Browsing by Author "Ocaranza, MP"

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    Angiotensin I-converting enzyme modulates neutral endopeptidase activity in the rat
    (LIPPINCOTT WILLIAMS & WILKINS, 2001) Oliveri, C; Ocaranza, MP; Campos, X; Lavandero, S; Jalil, JE
    Angiotensin I is a substrate for both ACE and for neutral endopeptidase 24.11 (NEP). We hypothesized that high ACE expression is related to low NEP activity. Accordingly, circulating and tissue NEP and ACE activities were measured by fluorometry in homozygous rats (FO and 172) for the Lewis microsatellite allele (LL, low ACE) and for the Brown Norway microsatellite allele (BB, high ACE). Plasma, lung, and aortic ACE activities in F-0 and F-2 were higher in BB rats than in LL rats (P <0.01), whereas left ventricular ACE activity was similar in both genotypes. In contrast, NEP activity in the LL group was higher in the serum, aorta, and lungs in F-0 and F-2 homozygous (P <0.05). Plasma ACE activity was inversely correlated with serum (r=-0.6 and -0.598 in F-0 and F-2, respectively; P <0.03) and lung NEP activities (r=-0.77 in F-0 and r=-0.59 in F-2, P <0.01). Aortic ACE and NEP activities were also correlated (r=-0.696 and -0.584 in F-0 and F-2, respectively; P <0.03). In conclusion, genetically determined high ACE expression in rats is inversely related to tissue NEP activity, which could determine lower angiotensin-(1-7) tissue levels.
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    Effect of hypertension on angiotensin-(1-7) levels in rats with different angiotensin-I converting enzyme polymorphism
    (PERGAMON-ELSEVIER SCIENCE LTD, 2006) Ocaranza, MP; Palomera, C; Roman, M; Bargetto, J; Lavandero, S; Jalil, JE
    To determine circulating angiotensin-(1-7) [Ang-(1,7)] levels in rats with different angiotensin converting enzyme (ACE) genotypes and to evaluate the effect of hypertension on levels of this heptapeptide, plasma levels of angiotensin II (Ang II) and Ang-(1-7) were determined by HPLC and radioimmunoassay in (a) normotensive F-0 and F-2 homozygous Brown Norway (BN; with high ACE) or Lewis (with low ACE) rats and (b) in hypertensive F-2 homozygous male rats (Goldblatt model). Genotypes were characterized by PCR and plasma ACE activity measured by fluorimetry. Plasma ACE activity was 2-fold higher (p < 0.05) in homozygous BN compared to homozygous Lewis groups. In the Goldblatt groups, a similar degree of hypertension and left ventricular hypertrophy was observed in rats with both genotypes. Plasma Ang II levels were between 300-400% higher (p < 0.05) in the BN than in the Lewis rats, without increment in the hypertensive animals. Plasma Ang-(1-7) levels were 75-87% lower in the BN rats (p < 0.05) and they were significantly higher(p < 0.05) in the hypertensive rats from both genotypes. Plasma levels of Ang II and Ang-(1-7) levels were inversely correlated in the normotensive rats (r = -0.64; p < 0.001), but not in the hypertensive animals. We conclude that there is an inverse relationship between circulating levels of Ang II and Ang-(1-7) in rats determined by the ACE gene polymorphism. This inverse relation is due to genetically determined higher ACE activity. Besides, plasma levels of Ang-(1-7) increase in renovascular hypertension. (c) 2005 Elsevier Inc. All rights reserved.
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    Increased aortic NADPH oxidase activity in rats with genetically high angiotensin-converting enzyme levels
    (LIPPINCOTT WILLIAMS & WILKINS, 2005) Jalil, JE; Perez, A; Ocaranza, MP; Bargetto, J; Galaz, A; Lavandero, S
    In humans and rats, angiotensin I-converting enzyme activity is significantly determined by a gene polymorphism. Homozygous Brown Norway rats have higher plasma angiotensin I-converting enzyme activity and circulating angiotensin II (Ang II) levels than Lewis rats. Because Ang II induces NAD(P) H oxidase activation, we hypothesized here that Brown Norway rats have higher vascular NAD(P) H oxidase activity and superoxide anion production than Lewis rats. Homozygous Brown Norway (n = 15) and Lewis (n = 13) male rats were used. Plasma angiotensin I-converting enzyme activity (by fluorimetry), Ang II levels (by high-performance liquid chromatography and radioimmunoassay), and aortic NAD(P) H oxidase activity, as well as superoxide anion production ( by chemiluminescence with lucigenin) were measured. Plasma angiotensin I-converting enzyme activity and Ang II levels were 100% higher in Brown Norway rats than in Lewis rats (P < 0.05). Aortic angiotensin I-converting enzyme, but not Ang II, was elevated (P < 0.05). Aortic superoxide anion production and NAD(P) H oxidase activity were 300% and 260% higher in Brown Norway than in Lewis rats, respectively (P < 0.05), which was not observed in Brown Norway rats treated with candesartan (10 mg/kg per day for 7 days). Endothelial NO synthase activity in the aorta from Brown Norway rats was significantly lower than in Lewis rats. However, inducible NO synthase activity and both endothelial NO synthase and inducible NO synthase mRNA and protein levels were similar in both genotypes. In summary, Brown Norway rats have higher vascular NAD(P) H oxidase activity and superoxide anion production than Lewis rats, suggesting the presence of a higher level of vascular oxidative stress in rats with genetically higher angiotensin I-converting enzyme levels. This effect is mediated through the angiotensin I receptor.
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    Perindopril regulates beta-agonist-induced cardiac apoptosis
    (LIPPINCOTT WILLIAMS & WILKINS, 2005) Galvez, AS; Fiedler, JL; Ocaranza, MP; Jalil, JE; Lavandero, S; Diaz Araya, G
    Administration of the P-adrenergic agonist isoproterenol results in cardiac apoptosis. The effect of short-term P-adrenergic stimulation by isoproterenol on the activity of plasma, lung, and left ventricular (LV) angiotensin 1-converting enzyme (ACE) activity and its association with the development of cardiac apoptosis was investigated. P-Adrenergic stimulation for 24 hours produced an early increase only in the proapoptotic proteins bax and bcl-XS without changes in the levels of the antiapoptotic protein bcl-XL. The ratio between these bcl family proteins was indicative of apoptosis and correlated with an early and significant increase (300%) in DNA laddering. However, after 5 days of the P-adrenergic stimulation, the ratio changed in favor of antiapoptotic proteins and correlated with the absence of DNA fragmentation. In addition, LV and plasma ACE activities increased markedly with isoproterenol over the study period up to 5 days. ACE activity also regulated expression of the antiapoptotic gene bcl-XL. The administration of perindopril (an ACE inhibitor) prevented the observed increase in bax and bcl-XS levels and attenuated (50% decrease, P < 0.05) the effect of isoproterenol on DNA fragmentation. Thus, early and transient cardiac apoptosis triggered by the beta-adrenergic agonist isoproterenol is reversed in the presence of perindopril.
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    Polymorphism in gene coding for ACE determines different development of myocardial fibrosis in rats
    (AMER PHYSIOLOGICAL SOC, 2004) Ocaranza, MP; Diaz Araya, G; Carreno, JE; Munoz, D; Riveros, JP; Jalil, JE; Lavandero, S
    In humans, the effect of angiotensin-converting enzyme (ACE) gene polymorphisms in cardiovascular disease is still controversial. In the rat, a microsatellite marker in the ACE gene allows differentiation of the ACE gene polymorphism among strains with different ACE levels. We tested the hypothesis that this ACE gene polymorphism determines the extent of cardiac fibrosis induced by isoproterenol (Iso) in the rat. We used a male F-2 generation (homozygous LL and BB ACE genotypes determined by polymerase chain reaction) derived from two rat strains [Brown-Norway (BB) and Lewis (LL)] that differ with respect to their plasma ACE activities. For induction of left ventricular (LV) hypertrophy (LVH) and cardiac fibrosis, rats were infused with Iso (5 mg.kg(-1).day(-1)) or saline (control) for 10 days and euthanized at day 1 after the last injection. The interstitial collagen volumetric fraction (ICVF), collagen I, and fibronectin content, but not collagen III content, were significantly higher in the homozygous BB rats than in homozygous LL rats. Differences in metalloprotease (MMP)-9, but not in MMP-2 activities as well as in cardiac cell proliferation, were also detected between LL and BB rats treated with Iso. LV ACE activity was higher in BB rats than LL rats and correlated with ICVF (r=0.61, P<0.002). No changes were observed in plasma ACE activities, ANG II plasma or LV levels, plasma renin activity, and ACE and ANG II type 1 receptor (AT1R) mRNA levels in the LV of rats with the two different ACE polymorphisms. Iso induced a similar degree of LVH [assessed by an increase in LV weight 100 per body weight, LV-to-right ventricle (RV) ratio, and LV protein content] in LL and BB rats. We concluded that rats in the F-2 generation with high plasma ACE activity developed more fibrosis but to a similar degree of LVH compared with rats with low plasma ACE activity.