Biomedical subjects

B Gigante

Publications and source records attributed to B Gigante.

At least 19 recordsLinked to original sources

PubMed2006

Fluorescence study of dehydroabietic acid-based bipolar arylamine-quinoxalines.

The absorption and fluorescence spectra, lifetimes and quantum yields of a series of triarylaminequinoxaline bipolar compounds, with and without the bulky dehydroabietic acid group, have been studied in toluene solution. This bulky group is introduced to improve solubility and thermal properties of these systems. It is shown that this does not affect their spectral or photophysical behavior. The compounds show relatively strong fluorescence, with the emission maximum strongly dependent upon the substituents present. Oxidation potentials have also been determined in acetonitrile solution, and again indicate that introduction of the resin acid moiety has no effect on these properties.

Journal Article↗

PubMed2003

Catechols from abietic acid synthesis and evaluation as bioactive compounds.

Catechols from abietic acid were prepared by a short and good yielding chemical process and further evaluated for several biological activities namely, antifungal, antitumoral, antimutagenic, antiviral, antiproliferative and inhibition of nitric oxide. Their properties were compared with those of carnosic acid (6), a naturally occurring catechol with an abietane skeleton and known to possess potent antioxidant activity, as well as anticancer and antiviral properties. From all the synthetic catechols tested compound 2 showed the best activities, stronger than carnosic acid.

Abietanes↗

PubMed2002

Antimicrobial activity of methyl cis-7-oxo deisopropyldehydroabietate on Botrytis cinerea and Lophodermium seditiosum: ultrastructural observations by transmission electron microscopy.

AIMS: To study the antifungal activity of methyl cis-7-oxo-deisopropyldehydroabietate (MCOD) against phytopathogenic fungi, Botrytis cinerea and Lophodermium seditiousm. The effect of the compound was studied by transmission electron microscopy (TEM) and the composition of sterols on both treated and untreated cultures was determined. METHODS AND RESULTS: MCOD was tested at concentrations in the range 0.003-0.5% by the agar plate dilution method. The radial growth of the colonies treated with MCOD was measured against colonies from untreated cultures. The radial growth of colonies of both fungi and the spore germination of B. cinerea were partially or completely inhibited. Fragments of active growing colonies treated and untreated with MCOD were submitted to the conventional procedure for ultrastructural observation by TEM. Observations by TEM on colonies of B. cinerea and L. seditiosum under 0.1% MCOD revealed several autophagic-like vacuoles, morphological alterations on lomasome and lipid accumulations in the apical zone of hyphae of both fungi. Observations on spore germination of B. cinerea revealed the presence of strongly stained lipid accumulations retained by vacuoles at the cell periphery of young hyphae. The sterol composition of B. cinerea and L. seditiosum was determined on MCOD treated and untreated cultures by gas-chromatography/mass-spectrometry (GC-MS) with molecular ions and fragmentation patterns characteristics of ergosterol (M+396) and dihydroergosterol (M+398) in both fungi. CONCLUSIONS: The morphological alterations are consistent with an unspecific mode of action of MCOD causing inhibition of normal growth or damaging the fungi cells. TEM observations suggest a mechanism of resistance based on the retention of MCOD by the lipid accumulation. SIGNIFICANCE AND IMPACT OF THE STUDY: The results obtained in the present work afforded a better understanding of the mode of action of a resin acid derivative on phytopathogenic fungi. The inhibition growth of both fungi by MCOD demonstrates the antifungal activity of this compound and the interest on further in vivo studies, in order to evaluate its potential as a benign alternative to conventional fungicides.

Abietanes↗

PubMed2001

Synthetic derivatives of abietic acid with radical scavenging activity.

In this work, studies on the arylation of anilines derived from dehydroabietic acid, the main component of disproportionated rosin, are presented. The redox properties of the new diarylamines were investigated by cyclic voltammetry, and their free radical scavenging activity was tested by reduction of the 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical. Three of the diarylamines with lower oxidation potential proved to be as active as isopropyldiphenylamine (IPPD) and superior to tert-butylhydroxytoluene (BHT), both commercially available synthetic antioxidants.

Abietanes↗

PubMed2001

Determinants and clinical significance of natriuretic peptides and hypertrophic cardiomyopathy.

AIMS: Atrial and brain natriuretic peptide levels closely reflect impaired left ventricular function in patients with heart failure. In the present study we assessed the determinants and the clinical significance of atrial and brain natriuretic peptide plasma levels in hypertrophic cardiomyopathy. METHODS AND RESULTS: In 44 patients with hypertrophic cardiomyopathy (40+/-15 years) we evaluated: (a) atrial and brain natriuretic peptide plasma levels; (b) left ventricular hypertrophy; (c) left ventricular ejection fraction; (d) transmitral and pulmonary venous flow velocity patterns, and left atrial fractional shortening; (e) left ventricular outflow tract gradient; (f) maximal oxygen consumption. Left ventricular hypertrophy influenced only brain natriuretic peptide levels (r=0.32;P<0.05). Atrial and brain natriuretic peptide plasma levels did not correlate with left ventricular ejection fraction, but correlated with left ventricular outflow tract gradient (r=0.35;P<0.05; and r=0.40, P=0.022, respectively) and left atrial fractional shortening (r=-0.57;P<0.001, and r=-0.35;P<0.05, respectively). Atrial but not brain natriuretic peptide plasma levels were inversely related to maximal oxygen consumption (r=-0.35;P<0.05). By stepwise multiple regression analysis, left atrial fractional shortening and left ventricular outflow tract gradient were the only predictors of atrial and brain natriuretic peptide plasma levels, respectively. CONCLUSIONS: In hypertrophic cardiomyopathy, atrial natriuretic peptide plasma levels are mainly determined by diastolic function: this explains the relationship with exercise tolerance. In contrast, brain natriuretic peptide plasma levels are mainly determined by left ventricular outflow tract gradient.

Adolescent↗

PubMed2001

Genetic susceptibility to cerebrovascular accidents.

Cerebrovascular accidents are the third leading cause of death after myocardial infarction and cancer in all Western societies. A more complete understanding of the pathogenetic determinants of stroke is required in order to achieve a better prevention and treatment of this common disease. Recently, based on convincing epidemiological and experimental evidence, the concept of stroke as a complex, multifactorial, polygenic disease has been well assessed. Thus, together with known modifiable determinants, such as smoking, obesity, hypertension, cardiac diseases and diabetes, specific hereditary factors for stroke are now taken into account when analysing the pathogenesis of cerebrovascular accidents. In particular, there have recently been important findings related to the genetic basis of stroke in suitable animal models and in humans, thus representing the promise of a more thorough understanding of the pathogenesis of stroke in the future and of a more specific preventive and therapeutic approach to this common pathological condition.

Animals↗

PubMed2001

Non-random chromosomal distribution of SSLPs: systematic assessment using a novel genetic linkage map between two closely related rat strains.

Simple sequence length polymorphisms (SSLPs) are a widely used tool for genetic studies in humans and model animals. Experimental crosses among closely related strains that differ primarily in the trait that is to be mapped carry the advantage of avoiding co-segregation of potentially confounding traits. However, their realization is encumbered by the limited availability of newly arisen informative SSLPs among such strains. Here we report the establishment of a genome-wide SSLP panel for the spontaneously hypertensive rat (SHR) and its close relative, the stroke-prone SHR (SHRSP), consisting of a total of 273 polymorphic markers that were found among 2,734 rat SSLPs screened. In addition to limitations in numbers, we also found the distribution of informative markers to be heterogeneous, with clustering and paucity of informative markers, respectively, in particular regions. Notably, the majority of regions thus identified was also seen when we examined an unrelated set of strains from the literature, indicating, on a more generic level, the presence of mutagenically more and less stable genomic regions.

Animals↗

PubMed2000

Role of angiotensin II AT1 and AT2 subtype receptors in the regulation of atrial natriuretic peptide expression in salt-restricted rats.

Previous studies have suggested that angiotensin II modulates ANP secretion and this action appears to be largely independent from its hemodynamic effects. In order to explore the contribution of angiotensin II AT1 (AT1r) and AT2 (AT2r) receptor subtypes in the regulation of cardiac ANP, we studied the effects of selective antagonists of these receptors on ANP mRNA levels in the cardiac chambers of salt-restricted rats. Thirty-one Sprague-Dawley rats (12 weeks-old) weighing 250-350 g were studied during a low salt regimen and randomly assigned to the following treatment groups: AT1r-blockade (losartan) (10 mg/kg/day) (n = 18), AT2r-blockade (PD123319) (50 microg/kg/min) (n = 6), Control (salt-restriction) (n = 7). Treatments were maintained for 7 days; subsequently, 12 rats from the AT1r-blockade group were subdivided in to two groups: AT1r/AT2r-blockade (losartan +PD123319) (n = 6) and AT1r-blockade/vehicle (losartan+vehible) (n = 6), and treated for 7 additional days. Systolic blood pressure was significantly reduced by AT1r-blockade (p < 0.001), while it was not affected by AT2r-blockade. Concomitant treatment with both antagonists (AT1r/AT2r-blockade) restored blood pressure values to baseline (p < 0.001 vs. AT1r-blockade, p = n.s. vs Control). Atrial ANP mRNA was reduced by AT1r-blockade (-42%, p < 0.05) and did not change during AT1r-blockade alone. On the contrary, concomitant treatment with both antagonists resulted in a further significant inhibition of ANP expression (-65% and -36% vs Control and AT1r-blockade, respectively, both p < 0.05). ANP expression in ventricles was not affected by any of these treatments. Our results demonstrate that angiotensin II tonically modulates cardiac ANP expression in our experimental model. In particular, angiotensin II receptor subtypes AT1r and AT2r regulate atrial ANP mRNA levels through a synergic action and independently from blood pressure changes.

Angiotensin II↗

PubMed2000

Defective suppression of the aldosterone biosynthesis during stroke permissive diet in the stroke-prone phenotype of the spontaneously hypertensive rat.

Previous studies have shown that short-term high salt intake unmasks blunted plasma aldosterone suppression in stroke-prone spontaneously hypertensive rats (SHRsp). The aim of this study was to evaluate the response of aldosterone biosynthesis and production to a sustained exposure to the stroke-permissive Japanese-style diet (JD) in young stroke-prone and stroke-resistant SHRs. For this purpose, 6-week old male rats from both strains were divided into 2 dietary groups and received regular diet (SHR = 37, SHRsp = 32) or the JD and 1% saline to drink (SHR = 34, SHRsp = 30) for 4 weeks. All measurements were carried out at the end of the dietary periods. After JD, plasma aldosterone levels were significantly decreased in SHR (from 357.8 +/- 57 to 163.3 +/- 31.5 pg/ml, p < 0.05) but markedly increased in SHRsp (from 442 +/- 56.5 to 739 +/- 125.7 pg/ml, p < 0.05). Consistently, the adrenal aldosterone synthase expression was reduced by JD in SHR (p < 0.05), whereas it was even slightly raised by JD in SHRsp so that, at the end of JD, aldosterone synthase mRNA was 5-fold higher in SHRsp than in SHR. Urinary sodium excretion (mEq/24h) achieved lower levels in SHRsp, so that fractional excretion of sodium was 80.2 +/- 9% in SHR and 40.3 +/- 8% in SHRsp (p < 0.05) in balance studies performed at the end of JD. These different responses of mineralocorticoid biosynthesis and urinary sodium excretion to JD were not accounted for by different adaptations of the renin-angiotensin and atrial natriuretic peptide systems, of serum potassium levels, or of adrenal 11beta-hydroxylase expression in the two strains. Systolic blood pressure was comparable in both strains throughout the experiment. These results demonstrate enhanced aldosterone biosynthesis, associated with reduced urinary excretion of sodium in response to JD in SHRsp before the onset of stroke. This abnormality may play a role in the higher susceptibility to stroke of this model.

Aldosterone↗

PubMed2000

Analysis of the genetic basis of the endothelium-dependent impaired vasorelaxation in the stroke-prone spontaneously hypertensive rat: a candidate gene approach.

OBJECTIVE: To investigate the role of potential candidate genes in the pathogenesis of the endothelium-dependent impaired vasorelaxation that associates and co-segregates with stroke in the stroke-prone spontaneously hypertensive rat (SHRsp) compared with the stroke-resistant SHR (SHRsr). DESIGN AND METHODS: An SHRsp/SHRsr F2-intercross (n = 137; 64 males, 73 females) was obtained and, at the age of 6 weeks, it was placed under a stroke permissive Japanese-style diet for 4 weeks. At the end of the treatment the vascular function of each rat was characterized. The maximal vasorelaxation to acetylcholine after maximal vasoconstriction (delta ratio) was considered as the quantitative phenotype. The following candidate genes were related to the delta ratio: renin, angiotensinogen, angiotensin-converting enzyme, angiotensin II AT1b receptor, atrial natriuretic peptide, brain natriuretic peptide, atrial natriuretic peptide GC-A receptor, kallikrein, endothelial nitric oxide synthase. In addition, polymorphic markers located inside areas of the rat genome where other candidates (i.e. adrenomedullin, endothelin, Ang II AT1a receptor) are known to map were included. RESULTS: The endothelial vascular dysfunction of the SHRsp showed a variable distribution among SHRsp/SHRsr F2 descendants, independently from the blood pressure levels. A genotype/phenotype co-segregation analysis for each of the genes tested did not show any statistically significant co-segregation with the vascular phenotype. CONCLUSION: A candidate gene approach used to investigate the genetic basis of the endothelial-dependent vascular dysfunction of the SHRsp strain did not reveal any evidence to support the hypothesis that the genes tested play any role in the pathogenesis of the stroke-related vascular abnormality.

Animals↗

PubMed1999

Altered structure, regulation, and function of the gene encoding the atrial natriuretic peptide in the stroke-prone spontaneously hypertensive rat.

Through the genotype/phenotype cosegregation analysis of an F(2) intercross, from the crossbreeding of stroke-prone spontaneously hypertensive rats (SHRSP) and stroke-resistant spontaneously hypertensive rats (SHR), we previously identified a quantitative trait locus for stroke on rat chromosome 5 (STR2) that colocalized with the genes encoding atrial and brain natriuretic peptides (ANP and BNP) and conferred a stroke-delaying effect. To further characterize ANP and BNP as candidates for stroke, we performed additional studies. Comparative sequence analysis revealed point mutations in both the coding and regulatory regions of ANP, whereas no interstrain differences were found for BNP. In in vitro studies in COS-7 and AtT-20 cells that were performed to test the relevance of a G-->A substitution at position 1125, a Gly-->Ser transposition in the SHRSP pro-ANP peptide resulted in different posttranslational processing of the SHRSP ANP gene product that was also associated with higher cGMP production (P<0.05). Furthermore, an analysis of a 5' end mutation affecting a PEA2 regulatory binding site in the 5' untranslated regulatory sequence of SHRSP ANP demonstrated a significantly lower ANP promoter activation in endothelial cells (P<0.05 versus the SHR ANP). In addition, the expression of ANP was significantly reduced in the brain, but not in the atria, of SHRSP compared with SHR (P<0.0001). No differences were detected with regard to BNP expression. The present results reveal substantial differences in ANP, but not BNP, structure and product among SHR and SHRSP, which supports a role of ANP in the pathogenesis of stroke in the SHRSP animal model.

Animals↗

PubMed1999

Antimicrobial activity of diterpene resin acid derivatives.

C-13 deisopropylated and/or C-7 oxidized resin acid derivatives were tested against various microorganisms to determine structural features responsible for biological activity and to determine the influence of the C-13 isopropyl group on antimicrobial activity. Test results show that methyl cis and trans 7-oxo-13-deisopropyldehydroabietate and a mixture of both isomers exhibited activity against fungi and bacteria.

Abietanes↗

PubMed1999

Modulation of the AT2 subtype receptor gene activation and expression by the AT1 receptor in endothelial cells.

OBJECTIVE: To investigate whether angiotensin II type 2 (AT2) receptor (AT2-r) promoter activity and expression are modulated by angiotensin II (Ang II), and whether the AT1 receptor (AT1-r) is involved in this effect. DESIGN AND METHODS: Primary endothelial cells obtained from NEONATAL rat aorta, expressing both receptors, were transfected with the rat AT2-r promoter region cloned into a pCAT-reporter vector. The reporter-expression study was performed in a transient transfection assay system. Transfected cells were studied following angiotensin-converting enzyme inhibition to prevent endogenous formation of Ang II. Cells were subsequently stimulated for 6 h with Ang II, either alone or in combination with the AT1-r antagonist DuP753. AT2-r mRNA was assessed by RNase protection assay during the same pharmacological stimuli. RESULTS: Stimulation with Ang II caused an increase in promoter activity (+50%, P < 0.05 versus baseline), whereas mRNA expression was reduced by 50% (P < 0.05 versus baseline). Concomitant treatment with DuP753 and Ang II was associated with a 98% increase in promoter activity (P < 0.05 versus baseline). DuP753 also prevented the reduction in mRNA; it actually produced a 100% increase in AT2-r mRNA accumulation (P < 0.01 versus baseline). Studies with the AT2-r antagonist PD123319 indicate that the AT2-r is also involved in the regulation of AT2-r gene promoter activity. CONCLUSIONS: These data indicate that Ang II increases AT2-r promoter activity and decreases AT2-r mRNA accumulation in endothelial cells. The AT1 subtype receptor is involved in the modulation of both effects of Ang II. These findings suggest that changes in the expression of AT2 receptors may occur during treatment with AT1-r antagonists, and they indicate the existence of a cross-talk between AT1 and AT2 receptors.

Angiotensin II↗

PubMed1998

Role of the angiotensin II AT2-subtype receptors in the blood pressure-lowering effect of losartan in salt-restricted rats.

OBJECTIVE: The aim of this study was to evaluate the potential role of the angiotensin II (Ang II) AT2 receptors (AT2) in the control of blood pressure (BP) in the rat and the effects of AT2 receptors on BP during AT1 receptor (AT1) antagonism. METHODS: The study was performed in 52 Sprague-Dawley rats, which were preliminarily salt-restricted (SR) to enhance circulating and tissue renin-angiotensin system activity. To explore whether AT2 plays a role in BP regulation, the BP effects of the selective AT2 and AT1 receptor antagonists PD123319 (PD) (50 microg/kg/min) and losartan (Los) (10 mg/kg/day), were studied. Seven rats were used as a control group. To define whether AT2 plays a role in the BP response observed during AT1 antagonism, 17 Los treated rats were divided into two groups: seven were treated with both antagonists (Los + PD) and 10 rats received Los + vehicle. The effects of both drugs were also studied in bilaterally nephrectomized rats (NX). All treatments were maintained for 1 week RESULTS: Los reduced BP significantly in both intact (P < 0.001) and NX (P < 0.05) rats, while PD increased BP in intact and NX rats (both P < 0.001). In the Los + PD group BP levels were significantly higher (P < 0.001 vs Los and Los + vehicle, P = ns vs pretreatment), while vehicle infusion did not modify the BP response to Los. CONCLUSION: The results show that in salt-restricted rats AT2 blockade offsets the BP-lowering effect of losartan and suggest that AT2 receptors contribute to the hypotensive effects of losartan. Thus, AT1 receptor antagonists such as losartan, which are becoming widely used in the clinical treatment of hypertension, may reduce BP not only by blockade of AT1 receptors, but also through the stimulation of AT2 receptors by the excess of angiotensin II.

Angiotensin II↗

PubMed1997

Intrarenal determinants of sodium retention in mild heart failure: effects of angiotensin-converting enzyme inhibition.

The onset and the mechanisms leading to Na+ retention in incipient congestive heart failure (CHF) have not been systematically investigated. To investigate renal Na+ handling in the early or mild stages of CHF, Na+ balance and renal clearances were assessed in 10 asymptomatic patients with idiopathic or ischemic dilated cardiomyopathy and mild heart failure (HF) off treatment (left ventricular ejection fraction, 29.7+/-2%) and in 10 matched normal subjects during a diet containing 100 mmol/d of NaCl and after 8 days of high salt intake (250 mmol/d). Six patients were studied again after 6 weeks of treatment with enalapril (5 mg/d P.O.). At the end of the high salt diet, in patients with mild HF the cumulative Na+ balance exceeded by 110 mmol that of normal subjects (F=3.86, P<.001). During high salt intake, renal plasma flow and glomerular filtration rate were similarly increased in both normal subjects and mild HF patients. In spite of comparable increases of filtered Na+ in the two groups, fractional excretion of Na+, fractional clearance of free water, and fractional excretion of K+ (indexes of distal delivery of Na+) increased in normal subjects and were reduced in patients with mild HF. During enalapril treatment, in the mild HF patients the cumulative Na+ balance was restored to normal; furthermore, enalapril significantly attenuated the abnormalities in the distal delivery of Na+. Our results indicate that a defective adaptation of Na+ reabsorption in the proximal nephron is associated with Na+ retention in response to increased salt intake in the early or mild stages of HF. These abnormalities of renal Na+ handling are largely reversed by enalapril.

Adult↗

PubMed1997

Opposite feedback control of renin and aldosterone biosynthesis in the adrenal cortex by angiotensin II AT1-subtype receptors.

The aims of this study were to identify whether tissue renin is regulated by a negative-feedback mechanism produced by locally generated angiotensin (Ang II) in the adrenal cortex and to detect the pathway of Ang II modulation. For this purpose, in 36 12-week old, salt-restricted, nephrectomized Sprague-Dawley rats, we studied the effects of the Ang II AT1-subtype receptor antagonist losartan and of the Ang II AT2-subtype receptor antagonist PD123319 on renin mRNA and activity, aldosterone synthase mRNA, and AT1a-, AT1b-, and AT2-subtype receptor expression in the adrenal cortex. Ten additional rats, kept on a regular diet and then nephrectomized, were also studied. In salt-restricted, nephrectomized rats, losartan administration caused increases of adrenal renin mRNA (P<.05) and activity (P<.05) and a concomitant reduction of aldosterone synthase mRNA (P<.05). In addition, after losartan AT1b, receptor mRNA was reduced (P<.05), AT1a receptor mRNA was unchanged, and AT2 mRNA was increased (P<.05). PD123319 did not significantly modify any of these parameters. In conclusion, in salt-restricted, nephrectomized rats, selective antagonism of AT1-subtype receptors stimulates the expression and the activity of renin in the adrenal cortex. This observation demonstrates that Ang II locally formed in the adrenal cortex exerts a modulatory negative-feedback action on adrenal renin biosynthesis independent of the influence of the circulating renin-Ang system; this action is largely mediated through the AT1b-subtype receptors.

Adrenal Cortex↗

PubMed1997

Role of tissue renin in the regulation of aldosterone biosynthesis in the adrenal cortex of nephrectomized rats.

The aim of the study was to investigate whether the adrenal renin-angiotensin system plays an independent role in the regulation of mineralocorticoid biosynthesis in the adrenal gland and to explore the mechanisms of this action. Twelve-week-old male Sprague-Dawley rats were studied: 22 rats were maintained on a regular diet; 27 and 22 rats received a low salt diet with and without treatment, respectively, with the angiotensin II (Ang II) AT1-subtype receptor antagonist losartan (10 mg/kg per day). A fraction of each group of rats underwent bilateral nephrectomy (n = 12, 15, and 10, respectively) and was killed 48 hours later. In an additional group of 24 (12 intact and 12 nephrectomized) rats, the effects of the Ang II AT2-subtype receptor antagonist PD123319 were investigated. In intact rats, plasma renin activity (PRA) and adrenal renin activity and expression were progressively raised by salt restriction and losartan, whereas aldosterone synthase mRNA and plasma aldosterone (PA) levels were increased by salt restriction and reduced by losartan. Forty-eight hours after nephrectomy, PRA fell to undetectable levels; in contrast, adrenal renin expression, assessed by semiquantitative reverse-transcriptase polymerase chain reaction (using GAPDH as a standard for gene expression), showed an 18-fold increase and was further increased after salt restriction and losartan (all P < .05). Also, adrenal renin activity was raised after nephrectomy and further increased after salt restriction (P < .05) and losartan. Cytochrome P450 aldosterone synthase expression in the adrenal cortex was stimulated by nephrectomy alone and by nephrectomy combined with low salt intake (P < .05), with consequent increases in PA concentrations. In losartan-treated salt-restricted nephrectomized rats, cytochrome P450 aldosterone synthase expression (P < .05 versus nephrectomy alone and nephrectomy plus salt restriction) and PA concentrations were diminished (P < .05) in spite of the observed increases of adrenal renin expression. The AT2-receptor antagonism did not significantly affect PRA, adrenal renin, and aldosterone biosynthesis and production in either intact or nephrectomized salt-restricted rats. These results demonstrate that the adrenal renin-angiotensin system plays an independent role in the regulation of mineralocorticoid biosynthesis in vivo. This action is mediated primarily via the Ang II AT1-subtype receptors.

Adrenal Glands↗

PubMed1995

Regulation of 11 beta-hydroxylase cytochrome p450 expression by cholesterol in spontaneously hypertensive rats.

OBJECTIVE: To investigate whether hypercholesterolaemia interferes with the expression of the enzymes involved in steroid biosynthesis in the adrenal cortex. METHODS: Twenty-four 5-week-old male spontaneously hypertensive rats (SHR) were randomly assigned to a high (1%) cholesterol diet (n = 8) or to a matched cholesterol-free diet (n = 8) for 6 weeks. A third group (n = 8) was studied after 2 weeks of washout from the high-cholesterol intake. A cohort of age- and sex-matched normotensive Wistar-Kyoto (WKY) rats (n = 24) underwent the same treatments and was used as a control. RESULTS: In SHR cholesterol feeding reduced urinary sodium excretion (0.8 +/- 0.1 versus 1.4 +/- 0.1 mmol/24 h in the cholesterol-free group), increased plasma aldosterone levels (299 +/- 60 versus 154 +/- 24) and reduced plasma corticosterone levels (142 +/- 21 versus 278 +/- 35 ng/ml). Those responses were associated with a reduction of 11 beta-hydroxylase cytochrome P450 messenger RNA (mRNA) in the adrenal cortex (-52.3 +/- 3.4%) whereas aldosterone synthase mRNA remained unchanged. That effect and the changes in electrolyte excretion and steroid levels were no longer detectable after withdrawal of the diet. In WKY rats high-cholesterol diet induced no significant changes in urinary electrolyte excretion, steroid levels and expression of 11 beta-hydroxylase cytochrome P450 and aldosterone synthase in the adrenals. CONCLUSIONS: The present results indicate that in SHR hypercholesterolaemia selectively interferes with the adrenal steroid biosynthetic pathway by reducing the expression of 11 beta-hydroxylase, leading to accumulation of mineralocorticoids and sodium retention.

Adrenal Cortex↗