Angiotensin II in cardiac pressure-overload hypertrophy in fetal sheep

We previously demonstrated in fetal sheep that blockade of ANG II type 1 (AT1) receptors did not attenuate an increase in right ventricle (RV) mass resulting from partial occlusion of the pulmonary artery (PA). We have now determined the effects of AT2-receptor blockade (PD-123319, 10 mg · kg−1· day−1continuous iv) on the response of the fetal RV to PA banding for 7 days. Four groups of fetuses (each n = 7) were studied beginning at 126 ± 1 days gestation (term 145 days). RV weight-to-body weight ratio (RV wt/body wt) increased ( P < 0.05) in PA-banded (6.00 ± 0.09 g/kg) and PA-banded + PD-123319 (6.19 ± 0.27 g/kg) compared with control (5.17 ± 0.17 g/kg) and PD-123319-infused (5.27 ± 0.35 g/kg) fetuses (means ± SE). Blood pressure and heart rate were similar in all groups. PD-123319 produced a decrease ( P < 0.05) in AT1but not AT2mRNA levels in both fetal ventricles. To examine the effect of ANG II on fetal heart growth, twin fetal sheep were infused with either ANG II (twin received vehicle) or phenylephrine (Phe) (twin received vehicle) continuously for 7 days. Mean arterial blood pressure was 20–25 mmHg higher in ANG II and Phe fetuses compared with controls. The rate-pressure product was similar in ANG II and Phe fetuses and 40–50% greater than controls. Phe resulted in no change in RV wt/body wt or left ventricle-to-body weight ratio (LV wt/body wt) compared with controls. In contrast, ANG II produced a selective increase (27 ± 5%, P < 0.05) in LV wt/body wt; no effect was seen on the RV. ANG II produced a decrease ( P < 0.05) in LV but not RV AT1mRNA levels compared with controls; no effect was seen with Phe. The data demonstrate that in the ovine fetus, AT2receptors do not contribute to the maintenance of blood pressure or the development of pressure-overload RV hypertrophy. Elevated ANG II levels produce a selective increase in LV mass in the fetal sheep that is, in part, independent of increased systolic load.

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Creatine Alleviates Doxorubicin-Induced Liver Damage by Inhibiting Liver Fibrosis, Inflammation, Oxidative Stress, and Cellular Senescence

Nutrients ◽

10.3390/nu13010041 ◽

2020 ◽

Vol 13 (1) ◽

pp. 41

Author(s):

Nouf Aljobaily ◽

Michael J. Viereckl ◽

David S. Hydock ◽

Hend Aljobaily ◽

Tsung-Yen Wu ◽

...

Keyword(s):

Oxidative Stress ◽

Dna Methylation ◽

Body Weight ◽

Liver Fibrosis ◽

Liver Damage ◽

Cellular Senescence ◽

Weight Ratio ◽

Mrna Levels ◽

Body Weight Ratio ◽

Chromosomal Stability

Background: Treatment with the chemotherapy drug doxorubicin (DOX) may lead to toxicities that affect non-cancer cells including the liver. Supplementing the diet with creatine (Cr) has been suggested as a potential intervention to minimize DOX-induced side effects, but its effect in alleviating DOX-induced hepatoxicity is currently unknown. Therefore, we aimed to examine the effects of Cr supplementation on DOX-induced liver damage. Methods: Male Sprague-Dawley rats were fed a diet supplemented with 2% Cr for four weeks, 4% Cr for one week followed by 2% Cr for three more weeks, or control diet for four weeks. Animals then received either a bolus i.p. injection of DOX (15 mg/kg) or saline as a placebo. Animals were then sacrificed five days-post injection and markers of hepatoxicity were analyzed using the liver-to-body weight ratio, aspartate transaminase (AST)-to- alanine aminotransferase (ALT) ratio, alkaline phosphatase (ALP), lipemia, and T-Bilirubin. In addition, hematoxylin and eosin (H&E) staining, Picro-Sirius Red staining, and immunofluorescence staining for CD45, 8-OHdG, and β-galactosidase were performed to evaluate liver morphology, fibrosis, inflammation, oxidative stress, and cellular senescence, respectively. The mRNA levels for biomarkers of liver fibrosis, inflammation, oxidative stress, and senescence-related genes were measured in liver tissues. Chromosomal stability was evaluated using global DNA methylation ELISA. Results: The ALT/AST ratio and liver to body weight ratio tended to increase in the DOX group, and Cr supplementation tended to attenuate this increase. Furthermore, elevated levels of liver fibrosis, inflammation, oxidative stress, and senescence were observed with DOX treatment, and Cr supplementation prior to DOX treatment ameliorated this hepatoxicity. Moreover, DOX treatment resulted in chromosomal instability (i.e., altered DNA methylation profile), and Cr supplementation showed a tendency to restore chromosomal stability with DOX treatment. Conclusion: The data suggest that Cr protected against DOX-induced hepatotoxicity by attenuating fibrosis, inflammation, oxidative stress, and senescence.

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Diminished effect of cAMP on Ca2+ accumulation in skinned fibers of hypertrophied rat heart

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1994.266.2.h749 ◽

1994 ◽

Vol 266 (2) ◽

pp. H749-H756

Author(s):

F. Tomita ◽

A. L. Bassett ◽

R. J. Myerburg ◽

S. Kimura

Keyword(s):

Body Weight ◽

Weight Ratio ◽

Pressure Overload ◽

Left Ventricular Pressure ◽

Left Ventricular ◽

Adrenergic Stimulation ◽

Body Weight Ratio ◽

The Right ◽

Hypertrophied Ventricle ◽

Concomitant Exposure

Sarcoplasmic reticulum (SR) Ca2+ uptake is reduced in the hypertrophied ventricle. To determine whether events initiated by beta-adrenergic stimulation are involved, we compared the effects of adenosine 3',5'-cyclic monophosphate (cAMP) on SR Ca2+ uptake between normal and pressure-overloaded hypertrophied hearts using saponin-skinned rat left ventricular muscles. Left ventricular pressure overload was induced by partial ligation of the abdominal aorta for 4–6 wk before study. Age-matched normal rats served as controls. Pressure overload increased the left ventricular weight-to-body weight ratio 60.8%. The SR was loaded by exposing the muscles to 10(-6) M Ca2+ solution; SR Ca2+ release was induced by 5 or 25 mM caffeine, and the amount of Ca2+ released from the SR was estimated by the area under the caffeine-induced transient contraction. Concomitant exposure to 10(-4) M cAMP did not influence caffeine-induced Ca2+ release in either normal or hypertrophied fibers. When 10(-4) M cAMP was applied during the Ca(2+)-loading periods, the amount of Ca2+ accumulated by the SR increased in both normal and hypertrophied fibers. However, the extent of increase was significantly smaller in hypertrophied fibers than in normal fibers [10.9 +/- 1.7 and 27.4 +/- 5.3% in 1 min of Ca2+ loading (P < 0.05), 12.2 +/- 3.2 and 24.7 +/- 3.8% in 4 min of Ca2+ loading (P < 0.05), respectively]. cAMP (10(-4) M) shifted the force-pCa relationship to the right similarly in normal and hypertrophied muscles, and there was no difference in the force-pCa relationship between the two groups either with or without cAMP.(ABSTRACT TRUNCATED AT 250 WORDS)

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Abstract 16205: MKP-5 Deficiency Attenuates Pressure Overload-induced Cardiac Hypertrophy

Circulation ◽

10.1161/circ.142.suppl_3.16205 ◽

2020 ◽

Vol 142 (Suppl_3) ◽

Author(s):

Kisuk Min ◽

Yan Huang ◽

Frank J Giordano ◽

Sudip Bajpeyi ◽

Anton M Bennett

Keyword(s):

Heart Failure ◽

Body Weight ◽

Cardiac Hypertrophy ◽

Cardiac Muscle ◽

Molecular Mechanisms ◽

Weight Ratio ◽

Pressure Overload ◽

Body Weight Ratio ◽

Pathological Cardiac Hypertrophy

Introduction: Cardiac remodeling occurs in response to pathological stimuli including chronic pressure overload, subsequently leading to heart failure. Despite considerable research efforts, the molecular mechanisms responsible for heart failure have yet to be fully elucidated. One of the prominent signaling pathways involved in the development of pathological cardiac hypertrophy is the mitogen-activated protein kinases (MAPKs) pathways. The MAPKs are inactivated by the MAPK phosphatases (MKPs) through direct dephosphorylation. Growing evidence suggests the importance of MKP-5 signaling mechanisms in physiological and pathological processes. However, the role of MKP-5 has not been explored in cardiac muscle. The objective of this study is to investigate how MKP-5-mediated MAPK activity contributes to mechanisms responsible for pressure overload-induced cardiac hypertrophy. Hypothesis: We tested the hypothesis that MKP-5 serves as a central regulator of MAPKs in pressure overload-induced cardiac hypertrophy. Methods: To investigate the role of MKP-5 in cardiac muscle, we caused pressure overload-induced cardiac hypertrophy in wild type (mkp-5 +/+ ) mice and MKP-5 deficient mice (mkp-5 -/- ) through transverse aortic constriction (TAC). Cardiac function was evaluated by echocardiographic analysis at 4 weeks after TAC. Cardiac hypertrophy was measured by heart-to-body weight ratio. Interstitial myocardial fibrosis was evaluated by Sirius red stains and expression of fibrogenic genes was determined by quantitative PCR. Results: Echocardiographic analysis showed that the ejection fraction and fractional shortening of mkp-5 +/+ mice significantly decreased by at 4 weeks after TAC. Heart-to-body weight ratio increased in mkp-5 +/+ mice. However, MKP-5-deficient heart was protected from cardiac dysfunction and cardiac hypertrophy induced by TAC. Importantly, the fibrogenic genes were markedly reduced in mkp-5 -/- mice as compared with mkp-5 +/+ mice at 4 weeks after TAC. Conclusions: Collectively, our study demonstrates that MKP-5 deficiency prevents the heart from pressure overload-induced cardiac hypertrophy and suggests that MKP-5 may serve as a novel therapeutic target for treatment of heart disease.

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Abstract 42: AT1 Angiotensin Receptors in Principal Cells of the Collecting Duct Have Minimal Impact on Blood Pressure and the Development of Hypertension.

Hypertension ◽

10.1161/hyp.60.suppl_1.a42 ◽

2012 ◽

Vol 60 (suppl_1) ◽

Author(s):

Daian Chen ◽

Johannes Stegbauer ◽

Matthew A. Sparks ◽

Donald Kohan ◽

Susan B. Gurley ◽

...

Keyword(s):

Blood Pressure ◽

Salt Intake ◽

Collecting Duct ◽

Weight Ratio ◽

Angiotensin Receptors ◽

Mrna Levels ◽

Ang Ii ◽

Mouse Line ◽

Dietary Salt ◽

Transgenic Mouse Line

The main actions of the renin angiotensin system to control blood pressure (BP) are mediated by the angiotensin type 1 receptors (AT 1 R). The major murine AT 1 R isoform, AT 1A is highly expressed in epithelial cells throughout the nephron, including the collecting duct (CD). The CD consists of two cell types, principal (PC) and intercalated cells (IC) with distinct functions. Activation of AT 1 R in PC stimulates solute reabsorption in the CD by increasing the activity of epithelial sodium channels. To examine the role of the AT 1A R in the PC to BP regulation and the development of hypertension in vivo , we generated inbred 129SvEv mice with cell-specific deletion of AT 1A R in PC (PC-KO, n=6). AQP2-Cre transgenic mouse line was used to excise the floxed Agtr1a allele in PC. mTmG reporter mouse line was used to confirm specific expression of AQP2-Cre transgene in PC, and found the pattern of expression to be predominantly in medullary CD. Using RT-PCR, mRNA levels for AT 1A R were reduced by ≈50% in the inner medulla of PC-KO mice ( P <0.05), but unaffected in cortex. Baseline BP measured by radiotelemetry was similar between PC-KO (122±1.6 mm Hg) and controls (122±1.6 mm Hg). During one week of feeding a low salt (<0.002% NaCl) diet, MAP fell significantly (P<0.05) and to a similar extent in both groups, (PC-KO: 116±1 mm Hg; Controls: 117±2 mm Hg). High salt (6% NaCl) diet increased BP (P<0.01), but was not different between groups (PC-KO: 129±2 mm Hg; Controls: 131±2 mm Hg). Finally, we induced hypertension with chronic infusion of Ang II (1000 ng/kg/min) by osmotic mini-pumps. During the initial phase (days 1-8), there was a modest but significant attenuation of hypertension in PC-KO (167±7 mm Hg) compared to controls (178±3 mm Hg, P<0.001). However, by day 9 levels of BP were indistinguishable between groups and there was no difference in BP in the later phase (days 9-14) of hypertension (PC-KO: 175±12 mm Hg; Controls: 177±7 mm Hg). Heart to body weight ratio after Ang II infusion was not different between groups. In summary, AT 1A R in PC of the medullary CD have little influence on BP, adaptation to changes in dietary salt intake or development of hypertension. We suggest that other mediators, such as aldosterone, may have a more important role to influence sodium handling in this nephron segment.

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Abstract 1393: Inhibition of Cardiac Remodeling by Pravastatin is Associated with Amelioration of Endoplasmic Reticulum Stress

Circulation ◽

10.1161/circ.118.suppl_18.s_319-d ◽

2008 ◽

Vol 118 (suppl_18) ◽

Author(s):

Hui Zhao ◽

Yulin Liao ◽

Tetsuo Minamino ◽

Yoshihiro Asano ◽

Masanori Asakura ◽

...

Keyword(s):

Endoplasmic Reticulum ◽

Body Weight ◽

Er Stress ◽

Cardiac Remodeling ◽

Weight Ratio ◽

Pressure Overload ◽

Left Ventricular ◽

Stress Signaling ◽

Body Weight Ratio ◽

Stress Signaling Pathway

Background We previously reported that prolonged endoplasmic reticulum (ER) stress contributes to progression from cardiac hypertrophy to heart failure. Statins have an inhibitory effect on cholesterol synthesis, oxidative stresses, protein synthesis and production of inflammatory cytokines, all of which could be associated with ER stress. However, it is unknown whether statins can ameliorate ER stress in heart disease. This study was designed to investigate whether pravastatin could inhibit cardiac remodeling and ameliorate ER stress caused by pressure overload or tumor necrosis factor α (TNF α ). Methods and Results Cardiac hypertrophy was induced by transverse aortic constriction (TAC) for four weeks in C57BL/6 male mice. Either pravastatin (5 mg/kg/d, n=20, TAC+prava group) or its vehicle (n=20) was orally administered to mice. The ER stress signaling pathway was also studied in pressure-overloaded mice hearts and in cultured cardiomyocytes treated with TNF α (10ng/ml) for 24 hours. Four weeks after TAC, both heart-to-body weight ratio (8.68 ± 1.23 in TAC group, 6.92 ± 1.11 in TAC+prava group) and lung-to-body weight ratio (11.08 ± 2.58 in TAC group, 7.92± 3.56 in TAC+prava group) became significantly lower in pravastatin-treated mice than in the TAC group. Left ventricular fractional shortening and left ventricular ejection fraction (LVFS and LVEF) were larger in TAC+prava group (48.0±1.9 % and 80±1.9% respectively) compared with TAC group (LVFS and LVEF, 34.8 ±1.4% and 65 ±3%; P<0.01 VS TAC group each). Markers of ER stress such as an increase in ER chaperones and CHOP expressions and enhanced phosphorylation of eIF2 α were observed in the hearts of TAC mice, while pravastatin treatment significantly blunted these changes. Pravastatin-treated TAC mice also showed a decrease of cardiac apoptosis. Cardiac expression of TNF α was increased in TAC mice, and TNF α induced ER stress in cultured neonatal rat cardiomyocytes, either of which was significantly inhibited by pravastatin. Conclusions These findings indicate that pravastatin inhibits cardiac remodeling in mice subjected to pressure overload, and this action is associated with inhibition of the ER stress signaling pathway.

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Vitamin C and quinapril abrogate LVH and endothelial dysfunction in aortic-banded guinea pigs

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.2001.281.4.h1704 ◽

2001 ◽

Vol 281 (4) ◽

pp. H1704-H1710 ◽

Cited By ~ 21

Author(s):

John P. Bell ◽

Salah I. Mosfer ◽

Derek Lang ◽

Francis Donaldson ◽

Malcolm J. Lewis

Keyword(s):

Body Weight ◽

Endothelial Dysfunction ◽

Vitamin C ◽

Weight Ratio ◽

Pressure Overload ◽

Left Ventricular ◽

Antioxidant Vitamin ◽

Ang Ii ◽

Text Production ◽

Tnf Α

Left ventricular hypertrophy (LVH) is a cardiovascular risk factor. A possible role for endothelial dysfunction in this condition was investigated in a Dunkin-Hartley guinea pig aortic-banded pressure overload-induced model of LVH. Aortic banding produced significant elevation of fore- and hindlimb blood pressure (BP), heart-to-body weight ratios, plasma angiotensin II (ANG II), endothelin-1 (ET-1), tumor necrosis factor-α (TNF-α) levels, and coronary microvascular endothelial cell (CMEC) NAD(P)H-dependent superoxide (O[Formula: see text]) production, and a significant decrease in basal and stimulated CMEC cGMP levels. Treatment of aortic-banded animals with the angiotensin-converting enzyme inhibitor quinapril and the antioxidant vitamin C, either alone or in combination, did not affect BP but caused a significant inhibition of the increases in the heart-to-body weight ratio, ANG II, ET-1, and TNF-α levels, and O[Formula: see text] production and restored cGMP responses to levels comparable with sham-operated animals. These data suggest that quinapril and vitamin C are capable of inhibiting LVH development due to pressure overload via mechanisms that involve the inhibition of oxidative stress, an improvement in coronary endothelial function, and increased nitric oxide bioavailability.

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Age-associated increase in rat ventricular ANP gene expression correlates with cardiac hypertrophy

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1995.269.3.h1003 ◽

1995 ◽

Vol 269 (3) ◽

pp. H1003-H1008 ◽

Cited By ~ 5

Author(s):

A. Younes ◽

M. O. Boluyt ◽

L. O'Neill ◽

A. L. Meredith ◽

M. T. Crow ◽

...

Keyword(s):

Gene Expression ◽

Body Weight ◽

Cardiac Hypertrophy ◽

Left Atrial ◽

Northern Blot Analysis ◽

Weight Ratio ◽

Left Ventricular ◽

Mrna Levels ◽

Body Weight Ratio ◽

Old Rats

Atrial natriuretic peptide (ANP), a cardiac-specific hormone, is stored in the atria and released in response to atrial stretch. During cardiac hypertrophy, ANP gene expression is markedly upregulated in the left ventricle (LV). Because the hearts of normotensive senescent rats exhibit left atrial (LA) and left ventricular (LV) hypertrophy and dilatation, we examined ANP mRNA levels by Northern blot analysis and ANP peptide concentrations by radioimmunoassay in atria, LVs, and plasma of rats at 2, 6, 18, and 22-24 mo of age. Compared with LVs of 6-mo-old rats, the LV-to-body weight ratio was elevated 30% by 18 mo of age, whereas levels of ANP mRNA were elevated twofold (not significant) and sevenfold (P < 0.05) in the LV of 18- and 22- to 24-mo-old rats, respectively. The concentration of immunoreactive ANP (ir-ANP) exhibited a four- to fivefold increase in LVs of 18- and 22- to 24-mo-old rats compared with values for 6-mo-old rats (43 +/- 4 pmol/g wet wt; means +/- SE). Among 18-and 22- to 24-mo-old rats a significant correlation was observed between ANP peptide concentration and LV hypertrophy (r 2 = 0.64). Levels of ANP mRNA and ir-ANP in the atria exhibited only modest changes with aging.(ABSTRACT TRUNCATED AT 250 WORDS)

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Ovariectomy augments pressure overload-induced hypertrophy associated with changes in Akt and nitric oxide synthase signaling pathways in female rats

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00246.2007 ◽

2007 ◽

Vol 293 (6) ◽

pp. E1606-E1614 ◽

Cited By ~ 49

Author(s):

Md. Shenuarin Bhuiyan ◽

Norifumi Shioda ◽

Kohji Fukunaga

Keyword(s):

Nitric Oxide ◽

Body Weight ◽

Diastolic Pressure ◽

Heart Function ◽

Weight Ratio ◽

Pressure Overload ◽

Left Ventricular ◽

Female Rats ◽

Ovariectomized Rats ◽

Body Weight Ratio

To elucidate the molecular mechanism underlying estrogen-mediated cardioprotection in left ventricular (LV) hypertrophy and remodeling, we analyzed myocardial hypertrophy as well as cardiac function and hypertrophy-related protein expression in ovariectomized, aortic-banded rats. Wistar rats subjected to bilateral ovariectomy (OVX) were further treated with abdominal aortic stenosis. Effects on LV morphology and function were assessed using echocardiography, and expression of protein levels was determined by Western blot analysis. The heart-to-body weight ratio was most significantly increased in the OVX-pressure overload (PO) group compared with the OVX group and in the PO group compared with sham. The LV weight-to-body weight ratio was also significantly increased in the OVX-PO group compared with the OVX group and in the PO group compared with sham. The most significant increases in LV end diastolic pressure, LV developed pressure, and ±dp/d tmax were observed in the OVX-PO group compared with the OVX group and represent compensatory phenotypes against hypertrophy. Both endothelial nitric oxide (eNOS) synthase expression and activity was markedly reduced in the OVX-PO group, and protein kinase B (Akt) activity was largely attenuated. Marked breakdown of dystrophin was also seen in hearts of OVX-PO groups. Finally, significantly increased mortality was observed in the OVX-PO group following chronic isoproterenol administration. Our results demonstrate that rats subjected to ovariectomy are unable to compensate for hypertrophy, showed deteriorated heart function, and demonstrated increased mortality. Simultaneous impairment of eNOS and Akt activities and reduced dystrophin by ovariectomy likely contribute to cardiac decompensation during PO-induced hypertrophy in ovariectomized rats.

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Apocynin attenuates pressure overload-induced cardiac hypertrophy in rats by reducing levels of reactive oxygen species

Canadian Journal of Physiology and Pharmacology ◽

10.1139/y10-063 ◽

2010 ◽

Vol 88 (7) ◽

pp. 745-752 ◽

Cited By ~ 17

Author(s):

Jinjun Liu ◽

Juan Zhou ◽

Wenjiao An ◽

Yuanxi Lin ◽

Yubai Yang ◽

...

Keyword(s):

Reactive Oxygen Species ◽

Nadph Oxidase ◽

Cardiac Hypertrophy ◽

Weight Ratio ◽

Pressure Overload ◽

Reactive Oxygen ◽

Oxygen Species ◽

Ang Ii ◽

Body Weight Ratio ◽

Local Expression

It has been shown that angiotensin II (Ang II) is involved in cardiac remodeling mediated by NADPH oxidase-dependent reactive oxygen species (ROS). Accordingly, NADPH oxidase-dependent ROS may play a role in cardiac hypertrophy induced by pressure overload. In the present study, we sought to determine whether inhibition of NADPH oxidase prevents cardiac hypertrophy. After abdominal aorta banding to induce cardiac hypertrophy, rats were treated for 8 weeks with apocynin (Apo) or captopril (Cap). Measures of cardiac hypertrophy were evaluated. Treatment with Cap or Apo reduced the left ventricle / body weight ratio (LV/BW), LV transnuclear myocyte diameter, and atrial natriuretic factor (ANF) mRNA expression relative to those of untreated rats subjected to aorta banding. The activity of NADPH oxidase and the ROS levels were decreased in treated animals. Cap, but not Apo, decreased Ang II levels and inhibited expression of p22phox and p67phox in LVs. In conclusion, local expression of Ang II appears to contribute to pressure overload-induced cardiac hypertrophy by upregulating NADPH oxidase expression and promoting ROS synthesis. Inhibition of NADPH oxidase and elimination of ROS may prevent or repair damage due to cardiac hypertrophy.

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Abstract 532: BIA 5-1058, Beyond Blood Pressure, Improves Cardiometabolism and Decrease End-organ Damage

Hypertension ◽

10.1161/hyp.62.suppl_1.a532 ◽

2013 ◽

Vol 62 (suppl_1) ◽

Author(s):

Bruno Igreja ◽

Nuno M Pires ◽

Lyndon C Wright ◽

Patrício Soares-da-Silva

Keyword(s):

Blood Pressure ◽

Body Weight ◽

Plasma Levels ◽

Weight Ratio ◽

Organ Damage ◽

Peripheral Vascular ◽

Hypertensive Rats ◽

Body Weight Ratio ◽

Spontaneously Hypertensive ◽

Plasma Triglycerides

The sympathetic nervous system (SNS) can alter blood pressure (BP) by modulation of cardiac output, peripheral vascular resistance and renal function. One strategy for controlling sympathetic nerve function is to reduce the biosynthesis of norepinephrine (NE) via inhibition of dopamine β-hydroxylase (DβH). BIA 5-1058 is a new peripheral DβH inhibitor that decreases NE levels in sympathetically innervated tissues and slows down the drive of SNS. In order to evaluate the cardiometabolic effects of BIA 5-1058 in aged spontaneously hypertensive rats (SHR), 12 male SHR 50-week-old were randomized into two groups and one group was treated with BIA 5-1058 (30 mg/Kg/day) mixed in the diet for 9 weeks. During week 8 of treatment, blood pressure (BP) and heart rate (HR) were measured by tail cuff. At the end of the study, 24-hour urine and plasma was collected and organs weight was recorded. BIA 5-1058 treatment reduced systolic BP (224±5 vs 183±8 mmHg, p<0.05) with no significant effect on HR. The heart/body weight ratio was decreased in animals treated with BIA 5-1058 (3.66±0.08 vs 3.45±0.04 mg/g, p<0.05), while the ratio kidney/body weight was unchanged. BIA 5-1058 significantly decreased plasma levels of the inflammatory markers CRP (447.3±7.1 vs 401.2±7.1 μg/ml, p<0.05), MCP-1 (90.3±10.5 vs 58.2±9.0 pg/ml, p<0.05) and ASAT (91.7±8.0 vs 67.3±4.0 U/l, p<0.05) but no significant effect on ALAT was observed. Concerning lipid metabolism, there was a decrease in plasma triglycerides (0.94±0.05 vs. 0.70±0.05 mmol/l, p<0.05) and free fatty acids levels (0.23±0.03 vs 0.11±0.01 mmol/l, p<0.05) induced by BIA 5-1058, while total cholesterol plasma levels was similar in both groups. BIA 5-1058 significantly reduced the 24-hour urine excretion (13.5±1.6 vs 8.9±1.2 ml, p<0.05), but had no significant effect in the amount of protein excreted in urine nor in the creatinine clearance rate. In conclusion, the new DBH inhibitor, BIA 5-1058, presents cardiometabolic benefits in aged SHR.

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