scholarly journals Ventricular-arterial coupling in nondilated chronic heart failure following coronary artery ligation in mice

2002 ◽  
Vol 39 ◽  
pp. 301
Author(s):  
Svetlana A. Voltchikhina ◽  
Bryan C. Yacono ◽  
Linda Cheng ◽  
Edward G. Lakatta ◽  
Mark I. Talan
Keyword(s):  
Heart Failure ◽  
Coronary Artery ◽  
Chronic Heart Failure ◽  
Coronary Artery Ligation ◽  
Artery Ligation

scholarly journals Inhibition of N-type calcium channels in cardiac sympathetic neurons attenuates ventricular arrhythmogenesis in heart failure

2020 ◽  
Author(s):  
Dongze Zhang ◽  
Huiyin Tu ◽  
Chaojun Wang ◽  
Liang Cao ◽  
Wenfeng Hu ◽  
...  
Keyword(s):  
Heart Failure ◽  
Coronary Artery ◽  
Ventricular Arrhythmias ◽  
Sympathetic Neurons ◽  
Coronary Artery Ligation ◽  
Channel Blockers ◽  
Artery Ligation ◽  
Cell Excitability ◽  
Ventricular Arrhythmogenesis

Abstract Aims Cardiac sympathetic overactivation is an important trigger of ventricular arrhythmias in patients with chronic heart failure (CHF). Our previous study demonstrated that N-type calcium (Cav2.2) currents in cardiac sympathetic post-ganglionic (CSP) neurons were increased in CHF. This study investigated the contribution of Cav2.2 channels in cardiac sympathetic overactivation and ventricular arrhythmogenesis in CHF. Methods and results Rat CHF was induced by surgical ligation of the left coronary artery. Lentiviral Cav2.2-α shRNA or scrambled shRNA was transfected in vivo into stellate ganglia (SG) in CHF rats. Final experiments were performed at 14 weeks after coronary artery ligation. Real-time polymerase chain reaction and western blot data showed that in vivo transfection of Cav2.2-α shRNA reduced the expression of Cav2.2-α mRNA and protein in the SG in CHF rats. Cav2.2-α shRNA also reduced Cav2.2 currents and cell excitability of CSP neurons and attenuated cardiac sympathetic nerve activities (CSNA) in CHF rats. The power spectral analysis of heart rate variability (HRV) further revealed that transfection of Cav2.2-α shRNA in the SG normalized CHF-caused cardiac sympathetic overactivation in conscious rats. Twenty-four-hour continuous telemetry electrocardiogram recording revealed that this Cav2.2-α shRNA not only decreased incidence and duration of ventricular tachycardia/ventricular fibrillation but also improved CHF-induced heterogeneity of ventricular electrical activity in conscious CHF rats. Cav2.2-α shRNA also decreased susceptibility to ventricular arrhythmias in anaesthetized CHF rats. However, Cav2.2-α shRNA failed to improve CHF-induced cardiac contractile dysfunction. Scrambled shRNA did not affect Cav2.2 currents and cell excitability of CSP neurons, CSNA, HRV, and ventricular arrhythmogenesis in CHF rats. Conclusions Overactivation of Cav2.2 channels in CSP neurons contributes to cardiac sympathetic hyperactivation and ventricular arrhythmogenesis in CHF. This suggests that discovering purely selective and potent small-molecule Cav2.2 channel blockers could be a potential therapeutic strategy to decrease fatal ventricular arrhythmias in CHF.

scholarly journals Mitigation of the progression of heart failure with sildenafil involves inhibition of RhoA/Rho-kinase pathway

2011 ◽  
Vol 300 (6) ◽  
pp. H2272-H2279 ◽  
Author(s):  
Vinh Q. Chau ◽  
Fadi N. Salloum ◽  
Nicholas N. Hoke ◽  
Antonio Abbate ◽  
Rakesh C. Kukreja
Keyword(s):  
Heart Failure ◽  
Coronary Artery ◽  
Rho Kinase ◽  
Inhibitory Effect ◽  
Left Ventricular ◽  
Coronary Artery Ligation ◽  
Artery Ligation ◽  
Saline Treatment ◽  
Kinase Pathway ◽  
Fractional Shortening

Chronic inhibition of phosphodiesterase-5 with sildenafil immediately after permanent occlusion of the left anterior descending coronary artery was shown to limit ischemic heart failure (HF) in mice. To mimic a more clinical scenario, we postulated that treatment with sildenafil beginning at 3 days post-myocardial infarction (MI) would also reduce HF progression through the inhibition of the RhoA/Rho-kinase pathway. Adult male ICR mice with fractional shortening < 25% at day 3 following permanent left anterior descending coronary artery ligation were continuously treated with either saline (volume matched, ip, 2 times/day) or sildenafil (21 mg/kg, ip, 2 times/day) for 25 days. Echocardiography showed fractional shortening preservation and less left ventricular end-diastolic dilatation with sildenafil treatment compared with saline treatment at 7 and 28 days post-MI ( P < 0.05). Both fibrosis and apoptosis, determined by Masson's trichrome and terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling (TUNEL), respectively, were attenuated in the sildenafil-treated mice ( P < 0.05 vs. saline). Western blot analysis showed enchanced Bcl-2-to-Bax ratio with sildenafil treatment ( P < 0.05 vs. saline). Activity assay showed sildenafil-mediated PKG activation 1 day after treatment ( P < 0.05 vs. sham and saline). PKG activation was associated with sildenafil-mediated inhibition of Rho kinase ( P < 0.05) compared with saline treatment, whereas PKG inhibition with KT-5823 abolished this inhibitory effect of sildenafil. In conclusion, for the first time, our findings show that chronic sildenafil treatment, initiated at 3 days post-MI, attenuates left ventricular dysfunction independent of its infarct-sparing effect, and this cardioprotection involves the inhibition of the RhoA/Rho-kinase pathway. Sildenafil may be a promising therapeutic tool for advanced HF in patients.

nNOS gene transfer to RVLM improves baroreflex function in rats with chronic heart failure

2003 ◽  
Vol 285 (4) ◽  
pp. H1660-H1667 ◽  
Author(s):  
Yu Wang ◽  
Kaushik P. Patel ◽  
Kurtis G. Cornish ◽  
Keith M. Channon ◽  
Irving H. Zucker
Keyword(s):  
Heart Failure ◽  
Chronic Heart Failure ◽  
Gene Transfer ◽  
Recombinant Adenovirus ◽  
Ventrolateral Medulla ◽  
Coronary Artery Ligation ◽  
Artery Ligation ◽  
Baroreflex Control ◽  
Intravenous Injections ◽  
Baroreflex Function

We hypothesized that gene transfer of neuronal nitric oxide synthase (nNOS) into the rostral ventrolateral medulla (RVLM) improves baroreflex function in rats with chronic heart failure (CHF). Six to eight weeks after coronary artery ligation, rats showed hemodynamic signs of CHF. A recombinant adenovirus, either Ad.nNOS or Ad.β-Gal, was transfected into the RVLM. nNOS expression in the RVLM was confirmed by Western blot analysis, NADPH-diaphorase, and immunohistochemical staining. We studied baroreflex control of the heart rate (HR) and renal sympathetic nerve activity (RSNA) in the anesthetized state 3 days after gene transfer by intravenous injections of phenylephrine and nitroprusside. Baroreflex sensitivity was depressed for HR and RSNA regulation in CHF rats (2.0 ± 0.3 vs. 0.8 ± 0.2 beats · min–1 · mmHg–1, P < 0.01 and 3.8 ± 0.3 vs. 1.2 ± 0.1% max/mmHg, P < 0.01, respectively). Ad.nNOS transfer into RVLM significantly increased the HR and RSNA ranges (152 ± 19 vs. 94 ± 12 beats/min, P < 0.05 and 130 ± 16 vs. 106 ± 5% max/mmHg, P < 0.05) compared with the Ad.β-Gal in CHF rats. Ad.nNOS also improved the baroreflex gain for the control of HR and RSNA (1.8 ± 0.2 vs. 0.8 ± 0.2 beats · min–1 · mmHg–1, P < 0.01 and 2.6 ± 0.2 vs. 1.2 ± 0.1% max/mmHg, P < 0.01). In sham-operated rats, we found that Ad.nNOS transfer enhanced the HR range compared with Ad.β-Gal gene transfer (188 ± 15 vs. 127 ± 14 beats/min, P < 0.05) but did not alter any other parameter. This study represents the first demonstration of altered baroreflex function following increases in central nNOS in the CHF state. We conclude that delivery of Ad.nNOS into the RVLM improves baroreflex function in rats with CHF.

scholarly journals ERK1/2 MAPK signaling in hypothalamic paraventricular nucleus contributes to sympathetic excitation in rats with heart failure after myocardial infarction

2016 ◽  
Vol 310 (6) ◽  
pp. H732-H739 ◽  
Author(s):  
Yang Yu ◽  
Shun-Guang Wei ◽  
Zhi-Hua Zhang ◽  
Robert M. Weiss ◽  
Robert B. Felder
Keyword(s):  
Myocardial Infarction ◽  
Heart Failure ◽  
Coronary Artery ◽  
Paraventricular Nucleus ◽  
Sympathetic Nerve ◽  
Sympathetic Nerve Activity ◽  
Mapk Signaling ◽  
Coronary Artery Ligation ◽  
Nerve Activity ◽  
Artery Ligation

Brain MAPK signaling pathways are activated in heart failure (HF) induced by myocardial infarction and contribute to augmented sympathetic nerve activity. We tested whether decreasing ERK1/2 (also known as p44/42 MAPK) signaling in the hypothalamic paraventricular nucleus (PVN), a forebrain source of presympathetic neurons, would reduce the upregulation of sympathoexcitatory mediators in the PVN and augmented sympathetic nerve activity in rats with HF. Sprague-Dawley rats underwent left anterior descending coronary artery ligation to induce HF, with left ventricular dysfunction confirmed by echocardiography. One week after coronary artery ligation or sham operation, small interfering (si)RNAs targeting ERK1/2 or a nontargeting control siRNA was microinjected bilaterally into the PVN. Experiments were conducted 5–7 days later. Confocal images revealed reduced phosphorylated ERK1/2 immunofluorescence in the PVN of HF rats treated with ERK1/2 siRNAs compared with HF rats treated with control siRNA. Western blot analysis confirmed significant reductions in both total and phosphorylated ERK1/2 in the PVN of HF rats treated with ERK1/2 siRNAs along with reduced expression of renin-angiotensin system components and inflammatory mediators. HF rats treated with ERK1/2 siRNAs also had reduced PVN neuronal excitation (fewer Fos-related antigen-like-immunoreactive neurons), lower plasma norepinephrine levels, and improved peripheral manifestations of HF compared with HF rats treated with control siRNAs. These results demonstrate that ERK1/2 signaling in the PVN plays a pivotal role in mediating sympathetic drive in HF induced by myocardial infarction and may be a novel target for therapeutic intervention.

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