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J Díez

Publications and source records attributed to J Díez.

At least 55 records · Page 3Linked to original sources
PubMed2000

Chronic AT(1) blockade stimulates extracellular collagen type I degradation and reverses myocardial fibrosis in spontaneously hypertensive rats.

It has been suggested that left ventricular fibrosis in spontaneously hypertensive rats (SHR) is the result of both exaggerated collagen synthesis and insufficient collagen degradation. We have shown previously that chronic treatment with the angiotensin II type 1 receptor antagonist losartan results in diminished synthesis of collagen type I molecules and reversal of myocardial fibrosis in SHR. This study was designed to investigate whether losartan also affects the extracellular degradation of collagen type I fibers in the left ventricle of SHR. The study was performed in 30-week-old normotensive Wistar-Kyoto rats (WKY), untreated SHR, and SHR treated with orally administered losartan (20 mg/kg per day) for 14 weeks before they were killed. Ventricular collagenase activity was determined by degradation of [(14)C]collagen with tissue extracts. Ventricular expression of tissue inhibitor of metalloproteinases 1 (TIMP-1) mRNA was analyzed by Northern blot. A histomorphometric study of the left ventricle was performed in all rats. Compared with WKY, SHR exhibited left ventricular hypertrophy, increased (P<0.05) blood pressure, left ventricular collagen volume fraction and TIMP-1 mRNA, and diminished (P<0.05) collagenase activity. After the treatment period, blood pressure was higher (P<0.05) in losartan-treated SHR than in WKY, and no significant differences were noted in the remaining parameters between the 2 strains of rats. Compared with untreated SHR, treated SHR showed no left ventricular hypertrophy, diminished (P<0.05) blood pressure, left ventricular collagen volume fraction and TIMP-1 mRNA, and increased (P<0.05) collagenase activity. These results suggest that the transcription of the TIMP-1 gene is upregulated in the hypertrophied and fibrotic left ventricle of adult SHR. Upregulation of TIMP-1 may account for diminished collagenase activity in the myocardium of those rats. Chronic angiotensin II type 1 receptor blockade with losartan resulted in inhibition of TIMP-1 expression and stimulation of collagenase activity in the left ventricle of SHR. It is proposed that angiotensin II may facilitate myocardial fibrosis in SHR by depressing the collagenase-mediated extracellular degradation of collagen fibers.

Angiotensin Receptor Antagonists↗
PubMed2000

Transforming growth factor beta in hypertensives with cardiorenal damage.

We investigated whether a relationship exists between circulating transforming growth factor beta -1 (TGF-beta(1)), collagen type I metabolism, microalbuminuria, and left ventricular hypertrophy in essential hypertension and whether the ability of the angiotensin II type 1 receptor antagonist losartan to correct microalbuminuria and regress left ventricular hypertrophy in hypertensives is related to changes in TGF-beta(1) and collagen type I metabolism. The study was performed in 30 normotensive healthy controls and 30 patients with never-treated essential hypertension classified into 2 groups: those with microalbuminuria (urinary albumin excretion >30 and <300 mg/24 h) associated with left ventricular hypertrophy (left ventricular mass index >116 g/m(2) for men and >104 g/m(2) for women) (group B; n=17) and those without microalbuminuria or left ventricular hypertrophy (group A; n=13). The measurements were repeated in all patients after 6 months of treatment with losartan (50 mg once daily). The serum concentration of TGF-beta(1) was measured by a 2-site ELISA method, and the serum concentrations of carboxy-terminal propeptide of procollagen type I (a marker of collagen type I synthesis) and carboxy-terminal telopeptide of collagen type I (a marker of collagen type I degradation) were measured by specific radioimmunoassays. The duration of hypertension and baseline values of blood pressure were similar in the 2 groups of patients. No differences in serum TGF-beta(1), carboxy-terminal propeptide of procollagen type I, and carboxy-terminal telopeptide of collagen type I were found between normotensives and group A of hypertensives. Serum TGF-beta(1), carboxy-terminal propeptide of procollagen type I, and the ratio of carboxy-terminal propeptide of procollagen type I to carboxy-terminal telopeptide of collagen type I were increased (P<0.05) in group B of hypertensives compared with group A of hypertensives and normotensives. No differences in carboxy-terminal telopeptide of collagen type I were found among the 3 groups of subjects. After treatment with losartan, microalbuminuria and left ventricular hypertrophy persisted in 6 patients (then considered nonresponders) and disappeared in 11 patients (then considered responders) from group B. Compared with nonresponders, responders exhibited similar control of blood pressure and higher (P<0.05) blockade of angiotensin II type 1 receptors (as assessed by a higher increase in plasma levels of angiotensin II). Whereas TGF-beta(1), carboxy-terminal propeptide of procollagen type I, and the ratio of carboxy-terminal propeptide of procollagen type I to carboxy-terminal telopeptide of collagen type I decreased (P<0.05) in responders, no changes in these parameters were observed in nonresponders. These findings show that an association exists between an excess of TGF-beta(1), stimulation of collagen type I synthesis, inhibition of collagen type I degradation, and cardiorenal damage in a group of patients with essential hypertension. In addition, our results suggest that the ability of losartan to blunt the synthesis of TGF-beta(1) and normalize collagen type I metabolism may contribute to protect the heart and the kidney in a fraction of patients with essential hypertension.

Albuminuria↗
PubMed2000

Mechanisms of increased susceptibility to angiotensin II-induced apoptosis in ventricular cardiomyocytes of spontaneously hypertensive rats.

Previous findings have shown that hypotensive doses of losartan prevent the excess of apoptosis present in the hypertrophied left ventricle of adult spontaneously hypertensive rats (SHR). This study was designed to determine whether angiotensin II facilitates apoptosis in cardiomyocytes of adult SHR. Primary cultures of ventricular cardiomyocytes from 30-week-old normotensive Wistar-Kyoto rats (WKY) and SHR with left ventricular hypertrophy were exposed to 10(-)(9) mol/L angiotensin II for 24 hours. Apoptotic cells were assessed by terminal deoxynucleotidyl transferase assay and confirmed by Annexin V detection. The expression of Bax-alpha, Bcl-2, p53, and caspase-3 proteins was assessed by Western blot assays. The expression of BAX gene was assessed by Northern blot. Angiotensin II increased (P<0.01) cardiomyocyte apoptosis, and this effect was higher (P<0.001) in SHR cells than in WKY cells. Whereas losartan (10(-7) mol/L) blocked the apoptotic effect of the octapeptide in cells from the two strains of rats, PD123319 (10(-7) mol/L) inhibited angiotensin II-mediated apoptosis only in SHR cells. Angiotensin II stimulated (P<0.01) Bax-alpha protein, and this effect was higher (P<0.01) in SHR cells than in WKY cells. Angiotensin II did not modify Bcl-2, p53, and BAX mRNA in cells from the two strains of rats. Angiotensin II induced a similar increase (P<0.05) in the ratio caspase-3/procaspase-3 (an index of caspase-3 activation) in cardiomyocytes from the two strains of rats. The present in vitro results indicate that SHR cardiomyocytes exhibit enhanced susceptibility to angiotensin II-induced apoptosis. Ligand binding to angiotensin II type 1 and type 2 receptors leading to changes in posttranscriptional processing of Bax-alpha and accumulation of this proapoptotic protein may be involved in the abnormal response of SHR cardiomyocytes. These data support a role for angiotensin II in apoptosis observed in the left ventricle of these rats.

Angiotensin II↗
PubMed2000

[Biochemical diagnosis of hypertensive myocardial fibrosis].

A substantial increase in fibrillar collagen has been observed in the left cardiac ventricle of animals and humans with arterial hypertension. Hypertensive myocardial fibrosis is the result of both increased collagen types I and III due to the fact that its synthesis by fibroblasts and myofibroblasts is stimulated and its extracellular collagen degradation unchanged or decreased extracellular collagen degradation. Hemodynamic and non-hemodynamic factors may be involved in the disequilibrium between collagen synthesis and degradation that occurs in hypertension. As shown experimentally and clinically, an exaggerated rise in fibrillar collagen content promotes abnormalities of cardiac function, contributes to the decrease in coronary reserve and facilitates alterations in the electrical activity of the left ventricle. Although microscopic examination of cardiac biopsies is the most reliable method for documenting and measuring myocardial fibrosis, the development of non-invasive methods to indicate the presence of myocardial fibrosis in hypertensive patients would be useful. We have therefore applied a biochemical method based on the measurement of serum peptides derived from the tissue formation when synthesized and degradation of fibrillar collagens to monitor the turnover of these molecules in rats with spontaneous hypertension and patients with essential hypertension.

Endomyocardial Fibrosis↗
PubMed1999

In vitro evidence for RNA binding properties of the coat protein of prunus necrotic ringspot ilarvirus and their comparison to related and unrelated viruses.

The RNA binding properties of the prunus necrotic ringspot virus (PNRSV) coat protein (CP) were demonstrated by northwestern and dot-blot analyses. The capability to bind PNRSV RNA 4 was compared with viruses representing three different interactions prevailing in the assembly and architecture of virions. The results showed that cucumber mosaic virus (CMV) and PNRSV CPs, which stabilise their virions mainly through RNA-protein interactions bound PNRSV RNA 4 even at very high salt concentrations. The CP of cherry leaf roll nepovirus, whose virions are predominantly stabilised by protein-protein interactions did not bind even at the lowest salt concentration tested. Finally the CP of carnation mottle carmovirus, that has an intermediate position in which both RNA-protein and protein-protein interactions are equally important showed a salt-dependent RNA binding.

Bromoviridae↗
PubMed1999

Characterization and in vitro translation analysis of pelargonium flower break virus.

Pelargonium flower break virus (PFBV) is one of the common viruses in the glasshouses of Western Europe and has been assigned to the genus Carmovirus. A Spanish isolate obtained from nursery-grown Pelargonium zonale plants (PFBV-m) has been characterized. The molecular weight of genomic RNA and coat protein of PFBV-m were determined to be 1.36 x 10(6) (corresponding to approximately 4 kb) and 36,000, respectively. Only genomic-size RNA was encapsidated in PFBV virions; making necessary to purify double-stranded RNA from infected tissue in order to detect putative PFBV subgenomic RNAs. PFBV RNA directed the synthesis of a major polypeptide of 34 kDa and three other relevant polypeptides of estimated sizes 88-90 kDa, 42 kDa and 35-36 kDa. Antisera specific to PFBV immunoprecipitated the in vitro translated 35-36 kDa polypeptide indicating that this polypeptide is the PFBV coat protein. The PFBV in vitro translation pattern was very similar to that of CarMV although the relative levels of translated coat protein differed dramatically between the two viruses, most probably due to the lack of encapsidation of subgenomic PFBV. In vitro translation studies with a different biological clone obtained from the same PFBV-m isolate revealed a prominent additional polypeptide which is postulated to be a truncation of the 5' proximal ORF.

Carmovirus↗
PubMed1999

Losartan inhibits the post-transcriptional synthesis of collagen type I and reverses left ventricular fibrosis in spontaneously hypertensive rats.

OBJECTIVE: Previous studies have shown that as well as left ventricular hypertrophy, myocardial fibrosis develops early in rats with spontaneous hypertension (SHR). The present study was designed to investigate whether chronic treatment with the angiotensin II type 1 (AT1) receptor antagonist losartan modifies collagen type I metabolism and reverses left ventricular fibrosis in young SHR with left ventricular hypertrophy. DESIGN: The study was performed in 30-week-old normotensive Wistar-Kyoto (WKY) rats, untreated SHR and SHR treated with losartan (20 mg/mg per day, orally) for 14 weeks before they were killed. METHODS: Ventricular pro-alpha 1 (I) collagen messenger RNA was analyzed by Northern blot. Serum levels of the carboxy-terminal propeptide of procollagen type I (PIP) and the pyridoline cross-linked telopeptide domain of collagen type I (CITP) were determined by specific radioimmunoassays as markers of collagen type I synthesis and degradation, respectively. Collagen volume fraction was determined in the left ventricle by quantitative morphometry. RESULTS: Compared with WKY rats, SHR exhibited increased (P < 0.05) mean arterial pressure, pro-alpha 1 (I) collagen messenger RNA, PIP and left ventricular collagen volume fraction, and similar CITP values. After the treatment period, mean arterial pressure was higher (P < 0.05) in losartan-treated SHR than in WKY rats. Compared with untreated SHR, treated SHR showed no left ventricular hypertrophy and diminished (P < 0.05) values of mean arterial pressure, PIP and left ventricular collagen volume fraction. No changes in pro-alpha 1 (I) collagen messenger RNA and CITP values were observed with treatment in SHR. No significant differences in the left ventricular collagen volume fraction were observed between treated SHR with normal blood pressure and treated SHR with abnormally high blood pressure at the end of the treatment period. CONCLUSIONS: These results suggest that chronic AT1 blockade with losartan decreases the post-transcriptional synthesis of fibril-forming collagen type I molecules in young SHR. This effect may be involved in the ability of this drug to reverse left ventricular fibrosis in young rats with genetic hypertension. Apart from its antihypertensive action, other mechanisms may mediate the antifibrotic effect of losartan in this animal model.

Animals↗
PubMed1999

p53-mediated upregulation of BAX gene transcription is not involved in Bax-alpha protein overexpression in the left ventricle of spontaneously hypertensive rats.

An association of increased apoptosis with overexpression of the proapoptotic protein Bax-alpha has been reported in the left ventricle of adult spontaneously hypertensive rats (SHR). Both alterations were corrected in SHR that received long-term treatment with the AT1 antagonist losartan. To gain insight into the regulation of cardiac Bax-alpha protein in genetic hypertension, we investigated the expression of the protein p53 (a BAX gene transcription factor) and BAX mRNA in the left ventricle of 30-week-old Wistar-Kyoto rats (WKY), SHR, and SHR treated with losartan (20 mg. kg-1. d-1) during 14 weeks before death. The expression of p53 and Bax proteins was assessed by Western blot analysis. The expression of BAX mRNA was assessed by Northern blot analysis. The density of apoptotic cells was assessed by direct immunoperoxidase detection of biotin-labeled deoxyuridine nucleotides. Compared with WKY, untreated SHR exhibited increased apoptosis (P<0.05), increased Bax-alpha protein (P<0.05), and similar levels of p53 protein and BAX mRNA. Losartan given long term was associated with the normalization of apoptosis and Bax-alpha protein expression. The expression of BAX mRNA was decreased (P<0. 05) in treated SHR compared with untreated SHR. No changes in the expression of p53 protein were observed in losartan-treated SHR. These results suggest that overexpression of the Bax-alpha protein seen in the left ventricle of adult SHR with increased apoptosis is not related to a p53-mediated upregulation of BAX gene transcription. Our data also suggest that normalization of Bax-alpha protein observed in SHR after long-term blockade of angiotensin II type 1 receptors may be due to the inhibition of BAX gene transcription.

Animals↗
PubMed1999

Torasemide inhibits angiotensin II-induced vasoconstriction and intracellular calcium increase in the aorta of spontaneously hypertensive rats.

Torasemide is a loop diuretic that is effective at low once-daily doses in the treatment of arterial hypertension. Because its antihypertensive mechanism of action may not be based entirely on the elimination of salt and water from the body, a vasodilator effect of this drug can be considered. In the present study, the ability of different concentrations of torasemide to modify angiotensin II (Ang II)-induced vascular responses was examined, with the use of an organ bath system, in endothelium-denuded aortic rings from spontaneously hypertensive rats. Ang II-induced increases of intracellular free calcium concentration ([Ca(2+)](i)) were also examined by image analysis in cultured vascular smooth muscle cells (VSMCs) from spontaneously hypertensive rats. A dose-response curve to Ang II was plotted for cumulative concentrations (from 10(-9) to 10(-6) mol/L) in endothelium-denuded aortic rings (pD(2)=7.5+/-0.3). Isometric contraction induced by a submaximal concentration of Ang II (10(-7) mol/L) was reduced in a dose-dependent way by torasemide (IC(50)=0.5+/-0.04 micromol/L). Incubation of VSMCs with different concentrations of Ang II (from 10(-10) to 10(-6) mol/L) resulted in a dose-dependent rise of [Ca(2+)](i) (pD(2)=7.5+/-0.3). The stimulatory effect of [Ca(2+)](i) induced by a submaximal concentration of Ang II (10(-7) mol/L) was blocked by torasemide (IC(50)=0.5+/-0.3 nmol/L). Our findings suggest that torasemide blocks the vasoconstrictor action of Ang II in vitro. This action can be related to the ability of torasemide to block the increase of [Ca(2+)](i) induced by Ang II in VSMCs. It is proposed that these actions might be involved in the antihypertensive effect of torasemide observed in vivo.

Angiotensin II↗
PubMed1999

[Sensitivity of group A beta-hemolytic Streptococcus isolated from pediatric pharyngotonsillitis to erythromycin and clarithromycin: a primary care multicenter study].

BACKGROUND: The recent increase in the prevalence of macrolide-resistant group A beta-haemolytic Streptococcus (BHSGA) strains reported in some areas in Spain and several neighboring countries underscores the need to perform a periodic surveillance, with the adequate methodology, of the level of its susceptibility to these antimicrobials which are frequently used in our country for the treatment of acute streptococcal pharingotonsillitis and respiratory tract infections. PATIENTS AND METHODS: The susceptibility of 293 isolates of BHSGA to the macrolides erythromycin and clarithromycin was evaluated by the broth microdilution procedure recommended by the NCCLS (1997). The isolates were prospectively obtained from children with acute pharyngotonsillitis (n = 757) who were seen at primary care centers in ten Spanish cities. RESULTS: An overall prevalence of 8.9 and 7.8% erythromycin- and clarithromycin-resistant BHSGA isolates was respectively found. The percentage of resistant isolates varied considerably among the different cities subjected to study (0-33%). Overall, the intrinsic activity of clarithromycin (MIC50 and MIC90 of 0.007 and 0.25 mg/ml, respectively) was slightly higher than that of erythromycin (MIC50 and MIC90 of 0.015 and 0.5 mg/ml, respectively). All strains studied were uniformly susceptible to penicillin. CONCLUSIONS: Macrolide antibiotics, erythromycin and clarithromycin, continue to be highly active against BHSGA. The mean level of resistant strains found in Spain from community acquired infections and recovered prospectively is comparable to that of our neighboring countries.

Adolescent↗
PubMed1999

[Apoptosis in hypertensive cardiopathy].

Numerous hypothesis have been considered to explain the fundamental mechanism(s) for the development of systolic dysfunction and heart failure in animals and humans with arterial hypertension. Besides contractile disturbances of cardiomyocytes and interstitial and perivascular fibrosis, cardiomyocyte loss is now being considered as one of the determinant factors of the maladaptive processes implicated in the transition from compensated to decompensated left ventricular hypertrophy. Much experimental evidence suggests that exaggerated apoptosis may account for the loss of cardiomyocytes in the hypertensive left ventricle. Furthermore, some factors intrinsic and extrinsic to the cardiomyocyte have emerged recently as potential candidates to trigger apoptosis. The elucidation of the possible interactions between these factors may be of major interest to prevent the progression to heart failure in patients with hypertensive heart disease.

Adult↗
PubMed1998

Abnormalities of the extracellular degradation of collagen type I in essential hypertension.

BACKGROUND: This study was designed to investigate whether collagen type I degradation is altered in patients with essential hypertension and whether this alteration could be related to disturbances in the serum matrix metalloproteinase pathway of collagen degradation. A second aim of the study was to assess whether some relation exists between serum markers of collagen type I degradation and left ventricular hypertrophy in hypertensive patients. METHODS AND RESULTS: We measured serum concentrations of carboxy-terminal telopeptide of collagen type I (CITP) as a marker of extracellular collagen type I degradation, of total matrix metalloproteinase-1 (MMP-1), or collagenase, of total tissue inhibitor of metalloproteinases 1 (TIMP-1), and of MMP-1/TIMP-1 complex in 37 patients with never-treated essential hypertension and in 23 normotensive control subjects. Serum concentrations of free MMP-1 and free TIMP-1 were calculated by subtracting the values of MMP-1/TIMP-1 complex from the values of total MMP-1 and total TIMP-1, respectively. Measurements were repeated in 26 hypertensive patients after 1 year of treatment with the ACE inhibitor lisinopril. Baseline free MMP-1 was decreased (P<0.001) and baseline free TIMP-1 was increased (P<0.001) in hypertensives compared with normotensives. No significant differences were observed in the baseline values of CITP between the 2 groups of subjects. Hypertensive patients with baseline left ventricular hypertrophy exhibited lower values of free MMP-1 (P<0.01) and CITP (P<0.05) and higher (P<0.001) values of free TIMP-1 than hypertensive patients without baseline left ventricular hypertrophy. Treated patients attained an increase (P<0.001) in free MMP-1 and a decrease (P<0.05) in free TIMP-1. In addition, serum CITP was increased (P<0.05) in treated hypertensives compared with normotensive subjects. CONCLUSIONS: These findings suggest that systemic extracellular degradation of collagen type I is depressed in patients with essential hypertension and can be normalized by treatment with lisinopril. A depressed degradation of collagen type I may facilitate organ fibrosis in hypertensive patients, namely, in those with left ventricular hypertrophy.

Adult↗
PubMed1998

Decreased excretion of nitrate and nitrite in essential hypertensives with renal vasoconstriction.

Most hypertensive patients exhibit increased renal vascular resistance (RVR). This study was designed to investigate whether there exists any relationship between RVR and the production of nitric oxide (NO) in patients with essential hypertension. The study was performed in 49 non-treated patients with mild-to-moderate essential hypertension, and 20 age- and sex-matched normotensive subjects on a controlled sodium diet. Renal hemodynamics was measured in terms of the clearance of para-aminohippuric acid and inulin. Urinary excretion of nitrate and nitrite (NO3- plus NO2-) was determined as an index of NO production. As compared with normotensives, hypertensive patients exhibited higher (P < 0.001) RVR and lower (P < 0.05) urinary excretion of NO3- plus NO2-. With the 100% confidence (upper) limit of the normotensive population as a cut-off point, a subgroup of 30 hypertensives had an abnormally high RVR. The excretion of NO3- plus NO2- was lower (P < 0.005) in hypertensives with high RVR than in normotensives and the remaining hypertensives. No differences were found in the urinary excretion of NO3- plus NO2- between normotensives and hypertensives with normal RVR. Statistically significant associations were seen between diastolic blood pressure and RVR (r = 0.341, P < 0.05) and urinary excretion of NO3- plus NO2- (r = -0.387, P < 0.01) in all hypertensives. These results indicate that there is a subgroup (61%) of hypertensive patients with diminished urine levels of NO3- plus NO2- in which RVR is abnormally increased. Thus, it is suggested that in essential hypertension a diminished renal ability to produce NO by the endothelium may be involved in exaggerated renal vasoconstriction.

Endothelium, Vascular↗
PubMed1998

Apoptosis in hypertensive heart disease.

Numerous hypotheses have been considered to explain the fundamental mechanism(s) for the development of systolic dysfunction and heart failure in animals and humans with arterial hypertension. Besides contractile disturbances of cardiomyocytes and interstitial and perivascular fibrosis, cardiomyocyte loss is now being considered as one of the determinants of the maladaptive processes implicated in the transition from compensated to decompensated left ventricular hypertrophy. A number of experimental evidence suggest that exaggerated apoptosis may account for the loss of cardiomyocytes in the hypertensive left ventricle. Furthermore, some factors intrinsic and extrinsic to the cardiomyocyte emerge as potential candidates to trigger apoptosis. The elucidation of the possible interactions between these factors may be of major interest to prevent the progression to heart failure in patients with hypertensive heart disease.

Animals↗
PubMed1998

Tissue availability of insulin-like growth factor I is inversely related to insulin resistance in essential hypertension: effects of angiotensin converting enzyme inhibition.

BACKGROUND: The insulin-like growth factor I possesses biologic actions that resemble those of insulin. Tissue access of the factor depends on the distribution of the circulating bound factor between its binding protein 3 that remains within the intravascular space and its binding protein I that is able to cross the endothelium. Preliminary results have shown that tissue availability of insulin-like growth factor I is a determinant of glucose regulation in essential hypertension OBJECTIVE: To investigate whether the tissue availability of circulating insulin-like growth factor I in patients with essential hypertension is related to insulin resistance and whether chronic angiotensin converting enzyme inhibition influences tissue availability of the factor and insulin resistance in these patients. DESIGN AND METHODS: We studied 29 patients with essential hypertension and 20 age-matched and sex-matched normotensive subjects. The measurements were repeated for 25 patients after 12 months of treatment with lisinopril. Tissue availability of circulating insulin-like growth factor I was assessed by analyzing its distribution between its binding proteins 3 and 1. An insulin resistance index was estimated using the homeostasis model analysis of fasting insulin-glucose interactions. Levels of serum insulin-like growth factor I binding proteins 3 and 1, plasma insulin-like growth factor I, and insulin were determined by specific radioimmunoassays. RESULTS: Baseline insulin resistance index was significantly higher in the hypertensive patients than it was in the normotensive controls. With the upper 100% confidence limit of the normotensive population as the cutoff point, a subgroup of 12 hypertensives had an abnormally high insulin resistance index. Compared with patients with normal insulin resistance indexes, patients with greater than normal indexes were characterized by lower binding protein 1 levels, similar binding protein 3 levels, lower binding protein 1 : binding protein 3 ratio and similar insulin-like growth factor I levels. The serum binding protein 1 level and the binding protein 1 : binding protein 3 ratio were inversely correlated to the insulin resistance index for the whole group of hypertensives. After treatment with lisinopril hypertensive patients with higher than normal insulin resistance indexes at baseline exhibited normalization of this parameter and significant increases of binding protein 1 levels and binding protein 1 : binding protein 3 ratio, with no significant changes in insulin-like growth factor I levels. These parameters remained unchanged for the remaining patients. CONCLUSIONS: These results suggest that tissue availability of circulating insulin-like growth factor I is a determinant of insulin sensitivity in patients with essential hypertension. Whereas the patients with normal insulin sensitivity exhibit greater than normal tissue access of circulating insulin-like growth factor I, patients with insulin resistance present normal tissue access of the factor. Our findings suggest that the ability of angiotensin converting enzyme inhibitors to restore insulin sensitivity in essential hypertensives may be related to their ability to facilitate the tissue availability of circulating insulin-like growth factor I.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1998

Overexpression of Bax protein and enhanced apoptosis in the left ventricle of spontaneously hypertensive rats: effects of AT1 blockade with losartan.

An association of increased apoptosis with overactivity of the local angiotensin-converting enzyme has been reported in cells from the left ventricle of adult rats with spontaneous hypertension (SHR). To gain insight into the regulation of cardiac apoptosis in arterial hypertension, we investigated the expression of the proteins Bcl-2 (an inhibitor of apoptosis) and Bax (an inducer of apoptosis) in the left ventricle of 30-week-old normotensive Wistar-Kyoto rats (WKY), SHR, and SHR treated with the angiotensin II type 1 receptor (AT1) antagonist losartan (20 mg x kg(-1) x d(-1)) during 14 weeks before death. The density of apoptotic cells was assessed by direct immunoperoxidase detection of biotin-labeled deoxyuridin nucleotides. The expression of Bcl-2 and Bax was assessed by Western blot analysis. Compared with WKY, untreated SHR exhibited increased (P<0.05) apoptosis, increased (P<0.01) Bax, and similar Bcl-2. The Bcl-2/Bax ratio (an inverse index of cell susceptibility to apoptosis) was lower (P<0.05) in untreated SHR than in WKY. The chronic administration of losartan was associated with the normalization of apoptosis, Bax expression, and the Bcl-2/Bax ratio in treated SHR. No changes in the expression of Bcl-2 were observed in these rats after treatment. No significant changes in the apoptotic density were observed between treated SHR with normal blood pressure and treated SHR with abnormally high blood pressure at the end of the treatment period. These results suggest that an association exists between increased apoptosis and overexpression of Bax oncoprotein in cells from the left ventricle of adult SHR. Chronic blockade of AT1 receptors prevents Bax overexpression and normalizes apoptosis in the left ventricle of SHR independently of its hemodynamic effect. On the basis of our findings, it can be proposed that the interaction of angiotensin II with its AT1 receptors may participate in the stimulation of Bax protein, which in turn renders cells from the left ventricle of SHR more susceptible to apoptosis.

Animals↗