Enalapril attenuates cardiorenal damage in nitric-oxide-deficient spontaneously hypertensive rats

Stereological structural alterations of the heart and kidney were studied in four groups (n=5) of spontaneously hypertensive rats (SHRs) treated for 30 days: (i) control, (ii) NG-nitro-L-arginine methyl ester [L-NAME; nitric oxide (NO) synthesis inhibitor] alone, (iii) enalapril alone and (iv) L-NAME plus enalapril. Blood pressure (BP) was elevated significantly in NO-deficient SHRs (rats receiving L-NAME) or significantly lower in enalapril-treated SHRs. Co-administration of L-NAME and enalapril caused a 20% decrease in BP compared with untreated SHRs. NO-deficient SHRs had a decrease in body mass, but this loss of body mass was prevented efficiently in the enalapril-treated group. Enalapril treatment decreased the left ventricular (LV) mass index in SHRs, even in animals with NO synthesis blocked. NO deficiency in SHRs caused a larger decrease in the number of LV cardiomyocyte nuclei, which had a negative correlation with both LV mass index and BP. The volume-weighted glomerular volume (VWGV) separated the SHRs into two groupings: (i) control and NO-deficient SHRs, and (ii) enalapril- and L-NAME plus enalapril-treated SHRs. There was a significant difference between these two groupings, with VWGV being more than 15% smaller in the latter compared with the former grouping. The present findings reinforce the evidence that enalapril efficiently treats genetic hypertension, and demonstrate that this effect is observed even when NO synthesis is inhibited. Enalapril administration also decreases cardiac and renal structural damage caused by genetic hypertension, as well as by the interaction between genetic hypertension and NO deficiency.

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LEFT VENTRICULAR DIASTOLIC DYSFUNCTION AND NITRIC OXIDE LEVELS. EXPERIMENTAL STUDY IN SPONTANEOUSLY HYPERTENSIVE RATS

Journal of Hypertension ◽

10.1097/00004872-201106001-01401 ◽

2011 ◽

Vol 29 ◽

pp. e466

Author(s):

R. Cabrera Sole ◽

L. Iñiguez ◽

J. Cañas ◽

M. J. Fernandez Martinez

Keyword(s):

Nitric Oxide ◽

Experimental Study ◽

Diastolic Dysfunction ◽

Spontaneously Hypertensive Rats ◽

Left Ventricular Diastolic Dysfunction ◽

Left Ventricular ◽

Hypertensive Rats ◽

Spontaneously Hypertensive ◽

Ventricular Diastolic Dysfunction

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Beneficial effect of simvastatin and pravastatin treatment on adverse cardiac remodelling and glomeruli loss in spontaneously hypertensive rats

Clinical Science ◽

10.1042/cs20040292 ◽

2005 ◽

Vol 108 (4) ◽

pp. 349-355 ◽

Cited By ~ 39

Author(s):

Daniele G. BEZERRA ◽

Carlos A. MANDARIM-de-LACERDA

Keyword(s):

Left Ventricle ◽

Spontaneously Hypertensive Rats ◽

Renal Cortex ◽

Interstitial Fibrosis ◽

Treated Group ◽

Left Ventricular ◽

Control Group ◽

Hypertensive Rats ◽

Spontaneously Hypertensive ◽

Significant Difference

The aim of the present study was to investigate the possibility of different effects of the hydrophobic statin simvastatin and the hydrophilic statin pravastatin on the remodelling process in the overloaded left ventricle and renal cortex of SHRs (spontaneously hypertensive rats). Fifteen SHRs were treated for 40 days with simvastatin, pravastatin or placebo (water) via orogastric administration. Left ventricle and renal cortex were examined by light microscopy and stereology. LV (left ventricular) cardiomyocyte nuclei (N[cmn]) and glomeruli (N[gl]) numbers were estimated by the dissector method. BP (blood pressure) and serum triacylglycerols (triglycerides) were lower in the statin-treated groups than in the untreated control group. The volume density of the interstitial connective tissue was smaller and length density of the intramyocardial arteries, as well as the arteries/cardiomyocyte ratio, was greater in the statin-treated groups than in the control group. No difference was observed between the two statin-treated groups. The cross-sectional cardiomyocyte area was significantly smaller in the simvastatin-treated group than in the control or pravastatin-treated groups, and it was smaller in the pravastatin-treated group than in the control group. N[cmn] and N[gl] were greater in the two statin-treated groups than in the control group, but no significant difference was observed between the two statin-treated groups. In conclusion, administration of the statins simvastatin and pravastatin to SHRs effectively prevented the elevation in BP and serum triaclyglycerols, and also attenuated adverse cardiac and kidney remodelling by preventing LV hypertrophy, enhancing myocardial vascularization with the decrease in interstitial fibrosis and attenuating cardiomyocyte and glomerular loss.

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Angiotensin-(1–7) prevents development of severe hypertension and end-organ damage in spontaneously hypertensive rats treated with l-NAME

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00632.2005 ◽

2006 ◽

Vol 290 (2) ◽

pp. H684-H691 ◽

Cited By ~ 137

Author(s):

Ibrahim F. Benter ◽

Mariam H. M. Yousif ◽

J. T. Anim ◽

C. Cojocel ◽

D. I. Diz

Keyword(s):

Nitric Oxide ◽

Spontaneously Hypertensive Rats ◽

Severe Hypertension ◽

Organ Damage ◽

Left Ventricular ◽

Protective Effects ◽

Additive Effects ◽

Hypertensive Rats ◽

Spontaneously Hypertensive ◽

End Organ Damage

We examined the influence of chronic treatment with ANG-(1–7) on development of hypertension and end-organ damage in spontaneously hypertensive rats (SHR) chronically treated with the nitric oxide synthesis inhibitor l-NAME (SHR-l-NAME). l-NAME administered orally (80 mg/l) for 4 wk significantly elevated mean arterial pressure (MAP) compared with SHR controls drinking regular water (269 ± 10 vs. 196 ± 6 mmHg). ANG-(1–7) (24 μg·kg−1·h−1) or captopril (300 mg/l) significantly attenuated the elevation in MAP due to l-NAME (213 ± 7 and 228 ± 8 mmHg, respectively), and ANG-(1–7) + captopril completely reversed the l-NAME-dependent increase in MAP (193 ± 5 mmHg). l-NAME-induced increases in urinary protein were significantly lower in ANG-(1–7)-treated animals (226 ± 6 vs. 145 ± 12 mg/day). Captopril was more effective (96 ± 12 mg/day), and there was no additional effect of captopril + ANG-(1–7) (87 ± 5 mg/day). The abnormal vascular responsiveness to endothelin-1, carbachol, and sodium nitroprusside in perfused mesenteric vascular bed of SHR-l-NAME was improved by ANG-(1–7) or captopril, with no additive effect of ANG-(1–7) + captopril. In isolated perfused hearts, recovery of left ventricular function from 40 min of global ischemia was significantly better in ANG-(1–7)- or captopril-treated SHR-l-NAME, with additive effects of combined treatment. The beneficial effects of ANG-(1–7) on MAP and cardiac function were inhibited when indomethacin was administered with ANG-(1–7), but indomethacin did not reverse the protective effects on proteinuria or vascular reactivity. The protective effects of the ANG-(1–7) analog AVE-0991 were qualitatively comparable to those of ANG-(1–7) but were not improved over those of captopril alone. Thus, during reduced nitric oxide availability, ANG-(1–7) attenuates development of severe hypertension and end-organ damage; prostaglandins participate in the MAP-lowering and cardioprotective effects of ANG-(1–7); and additive effects of captopril + ANG-(1–7) on MAP, but not proteinuria or endothelial function, suggest common, as well as different, mechanisms of action for the two treatments. Together, the results provide further evidence of a role for ANG-(1–7) in protective effects of angiotensin-converting enzyme inhibition and suggest dissociation of factors influencing MAP and those influencing end-organ damage.

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Abstract 243: Chloroquine Treatment Increases the Threshold of Aortic Contractile Responses to Norepinephrine in a Nitric Oxide Synthase-dependent Manner in Spontaneously Hypertensive Rats

Hypertension ◽

10.1161/hyp.62.suppl_1.a243 ◽

2013 ◽

Vol 62 (suppl_1) ◽

Author(s):

Cameron G McCarthy ◽

Camilla F Wenceslau ◽

Styliani Goulopoulou ◽

Kathryn Spitler ◽

Takayuki Matsumoto ◽

...

Keyword(s):

Nitric Oxide ◽

Nitric Oxide Synthase ◽

Spontaneously Hypertensive Rats ◽

Specific Inhibitor ◽

Dependent Manner ◽

Hypertensive Rats ◽

Contractile Responses ◽

Spontaneously Hypertensive ◽

Significant Difference ◽

Oxide Synthase

Toll-like receptors (TLRs) are pattern recognition receptors of the innate immune system that are located either on the plasma membrane or on membrane of endosomes. TLR activation in immune cells leads to a pro-inflammatory phenotype and TLRs have been associated with the development of hypertension. However, the role of TLRs in the development of vascular dysfunction, a hallmark of hypertension, has not been extensively investigated. Chloroquine (CQ), due to its ability to inhibit autophagy and block lysosomal degradation, has been used as a non-specific inhibitor of TLRs located on endosomes. We hypothesized that treatment with CQ (40mg/kg/day) for 21 days would attenuate aortic contractile responses in young spontaneously hypertensive rats (SHRs; 5-6 weeks old) compared to saline (Veh) control. Concentration response curves to norepinephrine (NE; 10 -11 -10 -6 M), in the presence or absence of nitric oxide synthase (NOS) inhibitor L-NNA (10 -4 M), were performed in isolated aortic rings ex vivo on a pin myograph. CQ increases the threshold of aortic contractile responses to NE compared to Veh (logEC 20 CQ: -8.8±0.1 vs. Veh: -9.6±0.3, p<0.05). In the presence of L-NNA, there was a significant difference between CQ and CQ+L-NNA (logEC 20 CQ: -8.8±0.1 vs. CQ+L-NNA: -9.4±0.2, *p<0.05) (A); however, this difference was absent between Veh and Veh+L-NNA (logEC 20 Veh: -9.4±0.3 vs. Veh+L-NNA: -10.0±0.4, p>0.05) (B). These data illustrate that CQ improves the threshold for SHR aortic contraction to NE by preserving NO. Therefore, maintenance of NOS activity and NO bioavailability by inhibition of endosomal TLRs could be a therapeutic target against the development of hypertension.

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Bioenergetic remodeling of heart during treatment of spontaneously hypertensive rats with enalapril

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00032.2002 ◽

2002 ◽

Vol 283 (2) ◽

pp. H540-H548 ◽

Cited By ~ 14

Author(s):

S. C. Leary ◽

D. Michaud ◽

C. N. Lyons ◽

T. M. Hale ◽

T. L. Bushfield ◽

...

Keyword(s):

Blood Pressure ◽

Spontaneously Hypertensive Rats ◽

Citrate Synthase ◽

Enzyme Inhibitor ◽

Mitochondrial Protein ◽

Left Ventricular ◽

Mitochondrial Enzyme ◽

Hypertensive Rats ◽

Spontaneously Hypertensive ◽

Lv Mass

We used spontaneously hypertensive rats to study remodeling of cardiac bioenergetics associated with changes in blood pressure. Blood pressure was manipulated with aggressive antihypertensive treatment combining low dietary salt and the angiotensin-converting enzyme inhibitor enalapril. Successive cycles of 2 wk on, 2 wk off treatment led to rapid, reversible changes in left ventricular (LV) mass (30% change in <10 days). Despite changes in LV mass, specific activities of bioenergetic (cytochrome- c oxidase, citrate synthase, lactate dehydrogenase) and reactive oxygen species (ROS) (total cellular superoxide dismutase) enzymes were actively maintained within relatively narrow ranges regardless of treatment duration, organismal age, or transmural region. Although enalapril led to parallel declines in mitochondrial enzyme content and ventricular mass, total ventricular mtDNA content was unaffected. Altered enzymatic content occurred without significant changes in relevant mRNA and protein levels. Transcript levels of gene products involved in mtDNA maintenance (Tfam), mitochondrial protein degradation (LON protease), fusion (fuzzy onion homolog), and fission (dynamin-like protein, synaptojanin-2α) were also unchanged. In contrast, enalapril-mediated ventricular and mitochondrial remodeling was accompanied by a twofold increase in specific activity of catalase, an indicator of oxidative stress, suggesting that rapid cardiac adaptation is accompanied by tight regulation of mitochondrial enzyme activities and increased ROS production.

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Progressive Myocardial Apoptosis and Cardiac Dysfunction in Spontaneously Hypertensive Rats During Aging

American Journal of Hypertension ◽

10.1093/ajh/hpz190 ◽

2020 ◽

Vol 33 (2) ◽

pp. 205-205

Author(s):

Yun Wu ◽

Li-yun Fu ◽

Qin-yun Ruan ◽

Lei Yan ◽

Chun-yan Huang ◽

...

Keyword(s):

Cardiac Dysfunction ◽

Spontaneously Hypertensive Rats ◽

B Cell Lymphoma ◽

Left Ventricular ◽

Left Ventricular Ejection ◽

Hypertensive Rats ◽

Spontaneously Hypertensive ◽

Myocardial Apoptosis ◽

Significant Difference ◽

Related Proteins

Abstract Objective To investigate myocardial apoptosis and the expression of apoptosis-related proteins [B-cell lymphoma-2 (Bcl-2) and Bax], cardiac hypertrophy, and function in spontaneously hypertensive rats (SHR) during aging. Methods Male SHR (n = 36) and Wistar-Kyoto rats (WKY, n = 30) were monitored for their cardiac function from 14 to 102 weeks of age using echocardiography. Myocardial apoptosis in the subendocardium and subepicardium was analyzed using TUNEL staining. The apoptosis-related proteins (Bcl-2 and Bax) were assessed by Western blot analysis. Results Left ventricular mass index (LVMI) in SHR increased progressively with age. Left ventricular ejection fraction (LVEF) showed no significant difference from 14 to 66 weeks of age, but decreased significantly in SHR from 84 to 102 weeks of age. The apoptotic index (APOI) of myocardial cells in SHR increased with age, in which subendocardial APOI (APOI-endo) increased at 66 weeks and was significantly higher than the age-matched WKY (9.83 ± 3.97 vs. 4.03 ± 2.06, P < 0.05). Additionally, the subepicardial APOI (APOI-epi) increased significantly at 84 weeks of age (P < 0.05). Bax/Bcl-2 ratio was higher in SHR than WKY at 66 weeks (3.98 ± 0.80 vs. 0.29 ± 0.06, P < 0.05), and enhanced further at 102 weeks of age (10.54 ± 1.60 vs. 0.70 ± 0.13, P < 0.05). Myocardial APOI was positively correlated with LVMI (r = 0.83, P < 0.01), negatively with LVEF in 66–102 weeks (r = −0.81, P < 0.01), and positively with Bax/Bcl-2 ratio (r = 0.79, P < 0.01). Conclusion Myocardial apoptosis increases with aging and is associated with progressive left ventricular remodeling and cardiac dysfunction in SHR.

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Atorvastatin Attenuates Myocardial Hypertrophy in Spontaneously Hypertensive Rats via the C/EBPβ/PGC-1α/UCP3 Pathway

Cellular Physiology and Biochemistry ◽

10.1159/000488832 ◽

2018 ◽

Vol 46 (3) ◽

pp. 1009-1018 ◽

Cited By ~ 2

Author(s):

Yintao Chen ◽

Ye Chang ◽

Naijin Zhang ◽

Xiaofan Guo ◽

Guozhe Sun ◽

...

Keyword(s):

Spontaneously Hypertensive Rats ◽

Myocardial Hypertrophy ◽

Intervention Group ◽

Left Ventricular ◽

Pleiotropic Effects ◽

Distilled Water ◽

Hypertensive Rats ◽

Atorvastatin Treatment ◽

Spontaneously Hypertensive ◽

Significant Difference

Background/Aims: Many clinical and experimental studies have shown that treatment with statins could prevent myocardial hypertrophy and remodeling induced by hypertension and myocardial infarction. But the molecular mechanism was not clear. We aimed to investigate the beneficial effects of atorvastatin on hypertension-induced myocardial hypertrophy and remodeling in spontaneously hypertensive rats (SHR) with the hope of revealing other potential mechanisms or target pathways to interpret the pleiotropic effects of atorvastatin on myocardial hypertrophy. Methods: The male and age-matched animals were randomly divided into three groups: control group (8 WKY), SHR (8 rats) and intervention group (8 SHR). The SHR in intervention group were administered by oral gavage with atorvastatin (suspension in distilled water, 10 mg/Kg once a day) for 6 weeks, and the other two groups were administered by gavage with equal quantity distilled water. Blood pressure of rats was measured every weeks using a standard tail cuff sphygmomanometer. Left ventricular (LV) dimensions were measured from short-axis views of LV under M-mode tracings using Doppler echocardiograph. Cardiomyocyte apoptosis was assessed by the TUNEL assay. The protein expression of C/EBPβ, PGC-1α and UCP3 were detected by immunohistochemistry or Western blot analysis. Results: At the age of 16 weeks, the mean arterial pressure of rats in three groups were 103.6±6.1, 151.8±12.5 and 159.1±6.2 mmHg respectively, and there wasn’t statistically significant difference between the SHR and intervention groups. Staining with Masson’s trichrome demonstrated that the increased interstitial fibrosis of LV and ventricular remodeling in the SHR group were attenuated by atorvastatin treatment. Echocardiography examination exhibited that SHR with atorvastatin treatment showed an LV wall thickness that was obviously lower than that of water-treated SHR. In hypertrophic myocardium, accompanied by increasing C/EBPβ expression and the percentage of TUNEL-positive cells, the expression of Bcl-2/Bax ratio, PGC-1α and UCP3 were reduced, all of which could be abrogated by treatment with atorvastatin for 6 weeks. Conclusion: This study further confirmed that atorvastatin could attenuate myocardial hypertrophy and remodeling in SHR by inhibiting apoptosis and reversing changes in mitochondrial metabolism. The C/EBPβ/PGC-1α/UCP3 signaling pathway might also be important for elucidating the beneficial pleiotropic effects of atorvastatin on myocardial hypertrophy.

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Protective Effects of Galium verum L. Extract against Cardiac Ischemia/Reperfusion Injury in Spontaneously Hypertensive Rats

Oxidative Medicine and Cellular Longevity ◽

10.1155/2019/4235405 ◽

2019 ◽

Vol 2019 ◽

pp. 1-11 ◽

Cited By ~ 4

Author(s):

Jovana Bradic ◽

Vladimir Zivkovic ◽

Ivan Srejovic ◽

Vladimir Jakovljevic ◽

Anica Petkovic ◽

...

Keyword(s):

Cardiac Function ◽

Plant Species ◽

Structural Damage ◽

Spontaneously Hypertensive Rats ◽

Ischemia Reperfusion ◽

Left Ventricular ◽

Herbaceous Plant ◽

Hypertensive Rats ◽

Spontaneously Hypertensive

Galium verum L. (G. verum, lady’s bedstraw) is a perennial herbaceous plant, belonging to the Rubiaceae family. It has been widely used throughout history due to multiple therapeutic properties. However, the effects of this plant species on functional recovery of the heart after ischemia have still not been fully clarified. Therefore, the aim of our study was to examine the effects of methanol extract of G. verum on myocardial ischemia/reperfusion (I/R) injury in spontaneously hypertensive rats (SHR), with a special emphasis on the role of oxidative stress. Rats involved in the research were divided randomly into two groups: control (spontaneously hypertensive rats (SHR)) and G. verum group, including SHR rats treated with the G. verum extract (500 mg/kg body weight per os) for 4 weeks. At the end of the treatment, in vivo cardiac function was assessed by echocardiography. Rats were sacrificed and blood samples were taken for spectrophotometric determination of systemic redox state. Hearts from all rats were isolated and retrogradely perfused according to the Langendorff technique. After a stabilization period, hearts were subjected to 20-minute ischemia, followed by 30-minute reperfusion. Levels of prooxidants were spectrophotometrically measured in coronary venous effluent, while antioxidant enzymes activity was assessed in heart tissue. Cell morphology was evaluated by hematoxylin and eosin (HE) staining. 4-week treatment with G. verum extract alleviated left ventricular hypertrophy and considerably improved in vivo cardiac function. Furthermore, G. verum extract preserved cardiac contractility, systolic function, and coronary vasodilatory response after ischemia. Moreover, it alleviated I/R-induced structural damage of the heart. Additionally, G. verum extract led to a drop in the generation of most of the measured prooxidants, thus mitigating cardiac oxidative damage. Promising potential of G. verum in the present study may be a basis for further researches which would fully clarify the mechanisms through which this plant species triggers cardioprotection.

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