Biomedical subjects

Chana Yagil

Publications and source records attributed to Chana Yagil.

23 records · Page 2Linked to original sources

PubMed2002

Endothelin-A receptor blockade prevents left ventricular hypertrophy and dysfunction in salt-sensitive experimental hypertension.

BACKGROUND: Salt-sensitive hypertension represents a major cause of left ventricular (LV) dysfunction. We therefore explored the potential effects of the selective endothelin-A (ETA) receptor antagonist darusentan on the development of hypertension, LV hypertrophy (LVH), and dysfunction in a genetic rat model of salt-sensitive hypertension. METHODS AND RESULTS: Animals from the salt-sensitive Sabra rat strain (SBH/y) and the salt-resistant strain (SBN/y) were treated with either normal diet (SBH/y and SBN/y) or with deoxycorticosterone-acetate (DOCA) and salt (SBN/y-DOCA and SBH/y-DOCA). Additional groups were treated with 50 mg x kg(-1) x d(-1) of darusentan (SBH/y-DOCA-DA and SBN/y-DOCA-DA). Systolic blood pressure and LV weight increased in response to DOCA only in the SBH/y strain (+75 mm Hg and +30%; P<0.05). LV end-diastolic pressure increased and -dP/dtmax decreased in SBH/y-DOCA compared with SBH/y (P<0.05). This was paralleled by a 5-fold upregulation of LV mRNA expression of atrial natriuretic factor (ANF) and a significant reduction of sarcoplasmic reticulum (SR) Ca2+-reuptake and the SR Ca2+-ATPase to phospholamban protein ratio (-30%). Whereas treatment with darusentan in SBH/y-DOCA-DA reduced the SBP increase by 50%, LVH elevation of ANF mRNA and LV dysfunction were completely prevented (P<0.05); this was associated with a normalization of SR Ca2+-reuptake and SR Ca2+-ATPase to phospholamban ratio by darusentan (P<0.05). A moderate elevation of interstitial fibrosis in SBH/y-DOCA (P<0.05) remained unaffected by darusentan treatment. CONCLUSION: In the Sabra model of salt-sensitive hypertension, ETA-receptor blockade demonstrated striking effects on the prevention of LVH and LV dysfunction beyond its considerable antihypertensive effect.

Animals↗

PubMed2002

Angiotensin-converting enzyme 2 is an essential regulator of heart function.

Cardiovascular diseases are predicted to be the most common cause of death worldwide by 2020. Here we show that angiotensin-converting enzyme 2 (ace2) maps to a defined quantitative trait locus (QTL) on the X chromosome in three different rat models of hypertension. In all hypertensive rat strains, ACE2 messenger RNA and protein expression were markedly reduced, suggesting that ace2 is a candidate gene for this QTL. Targeted disruption of ACE2 in mice results in a severe cardiac contractility defect, increased angiotensin II levels, and upregulation of hypoxia-induced genes in the heart. Genetic ablation of ACE on an ACE2 mutant background completely rescues the cardiac phenotype. But disruption of ACER, a Drosophila ACE2 homologue, results in a severe defect of heart morphogenesis. These genetic data for ACE2 show that it is an essential regulator of heart function in vivo.

Angiotensin II↗

PubMed2002

Proteinuria and glomerulosclerosis in the Sabra genetic rat model of salt susceptibility.

In search of an experimental model that would simulate the association between proteinuria and salt sensitivity in humans, we studied protein excretion in the Sabra rat model of salt susceptibility. Monthly measurements of urinary protein excretion in animals fed standard rat chow revealed that normotensive salt-sensitive SBH/y developed proteinuria that averaged 65 +/- 7 mg/day (n = 10) at 9 mo, whereas proteinuria in normotensive salt-resistant SBN/y was 39 +/- 4 mg/day (n = 10) (P < 0.01). Histopathological evaluation revealed focal and segmental glomerulosclerosis (FSGS) lesions grade 2 in SBH/y and normal histology in SBN/y. To amplify the differences between the strains, uninephrectomy was performed. At 9 mo, proteinuria in SBH/y with one kidney (SBH/y-1K) was 195 +/- 12 mg/day (n = 10) and in SBN/y was 128 +/- 10 mg/day (n = 10) (P < 0.001); histopathology revealed FSGS grade 3 in SBH/y-1K and grade 1-2 in SBN/y-1K. To determine the effect of salt loading, animals were provided with 8% NaCl in chow, causing hypertension in SBH/y but not in SBN/y. Proteinuria markedly increased in both SBH/y with two kidneys (SBH/y-2K) and SBH/y-1K, but not in SBN/y; histopathology revealed FSGS grade 1-2 in SBH/y-2K, grade 2 in SBH/y-1K, no lesions in SBN/y-2K, and grade 0-1 in SBN/y-1K. We concluded that the SBH/y strain is more susceptible to develop proteinuria and glomerulosclerosis than SBN/y. In search for the genetic basis of this phenomenon, we investigated the role of candidate proteinuric gene loci. Consomic strains were constructed by introgressing chromosome 1 (which harbors the rf-1 and rf-2 proteinuric loci) or chromosome 17 (which harbors rf-5) from SBH/y onto the SBN/y genomic background. The resulting consomic strains developed marked proteinuria that was severalfold higher than in SBN/y-1K; histopathological evaluation, however, revealed FSGS lesions grade 1-2, similar to those found in SBN/y-1K and less severe than in SBH/y-1K. These results suggest a functional role of gene systems located on chromosomes 1 and 17 in inducing proteinuria in the salt-susceptible Sabra rat strain. These genetic loci do not appear to harbor major genes for glomerulosclerosis.

Age Factors↗

PubMed2002

Insights into pharmacogenomics and its impact upon immunosuppressive therapy.

The advent of the genomic era has brought about several new fields of study, one of them being pharmacogenomics, which seeks to link drug treatment (pharmaco-) with the individual's genetic make-up (genomics). Pharmacogenomics holds many promises for improved treatment of a large variety of medical conditions, including immunosuppression for organ transplantation and autoimmune disease. Many of these promises have, however, not yet been fulfilled. In this brief overview of the subject, we attempt to provide insights into the evolving field of pharmacogenomics and discuss some of its potential benefits and promises, technological tools used by pharmacogenomics, the reasons for delays in breakthroughs in the field, and the relevance of pharmacogenornics to immunosuppression.

Animals↗

PubMed2001

Impaired function of endothelial pressure-activated cation channel in salt-sensitive genetic hypertension.

Mechanosensitive ion channels have been suggested to act as endothelial mechanosensors for hemodynamic forces. The present study tested the hypothesis that the pressure-activated cation channel (PAC), a novel type of endothelial mechanosensitive ion channel, is involved in salt sensitivity in the Sabra rat model of hypertension. Groups of Sabra salt-sensitive (SBH/y) and salt-resistant (SBN/y) rats were loaded with deoxycorticosterone-acetate (DOCA)-salt for 8 wk or were fed a regular diet. Single channel function of PAC in SBH/y and SBN/y rats was investigated in intact endothelium of mesenteric artery using the patch-clamp technique. After DOCA-salt treatment, the SBH/y rats showed a full hypertensive response, whereas SBN/y rats were normotensive. Rats of both strains that received a regular diet were normotensive. In endothelium of both Sabra rats, Ca(2+) permeable PAC that was activated by positive pipette pressures was identified. Apparent PAC density (percentage of patches with PAC activity) was reduced in hypertensive SBH/y rats that were loaded with DOCA-salt compared with salt-loaded normotensive SBN/y rats (6 +/- 2% versus 24 +/- 8%, respectively; P < 0.05). In normotensive SBH/y and SBN/y rats that received a regular diet, PAC density was not altered. Mechanosensitivity and unitary conductance of endothelial PAC were similar in both strains under a regular diet as well as salt loading with DOCA-salt. In conclusion, the decreased density of PAC in mesenteric endothelium from hypertensive SBH/y rats indicates an impaired ion channel regulation. The defective PAC function presumably leads to an impaired mechanosensitive Ca(2+) entry and might contribute to endothelial dysfunction and high BP in this type of salt-sensitive genetic hypertension.

Animals↗