aimed to identify those receptor(s) that are most likely to be involved with or mediate antipsychotics-induced diabetes. Two independent measures taken from literature to indicate the risk of type 2 diabetes associated with 25 typical and atypical antipsychotic drugs were considered, along with their binding affinities to 21 specific receptors (obtained from the resources of Prous Science Integrity). A range of both exploratory and predictive statistical analyses were applied, including principal component factorial analysis, multivariable linear regression analysis, and discriminant analysis. Binding affinities (pKi) to human neurotransmitter receptors and monoaminergic transporters were used as independent variables (predictors). Measures to determine the risk to induce new-onset type 2 diabetes associated with each antipsychotic, logistic regression odds-ratio (dOR) and a discrete scale-based risk (three levels: 'low,' 'moderate,' 'high'), were used as the dependent variables (criteria). Similarly, parallel analyses were also conducted for other measures (average effective therapeutic dose) or adverse effects (weight gain, extrapyramidal side effects, hyperprolactinemia, anticholinergic, hypotension, and sedation) associated with antipsychotics, where underlying mechanisms have been previously established and, therefore, serve as positive-control references. Affinity for the cholinergic muscarinic M3 receptor subtype was presented as the best predictor for the propensity of antipsychotics to induce type 2 diabetes. This was independently revealed by means of multiple linear regression analysis, using the dOR as criterion (R=0.90, p<0.0001), and discriminant analysis, using the scale-based risk of type 2 diabetes (3 levels) as criterion (Wilks' lambda=0.33, chi2=14.11, p<0.001). To our knowledge, this study provides the first direct evidence to indicate that antipsychotic agents with high binding affinity to the muscarinic M3 receptor are associated with an elevated risk for type 2 diabetes. Rationale of the M3 receptor involvement in this adverse effect is discussed further in relation to M3 receptor mediation of glucose-dependent parasympathetic acetylcholine regulation of insulin secretion by pancreatic beta-cells. This study is the first in a series of investigations that aim to further our understanding of mechanisms underlying adverse drug effects.

Antipsychotic Agents↗
PubMed2005

Plasticity of adipose tissue: a promising therapeutic avenue in the treatment of cardiovascular and blood diseases?

The adipose tissue represents a large amount of adult tissues. For long time, it was considered as a poorly active overgrown and undesirable tissue even if its usefulness was demonstrated in reconstructive surgery. It was studied for its main involvement in energy metabolism and disorders as diabetes and obesity. More recently, its endocrine functions emerged and appeared to play a key role in many physiological situations such as inflammation and immunity. The presence of preadipocytes throughout life was demonstrated using primary culture technology from cells derived from adipose tissue. These cells can display a macrophagic or endothelial potential according to their environment and could be now considered as vascular progenitors. Differentiation of various adipose derived cell subsets towards functional cardiomyocytes, osteoblasts, haematopoietic and neural cells was also obtained in vitro. Altogether, these data emphasise the need to consider with a new look preadipocyte status and adipose tissue biology. These spectacular data, together with the fact that adipose tissue is easy to obtain lead to numerous and promising perspectives in regenerative medicine. They highlight the concept that progenitor cells from adipose tissue constitute an alternative for cells-based strategies designed for the treatment of cardiovascular diseases.

Adipose Tissue↗
PubMed2004

Acyl coenzyme A:cholesterol acyltransferase inhibitors as hypolipidemic and antiatherosclerotic drugs.

Acyl coenzyme A:cholesterol acyltransferase (ACAT) is the enzyme that catalyzes the conversion of intracellular cholesterol into cholesteryl esters. Two ACAT isoforms, termed ACAT1 and ACAT2, have been described. ACAT1 is ubiquitously found, with high expression levels in macrophages, adrenals, sebaceous glands and foam cells from human atherosclerotic lesions. In contrast, ACAT2 expression is restricted to the intestine and the liver of mice and non-human primates. The reaction catalyzed by ACAT is essential for intestinal cholesterol absorption, synthesis and secretion of apolipoprotein B (apoB)-containing lipoproteins, and intracellular storage of cholesterol. Therefore, ACAT inhibitors would theoretically reduce plasma cholesterol levels by blocking cholesterol absorption from the diet and by reducing hepatic VLDL synthesis. Moreover, ACAT inhibition could limit the accumulation of cholesteryl esters in the cytoplasm of macrophages, thus reducing the formation of foam cells. In view of these attractive possibilities, a great deal of molecules with ACAT inhibitory properties have been synthesized in the last 20 years. However, only a few of them have reached clinical studies, mainly due to unexpected side effects. On the other hand, most of the compounds assayed in humans have not shown substantial hypolipidemic efficacy. The present article focuses on the current knowledge of the pharmacology of ACAT inhibitors, and, specifically, on the different pharmacological approaches used to evaluate these compounds as hypolipidemic and antiatherosclerotic agents.

Animals↗
PubMed2002

Experimental approaches to study PPAR gamma agonists as antidiabetic drugs.

Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear hormone receptor superfamily of ligand-activated transcription factors that are related to retinoid, steroid and thyroid hormone receptors. Since PPARs appear to be closely involved in the regulation of dietary fat storage and catabolism, they have been established as an important target for the treatment of type 2 diabetes and other disorders associated with the high intake of dietary fat. Thiazolidinediones (TZDs) were the first class of compounds to be identified as PPAR gamma-ligands, constituting a new class of antidiabetic drugs that have recently been introduced as therapeutic agents for the treatment of type 2 diabetes mellitus by acting as insulin sensitizers. These compounds improve insulin resistance by increasing cell sensitivity to insulin. In fact, PPAR gamma agonists increase peripheral insulin sensitivity by increasing the transcription of genes, which, in turn, increase glucose uptake, also improving insulin-stimulated glucose disposal in muscle. PPAR gamma agonists increase insulin signaling, reduce circulating levels of free fatty acids and stimulate adipocyte differentiation, thus favoring the formation of smaller, more insulin-sensitive adipocytes. TZDs have been proven effective in different experimental models to evaluate their effectiveness as an antidiabetic agent, and the involvement of PPAR gamma in the pharmacological effects of these compounds has been supported by studies showing an excellent correlation between the hypoglycemic action of these drugs and their affinity for PPAR gamma. Despite this evidence, the site of action and the molecular mechanism of TZDs remain unclear. The aim of the present article was to review and discuss the most relevant pharmacological studies performed in the search for establishing the mechanism of action of antidiabetic TZDs and related compounds acting as PPAR gamma agonists, as well as to summarize those representative experimental approaches currently used to evaluate PPAR gamma agonists as therapeutic agents for the treatment of insulin-resistant type 2 diabetes mellitus.

Animals↗
PubMed2002

Angiogenesis therapy in ischemic disease.

The ability of organisms to spontaneously develop collateral vessels represents an important response to vascular occlusive diseases that determines the severity of residual tissue ischemia. Neovascularization of ischemic cardiac or skeletal muscle may be sufficient to preserve tissue integrity and/or function, and may thus be considered to be therapeutic. Innovative gene technologies and advances in animal modeling have enabled research scientists to develop therapeutic angiogenesis strategies applied in animal models of limb or myocardial ischemia and in treatment of patients with peripheral vascular obstruction or coronary artery diseases. Several therapeutic strategies have been proposed and tested even at the clinical level. Recent studies have established the feasibility of using recombinant angiogenic growth factors (mainly VEGF and FGF) to enhance angiogenesis in patients with limb or myocardial ischemia. Angiogenesis therapies using cells as a support for growth factor delivery or using endothelial progenitor cells which may directly participate in the angiogenic process have also been developed. Finally, one potential alternative strategy may be the use of drugs with pro-angiogenic activity, available in an oral formulation and which are currently administered to patients for treatment of different pathologies. All strategies of angiogenesis therapy currently being tested have the potential to be effective in the treatment of ischemic disease. However, such strategies may cause harmful side effects which emphasize the need to be aware of the biological effects of each angiogenic agent proposed for clinical studies.

Administration, Oral↗
PubMed2001

Increased ischemia-induced angiogenesis in the staggerer mouse, a mutant of the nuclear receptor Roralpha.

Ror alpha is an orphan nuclear receptor. In homozygous staggerer mutant mice (Ror alpha(sg/sg)), a deletion within the Ror alpha gene leads to an overexpression of inflammatory cytokines. Because inflammation and hypoxia are 2 key stimuli of ischemia-induced angiogenesis, we studied the role of Ror alpha in this setting. Ischemia was induced by ligation of the right femoral artery in C57BL/6 Ror alpha(+/+) and Ror alpha(sg/sg) mice. After 3 and 28 days, angiogenesis was evaluated by microangiography, measurement of capillary density using immunohistochemistry (anti-CD31), and measurement of blood flow by laser Doppler imaging. At day 3, angiographic score and blood flow were similar in Ror alpha(sg/sg) mice and in Ror alpha(+/+) littermates. Conversely, at day 28, Ror alpha(sg/sg) mice showed a significant 2-fold increase in angiographic score and a 3-fold increase in capillary density within the ischemic hindlimb compared with control. Functionally, this coincided with a significant rise in leg perfusion in Ror alpha(sg/sg) mice (0.83+/-0.05 for ischemic/nonischemic leg perfusion ratio) compared with Ror(+/+) mice (0.66+/-0.04, P<0.05). In addition, more extensive angiogenesis in Ror alpha(sg/sg) mice correlated with an increased expression of eNOS protein by 83+/-12% and 71+/-24% at 3 and 28 days, respectively (P<0.05), whereas the level of the antiangiogenic cytokine IL-12 was significantly reduced by 38+/-10% at day 28 (P<0.05). Conversely, no changes in VEGF expression were observed. Our study identifies for the first time a new role for Ror alpha as a potent negative regulator of ischemia-induced angiogenesis.

Animals↗
PubMed2001

Proangiogenic effect of angiotensin-converting enzyme inhibition is mediated by the bradykinin B(2) receptor pathway.

Recent studies have suggested a proangiogenic effect of angiotensin-converting enzyme (ACE) inhibition. We hypothesized that such a proangiogenic effect of ACE inhibition may be mediated, in part, by bradykinin (BK) B(2)-receptor pathway. This study therefore examined the neovascularization induced by ACE inhibitor treatment in B(2) receptor-deficient mice (B(2)(-/-)) in a model of surgically induced hindlimb ischemia. After artery femoral occlusion, wild-type and B(2)(-/-) mice were treated with or without ACE inhibitor (perindopril, 3 mg/kg/d) for 28 days. Angiogenesis was then quantitated by microangiography, capillary density measurement, and laser Doppler perfusion imaging. The protein levels of vascular endothelial growth factor (VEGF) and endothelial nitric oxide synthase (eNOS) were determined by Western blot. In wild-type animals, vessel density and capillary number in the ischemic leg were raised by 1.8- and 1.4-fold, respectively, in mice treated with ACE inhibitor when compared with the nontreated animals (P<0.01). This corresponded to an improved ischemic/nonischemic leg perfusion ratio by 1.5-fold in ACE inhibitor-treated animals when compared with the untreated ones (0.87+/-0.07 versus 0.59+/-0.05, respectively, P<0.01). Activation of the angiogenic process was also associated with a 1.7-fold increase in tissue eNOS protein level in mice treated with ACE inhibitor (P<0.05 versus control) but not with changes in VEGF protein level. Conversely, ACE inhibition did not affect vessel density, blood flow, and eNOS protein level in ischemic hindlimb of B(2)(-/-) mice. Therefore, proangiogenic effect of ACE inhibition is mediated by B(2)-receptor signaling and was associated with upregulation of eNOS content, independently of VEGF expression.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed2001

Regulation of matrix metalloproteinase activity in ischemic tissue by interleukin-10: role in ischemia-induced angiogenesis.

We have previously shown that deficiency in the anti-inflammatory cytokine interleukin-10 (IL-10) is responsible for enhanced angiogenesis after hindlimb ischemia. This study examined the putative involvement of matrix metalloproteinase (MMP) activation in this process. Ischemia was produced by artery femoral occlusion in both C57BL6 IL-10(+/+) and IL-10(-/-) mice. Angiographic vessel density and laser Doppler perfusion data at day 28 showed significant improvement in ischemic/nonischemic leg ratio by, respectively, 1.8-fold and 1.4-fold in IL-10(-/-) mice compared with IL-10(+/+) mice. This was associated with an increase in vascular endothelial growth factor (VEGF) protein content in the ischemic hindlimb. Three days after ischemia, gelatin zymography showed a significant increase in both pro- and active forms of MMP-2 and MMP-9 in ischemic hindlimbs of IL-10(-/-) mice compared with IL-10(+/+) mice (P<0.01). This increase in MMP activity in IL-10(-/-) mice was completely inhibited by treatment with BB-94 (5 mg/kg IP), a specific MMP inhibitor. Furthermore, increases in both vessel density and blood perfusion indexes at day 28 in IL-10(-/-) mice were abolished after treatment with BB-94 (0.78+/-0.06 versus 1.17+/-0.09 and 0.62+/-0.02 versus 0.88+/-0.04, for vessel density and blood perfusion ratio, respectively, in IL-10(-/-) mice treated with BB-94 versus untreated IL-10(-/-) mice, P<0.05). In contrast, BB-94 treatment did not affect the rise in VEGF protein content. These findings in IL-10(-/-) mice underscore the critical role of MMP activation, in a context of increased VEGF expression, in promoting ischemia-induced angiogenesis.

Angiography↗
PubMed2001

Chronic blockade of endothelin receptors improves ischemia-induced angiogenesis in rat hindlimbs through activation of vascular endothelial growth factor-no pathway.

This study investigated in vivo the putative angiogenic role of endothelin (ET)-1 in a model of ischemia-induced angiogenesis. Ischemia was produced by unilateral femoral artery occlusion in Wistar rats submitted to either chronic ET-1 infusion (2 nmol. kg(-1). min(-1)) or to a dual ET(A)/ET(B) receptor antagonist (bosentan, 100 mg. kg(-1). d(-1)) for 3 and 28 days. Arterial density was evaluated by microangiography and measurement of capillary and arteriolar density in hindlimb muscles. ET-1 infusion had no effect on ischemia-induced angiogenesis and was associated with a slight decrease in vascular endothelial growth factor (VEGF) content measured by Western blot analysis. Conversely, bosentan induced a marked increase in vessel density at 3 and 28 days (1.4-fold and 1.7-fold, respectively, compared with no treatment; P<0.05), which was associated with an increase in VEGF and endothelial NO synthase levels in ischemic legs (by 31+/-8% and 45+/-23%, respectively, at 3 days and by 65+/-13% and 55+/-15%, respectively, at 28 days; P<0.05 versus nontreated rats). At day 28, the proangiogenic effect of bosentan was abolished when NO synthesis inhibitor N(G)-nitro-L-arginine methyl ester (10 mg. kg(-1). d(-1)) or VEGF-neutralizing antibody (2.5 micro/kg twice a week) were coadministered with bosentan. Those results provide the first evidence of an early and sustained proangiogenic effect of endothelin antagonism associated with an upregulation of VEGF and endothelial NO synthase in vivo.

Animals↗
PubMed2000

Antiangiogenic effect of interleukin-10 in ischemia-induced angiogenesis in mice hindlimb.

Ischemia induces both hypoxia and inflammation that trigger angiogenesis. The inflammatory reaction is modulated by production of anti-inflammatory cytokines. This study examined the potential role of a major anti-inflammatory cytokine, interleukin (IL)-10, on angiogenesis in a model of surgically induced hindlimb ischemia. Ischemia was produced by artery femoral occlusion in both C57BL/6J IL-10(+/+) and IL-10(-/-) mice. After 28 days, angiogenesis was quantified by microangiography, capillary, and arteriole density measurement and laser Doppler perfusion imaging. The protein levels of IL-10 and vascular endothelial growth factor (VEGF) were determined by Western blot analysis in hindlimbs. IL-10 was markedly expressed in the ischemic hindlimb of IL-10(+/+) mice. Angiogenesis in the ischemic hindlimb was significantly increased in IL-10(-/-) compared with IL-10(+/+) mice. Indeed, angiographic data showed that vessel density in the ischemic leg was 10.2+/-0.1% and 5.7+/-0.4% in IL-10(-/-) and IL-10(+/+) mice, respectively (P:<0.01). This corresponded to improved ischemic/nonischemic leg perfusion ratio by 1.4-fold in IL-10(-/-) mice compared with IL-10(+/+) mice (0.87+/-0. 05 versus 0.63+/-0.01, respectively; P:<0.01). Revascularization was associated with a 1.8-fold increase in tissue VEGF protein level in IL-10(-/-) mice compared with IL-10(+/+) mice (P:<0.01). In vivo electrotransfer of murine IL-10 cDNA in IL-10(-/-) mice significantly inhibited both the angiogenic process and the rise in VEGF protein level observed in IL-10(-/-) mice. No changes in vessel density or VEGF content were observed in the nonischemic hindlimb. These findings underscore the antiangiogenic effect of IL-10 associated with the downregulation of VEGF expression and suggest a role for the inflammatory balance in the modulation of ischemia-induced angiogenesis.

Animals↗
PubMed2000

Different regulation of cardiac and renal corticosteroid receptors in aldosterone-salt treated rats: effect of hypertension and glucocorticoids.

This study analysed the regulation of cardiac mineraloreceptor (MR) and glucoreceptor (GR) in aldosterone-salt treatment (AST). AST causes hypertension, left ventricle (LV) hypertrophy and decreases plasma corticosterone level. Ribonuclease protection assay and Western blot analysis showed a rise of MR mRNA (1.5- and 1.4-fold at day 15 and 30, respectively) and protein levels (1.8- and 4.1-fold at day 30 and 60, respectively) in the LV, but not in either the right ventricle (RV) or in kidney of treated rats. Addition of MR antagonist spironolactone (20 mg/kg/day) for 30 days failed to prevent these changes but was able to reduce AST-induced cardiac fibrosis. Similar hypertension-induced MR upregulations were observed in the LV of AngII-hypertensive rats and of 12-week-old SHR when compared to 4-week-old prehypertensive SHR. AST also enhanced left ventricular GR mRNA (2.0- and 3.0-fold at day 7 and 15, respectively) and protein contents (2.0- and 1.7-fold at day 30 and 60, respectively). In contrast to MR, GR levels were also upregulated in both RV and kidney. Such an upregulation was equally observed at mRNA and protein levels in LV, RV and kidney after adrenalectomy (15 days) and was prevented in both tissues after glucocorticoid replacement (adrenalectomy + dexamethasone at 100 micro g/kg/day for 15 days). Therefore, MR level may be controlled by hemodynamical factors whereas that of GR depends upon glucocorticoids level.

Adrenalectomy↗
PubMed2000

Cardiac aldosterone production and ventricular remodeling.

An intracardiac production of aldosterone has been recently reported in rat. This production is increased both acutely and chronically by angiotensin II, observations suggesting that the heart contains a steroidogenic system that is regulated similarly to the adrenal one. Cardiac production of aldosterone is small compared with that of the adrenal, raising the question of its function in normal conditions. Moreover, the regulation of this synthesis in pathophysiologic states remains unknown. In an analysis of the effects of a one-month myocardial infarction (MI) on the cardiac steroidogenic system, it was observed that aldosterone-synthase mRNA and the aldosterone concentration were increased by 2- and 3.5-fold, respectively, in the noninfarcted part of the rat left ventricle. MI also induced a 1. 9-fold increase in the cardiac angiotensin II level. Losartan prevented these changes, and the MI-induced collagen deposition in noninfarcted area of the left ventricle was reduced by 1.6- and 2. 5-fold by both spironolactone and losartan treatments, respectively. Thus, these observations indicate that MI is associated with tissue-specific activation of myocardial aldosterone synthesis. This activation is mediated by cardiac angiotensin II via the angiotensin II type 1 (AT1) receptor, and the resultant increase of intracardiac aldosterone level may be involved in post-MI ventricular remodeling.

Aldosterone↗
PubMed2000

[Hypertension: microvascular complications].

The arterioles, vessels situated before the capillary bed, are responsible for the increased systemic resistances characteristic of hypertension. In short, three abnormalities are observed in the arterioles of hypertensives: abnormally high vasoconstrictor tone, essentially due to sympathetic hyperactivity, hypertrophic remodelling or increased wall thickness/radius ratio of the arteriole promoting both the increase in vasoconstriction tone and reduction of the vascular lumen, rarefaction of the microvascular bed which contributes to the increase in the haemodynamic resistances. These three factors are observed to different degrees in all forms of hypertension; their influence varies with the organ involved and the stage of the disease. A change in therapeutic strategy has occurred over the last 20 years in the field of hypertension. Before the 1980's, anti-hypertensive therapy was essentially aimed at a vasomotor target: the drugs used had a vasodilatory effect on the resistive arterioles or decreased their response to vasoconstrictor agents. From the mid-1980's, a lot of research was made into the therapeutic possibilities of limiting or correcting the hypertrophic remodelling of the arteries and arterioles of hypertensive patients. In the last few years, the vascular rarefaction in hypertension has been considered to be a significant factor and the possibility of correcting the structural abnormality has become a new therapeutic option.

Antihypertensive Agents↗
PubMed1999

Activation of cardiac aldosterone production in rat myocardial infarction: effect of angiotensin II receptor blockade and role in cardiac fibrosis.

BACKGROUND: This study analyzed the regulation and the role of the cardiac steroidogenic system in myocardial infarction (MI). METHODS AND RESULTS: Seven days after MI, rats were randomized to untreated infarcted group or spironolactone- (20 and 80 mg x kg-1 x d-1), losartan- (8 mg x kg-1 x d-1), spironolactone plus losartan-, and L-NAME- (5 mg x kg-1 x d-1) treated infarcted groups for 25 days. Sham-operated rats served as controls. In the noninfarcted myocardium of the left ventricle (LV), MI raised aldosterone synthase mRNA (the terminal enzyme of aldosterone synthesis) by 2. 0-fold and the aldosterone level by 3.7-fold. Conversely, MI decreased 11beta-hydroxylase mRNA (the terminal enzyme of corticosterone synthesis) by 2.4-fold and the corticosterone level by 1.9-fold. MI also induced a 1.9-fold increase in cardiac angiotensin II level. Such cardiac regulations were completely prevented by treatment of the infarcted heart with losartan. The MI-induced collagen deposition in noninfarcted LV myocardium was prevented by 1.6-fold by both low and high doses of spironolactone and by 2.5-fold by losartan. In addition, norepinephrine level was unchanged in infarcted heart but was attenuated by both losartan and spironolactone treatments. CONCLUSIONS: MI is associated with tissue-specific activation of myocardial aldosterone synthesis. This increase is mediated primarily by cardiac angiotensin II via AT1-subtype receptor and may be involved in post-MI ventricular fibrosis and in control of tissue norepinephrine concentration.

Aldosterone↗