Chronic blockade of brain "ouabain" prevents sympathetic hyper-reactivity and impairment of acute baroreflex resetting in rats with congestive heart failure

1999 ◽  
Vol 78 (1) ◽  
pp. 45-53
Author(s):  
Bing S Huang ◽  
Baoxue Yuan ◽  
Frans HH Leenen
Keyword(s):  
Heart Failure ◽  
Heart Rate ◽  
Congestive Heart Failure ◽  
Venous Pressure ◽  
Control Group ◽  
Coronary Artery Ligation ◽  
Artery Ligation ◽  
Sympathetic Hyperactivity ◽  
Air Jet ◽  
Baroreflex Function

In rats with congestive heart failure (CHF) post myocardial infarction (MI) acute blockade of brain "ouabain" reverses sympathetic hyperactivity and chronic blockade prevents the desensitization of baroreflex function. This study was conducted to determine: i) if chronic blockade of brain "ouabain" maintains normal sympathetic reactivity; andii) if acute baroreflex resetting (another parameter of baroreflex function) also becomes impaired, and if so, does brain "ouabain" contribute to impairment in acute baroreflex resetting. CHF post MI was induced by acute coronary artery ligation in Wistar rats. Animals were treated with 200 µg·day-1 i.c.v. or i.v. Fab fragments (which bind brain "ouabain" with high affinity), or treated with 200 µg·day-1 i.c.v. gamma-globulins (control group). The length of treatment was 0.5-8 weeks or 4-8 weeks post MI. At 8 weeks mean arterial pressure (MAP), central venous pressure (CVP), heart rate (HR), and renal sympathetic nerve activity (RSNA) were recorded in concious rats at rest and in response to: i) air-jet stress, ii) i.c.v. guanabenz (an α2-adrenoceptor agonist), and iii) a 30 min i.v. infusion of nitroprusside (NP). Excitatory responses to air stress and inhibitory responses to guanabenz of MAP, HR, and RSNA were significantly enhanced in rats with CHF versus the sham-operated treated group. This enhancement was prevented in the CHF group treated with i.c.v., but not i.v., Fab. Nitroprusside induced a sustained decrease in MAP (~ 25 mmHg) and a transient decrease in CVP. Heart rate and RSNA increased significantly within 1 min of beginning the infusion. The peak increases as well as the product of changes in MAP-HR and RSNA-HR were significantly smaller in rats with CHF treated with gamma-globulins versus sham rats and versus CHF rats treated with i.c.v. Fab. In sham-operated rats and CHF rats treated with i.c.v. Fab, RSNA and HR began to decrease within 3-4 min of beginning the NP infusion and had returned to baseline by 20 min. In contrast, RSNA and HR remained increased throughout the infusion in the CHF rats treated with gamma-globulins. These data indicate that in rats with CHF acute resetting of the arterial baroreflex in response to a lower BP becomes impaired, and chronic blockade of brain "ouabain" prevents both this change in baroreflex resetting as well as sympathetic hyperactivity.Key words: heart failure, acute baroreflex resetting, sympathetic hyperactivity, nitroprusside.

Blockade of brain mineralocorticoid receptors or Na+ channels prevents sympathetic hyperactivity and improves cardiac function in rats post-MI

2005 ◽  
Vol 288 (5) ◽  
pp. H2491-H2497 ◽  
Author(s):  
Bing S. Huang ◽  
Frans H. H. Leenen
Keyword(s):  
Cardiac Function ◽  
Left Ventricular ◽  
Coronary Artery Ligation ◽  
Mineralocorticoid Receptors ◽  
Artery Ligation ◽  
Sympathetic Hyperactivity ◽  
Air Jet ◽  
Baroreflex Function ◽  
Adrenoceptor Agonist ◽  
The Brain

In rats post-myocardial infarction (MI), sympathetic hyperactivity can be prevented by blockade of brain mineralocorticoid receptors (MR). Stimulatory responses to central infusion of aldosterone can be blocked by benzamil and therefore appear to be mediated via Na+ channels, presumably epithelial Na+ channels (ENaC), in the brain. To evaluate this concept of endogenous mineralocorticoids in Wistar rats post-MI, we examined effects of blockade of MR and Na+ channels in the brain. At 3 days after coronary artery ligation, intracerebroventricular infusions were started with spironolactone (400 ng·kg−1·h−1) or its vehicle, or with benzamil (4 μg·kg−1·h−1) or its vehicle, using osmotic minipumps. Rats with sham ligation served as control. After 4 wk, in conscious rats, mean arterial pressure, heart rate, and renal sympathetic nerve activity were recorded at rest and in response to air-jet stress, intracerebroventricular injection of the α2-adrenoceptor agonist guanabenz, and intravenous infusion of phenylephrine and nitroprusside for baroreflex function. MI size was similar among the four groups of rats (∼31%). In rats treated post-MI with vehicles, cardiac function was decreased, sympathetic reactivity was enhanced, and baroreflex function was impaired. Blockade of brain Na+ channels or brain MR similarly prevented sympathetic hyperactivity and impairment of baroreflex function and improved cardiac function. These findings suggest that in rats post-MI, increased binding of endogenous agonists to MR increases ENaC activity in the brain and thereby leads to sympathetic hyperactivity and progressive left ventricular dysfunction.

Role of ETA receptors in the regulation of vascular reactivity in rats with congestive heart failure

2000 ◽  
Vol 279 (2) ◽  
pp. H844-H851 ◽  
Author(s):  
Eric Thorin ◽  
Martin Lucas ◽  
Peter Cernacek ◽  
Jocelyn Dupuis
Keyword(s):  
Heart Failure ◽  
Congestive Heart Failure ◽  
Smooth Muscle ◽  
Vascular Reactivity ◽  
Cerebral Arteries ◽  
No Synthase ◽  
Cerebrovascular Reactivity ◽  
Coronary Artery Ligation ◽  
Artery Ligation ◽  
Endothelial Denudation

Endothelium-derived nitric oxide (NO) and endothelin (ET)-1 interact to regulate vascular tone. In congestive heart failure (CHF), the release and/or the activity of both factors is affected. We hypothesized that the increased ET-1 production associated with CHF may result in a reduced smooth muscle sensitivity to NO. The aim of this study was to evaluate the effects of a chronic treatment with the ETA-receptor (ET receptor A) antagonist LU-135252 (LU) on cerebrovascular reactivity to sodium nitroprusside (SNP) in the rat infarct model of CHF. Rats were subjected to coronary artery ligation and were treated for 4 wk with placebo ( n = 24) or LU (50 mg · kg−1 · day−1, n = 29). CHF was associated with a decreased ( P < 0.05) efficacy of SNP to induce relaxation of isolated middle cerebral arteries. Furthermore, neither NO synthase inhibition with N ω-nitro-l-arginine (l-NNA) nor endothelial denudation affected the efficacy of SNP. Thus the endothelium no longer influences smooth muscle sensitivity to SNP. LU treatment, however, normalized ( P < 0.05) smooth muscle sensitivity to SNP. Sensitivity of ET-1-induced contraction was increased in CHF only in the presence of l-NNA, whereas contraction induced by ETB receptor (receptor B) stimulation was increased ( P < 0.05) in endothelium-denuded vessels. LU treatment restored these changes in reactivity and revealed a significant endothelium-dependent ETB-mediated relaxation after NO synthase inhibition. In conclusion, CHF decreases and uncouples cerebrovascular smooth muscle sensitivity to SNP from endothelial regulation. The observation that chronic ETAblockade restored most of the changes associated with CHF suggests that activation of the ET-1 system importantly contributes to the alteration in vascular reactivity observed in experimental CHF.

Brain renin-angiotensin system and sympathetic hyperactivity in rats after myocardial infarction

1999 ◽  
Vol 276 (5) ◽  
pp. H1608-H1615 ◽  
Author(s):  
Weiguo Zhang ◽  
Bing S. Huang ◽  
Frans H. H. Leenen
Keyword(s):  
Renin Angiotensin System ◽  
Coronary Artery Ligation ◽  
Arterial Baroreflex ◽  
Baroreflex Control ◽  
Angiotensin System ◽  
Sympathetic Hyperactivity ◽  
Renin Angiotensin ◽  
Air Jet ◽  
Baroreflex Function ◽  
The Brain

Blockade of brain “ouabain” prevents the sympathetic hyperactivity and impairment of baroreflex function in rats with congestive heart failure (CHF). Because brain “ouabain” may act by activating the brain renin-angiotensin system (RAS), the aim of the present study was to assess whether chronic treatment with the AT1-receptor blocker losartan given centrally normalizes the sympathetic hyperactivity and impairment of baroreflex function in Wistar rats with CHF postmyocardial infarction (MI). After left coronary artery ligation (2 or 6 wk), rats received either intracerebroventricular losartan (1 mg ⋅ kg−1 ⋅ day−1, CHF-Los) or vehicle (CHF-Veh) by osmotic minipumps. To assess possible peripheral effects of intracerebroventricular losartan, one set of CHF rats received the same rate of losartan subcutaneously. Sham-operated rats served as control. After 2 wk of treatment, mean arterial pressure (MAP), heart rate (HR), and renal sympathetic nerve activity (RSNA) at rest and in response to air-jet stress and intracerebroventricular injection of the α2-adrenoceptor-agonist guanabenz were measured in conscious animals. Arterial baroreflex function was evaluated by ramp changes in MAP. Compared with sham groups, CHF-Veh groups showed impaired arterial baroreflex control of HR and RSNA, increased sympathoexcitatory and pressor responses to air-jet stress, and increased sympathoinhibitory and hypotensive responses to guanabenz. The latter is consistent with decreased activity in sympathoinhibitory pathways. Chronic intracerebroventricular infusion of losartan largely normalized these abnormalities. In CHF rats, the same rate of infusion of losartan subcutaneously was ineffective. In sham-operated rats, losartan intracerebroventricularly or subcutaneously did not affect sympathetic activity. We conclude that the chronic increase in sympathoexcitation, decrease in sympathoinhibition, and desensitized baroreflex function in CHF all appear to depend on the brain RAS, since this whole pattern of changes can be normalized by chronic central AT1-receptor blockade with losartan.

Abstract 17163: Prolonged Increase in Endothelium-Specific NOX2-Derived Cytosolic Oxidants Exacerbates Maladaptive Cardiac Remodeling in Ischemic Myocardium

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Rayane Brinck Teixeira ◽  
Melissa Pfeiffer ◽  
Catherine Karbasiafshar ◽  
Frank W Sellke ◽  
Ruhul Abid
Keyword(s):  
Heart Failure ◽  
Heart Rate ◽  
Left Ventricle ◽  
Wall Thickness ◽  
Molecular Mechanisms ◽  
Prolonged Exposure ◽  
Coronary Artery Ligation ◽  
Artery Ligation ◽  
Left Ventricle Mass

Introduction: Global increase in reactive oxygen species (ROS) in endothelial cells (EC) plays major roles in cardiovascular disease (CVD). However, the precise role of ROS within specific compartments of ECs are not yet known. This study aims to address the role of endothelium-derived cytosolic ROS in myocardial infarction (MI). Hypothesis: We hypothesized that an extended exposure to increased NADPH oxidase 2 (NOX2)-derived cytosolic ROS in EC would result in a worse post-MI outcome. Methods: Binary conditional transgenic mice expressing NOX2 in an EC-specific manner (NOX2VE) were studied. NOX2VE mice were assigned to tetracycline (Tet)-ON (control) to turn off transgene, or without Tet as Tet-OFF, i.e. NOX2- O ver E xpressing (NOX2VE-OE) groups. After 15 weeks of Tet-ON/OFF treatment, all mice were subjected to left anterior descending (LAD) coronary artery ligation that mimics acute MI (n=10/group). Left ventricle function was assessed by echocardiography 28 days post LAD. Ejection fraction (EF), fractional shortening (FS), left ventricle mass, wall thickness, heart rate, chamber diameter and volume at systole and diastole were analyzed by Student’s t-test. Results: Echocardiographic data showed that mice subjected to an increased NOX2-derived ROS in EC (NOX2VE-OE) presented with 19.3 ± 7.7% and 20.8 ± 7.9% decrease in EF and FS, respectively (p<0.05) compared to control (NOX2VE, Tet-ON). NOX2VE-OE mice showed an increase (by 14.1 ± 3.4%, p<0.01) in diastolic posterior wall thickness (DPWT) suggesting ventricular stiffness. NOX2VE-OE group also showed increased cardiac mass (by 14.0 ± 5.4%, p<0.05), which, along with DPWT indicates hypertrophy with a likelihood to develop heart failure. Interestingly, heart rate, systolic and diastolic chamber volume and diameters, stroke volume, and cardiac output showed no differences between the groups (p>0.05). Conclusions: Together, these results suggest that prolonged exposure to increased cytosolic ROS in coronary EC results in worse cardiac performance and myocardial stiffness, leading to a higher propensity to heart failure after MI. Currently, in vivo signaling studies are being carried out to understand molecular mechanisms by which NOX2-derived ROS in ECs result in impaired cardiac function.

scholarly journals Effects of Dantrolene on Arrhythmogenicity in Isolated Regional Ischemia-Reperfusion Rabbit Hearts with or without Pacing-Induced Heart Failure

2015 ◽  
Vol 2015 ◽  
pp. 1-12 ◽  
Author(s):  
Chung-Chuan Chou ◽  
Hui-Ling Lee ◽  
Po-Cheng Chang ◽  
Hung-Ta Wo ◽  
Ming-Shien Wen ◽  
...  
Keyword(s):  
Heart Failure ◽  
Ischemia Reperfusion ◽  
Rabbit Model ◽  
Control Group ◽  
Ventricular Premature Beat ◽  
Coronary Artery Ligation ◽  
Artery Ligation ◽  
Regional Ischemia ◽  
Intracellular Ca

Dantrolene was reported to suppress ventricular fibrillation (VF) in failing hearts with acute myocardial infarction, but its antiarrhythmic efficacy in regional ischemia-reperfusion (IR) hearts remains debatable. Heart failure (HF) was induced by right ventricular pacing. The IR rabbit model was created by coronary artery ligation for 30 min, followed by reperfusion for 15 min in vivo in both HF and non-HF groups (n= 9 in each group). Simultaneous voltage and intracellular Ca2+(Cai) optical mapping was then performed in isolated Langendorff-perfused hearts. Electrophysiological studies were conducted and VF inducibility was evaluated by dynamic pacing. Dantrolene (10 μM) was administered after baseline studies. The HF group had a higher VF inducibility than the control group. Dantrolene had both antiarrhythmic (prolonged action potential duration (APD) and effective refractory period) and proarrhythmic effects (slowed conduction velocity, steepened APD restitution slope, and enhanced arrhythmogenic alternans induction) but had no significant effects on ventricular premature beat (VPB) suppression and VF inducibility in both groups. A higher VF conversion rate in the non-HF group was likely due to greater APD prolonging effects in smaller hearts compared to the HF group. The lack of significant effects on VPB suppression by dantrolene suggests that triggered activity might not be the dominant mechanism responsible for VPB induction in the IR model.

The nonpeptide angiotensin-(1–7) receptor Mas agonist AVE-0991 attenuates heart failure induced by myocardial infarction

2007 ◽  
Vol 292 (2) ◽  
pp. H1113-H1119 ◽  
Author(s):  
Anderson J. Ferreira ◽  
Bruno A. Jacoby ◽  
Cícero A. A. Araújo ◽  
Filipe A. F. F. Macedo ◽  
Gerluza A. B. Silva ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Heart Failure ◽  
Heart Rate ◽  
Renin Angiotensin System ◽  
Coronary Artery Ligation ◽  
Artery Ligation ◽  
Beneficial Effects ◽  
Isolated Hearts ◽  
Infarcted Area ◽  
Selective Ligand

The nonpeptide AVE-0991, which has been reported as a selective ligand for the angiotensin-(1–7) [ANG-(1–7)] receptor Mas, has actions similar to those attributed to the cardioprotective product of the renin-angiotensin system, ANG-(1–7). In this study, we evaluated the cardiac effects of AVE-0991 in normal and infarcted male Wistar rats. Myocardial infarction was induced by left coronary artery ligation. At the end of the treatment, the Langendorff technique was used to analyze cardiac function. Left ventricle serial sections were dyed with Gomori trichrome stain to quantify the infarcted area. In normal hearts, AVE-0991 produced a significant decrease in perfusion pressure and an increase in systolic tension, rate of tension rise and fall (±dT/d t), and heart rate. These effects were completely blocked by the perfusion of the hearts with a solution containing the selective ANG-(1–7) antagonist A-779. NG-nitro-l-arginine methyl ester treatment abolished the AVE-0991-induced vasodilation in isolated hearts. AVE-0991 significantly attenuated the decrease in systolic tension (sham operated, 13.00 ± 1.02 g; infarction, 7.18 ± 0.66 g; AVE treated, 9.23 ± 1.05 g, n = 5), +dT/d t, −dT/d t, and heart rate induced by myocardial infarction. Infarction-induced vasoconstriction was completely prevented by AVE-0991 treatment. Furthermore, AVE-0991 significantly decreased the infarcted area (6.98 ± 1.01 vs. 3.94 ± 1.04 mm2 in AVE-treated rats). These data indicate that the compound AVE-0991 produces beneficial effects in isolated perfused rat hearts involving the ANG-(1–7) receptor Mas and the release of nitric oxide. In addition, our results indicate that AVE-0991 attenuates postischemic heart failure.

Persistent alterations in heart rate variability, baroreflex sensitivity, and anxiety-like behaviors during development of heart failure in the rat

2008 ◽  
Vol 295 (1) ◽  
pp. H29-H38 ◽  
Author(s):  
Marcus Henze ◽  
Davin Hart ◽  
Allen Samarel ◽  
John Barakat ◽  
Laurie Eckert ◽  
...  
Keyword(s):  
Heart Failure ◽  
Heart Rate ◽  
Heart Rate Variability ◽  
Baroreflex Sensitivity ◽  
Elevated Plus Maze ◽  
Low Frequency ◽  
Coronary Artery Ligation ◽  
Artery Ligation ◽  
Arterial Blood ◽  
Plus Maze

Depressed heart rate variability and mood are associated with increased mortality in patients with congestive heart failure (CHF). Here autonomic indexes were assessed 3 and 7 wk after left coronary artery ligation in telemetered rats, after which anxiety-like behaviors were assessed in an elevated plus maze. Low frequency (LF) and high frequency (HF) heart rate variability were reduced in CHF rats 3 wk after infarction (LF, 1.60 ± 0.52 vs. 6.97 ± 0.79 ms2; and HF, 1.53 ± 0.39 vs. 6.20 ± 1.01 ms2; P < 0.01). The number of sequences of interbeat intervals that correlated with arterial pressure was decreased in CHF rats at 3 and 7 wk ( week 3, 26.60 ± 10.85 vs. 59.75 ± 11.4 sequences, P < 0.05; and week 7, 20.80 ± 8.97 vs. 65.38 ± 5.89 sequences, P < 0.01). Sequence gain was attenuated in CHF rats by 7 wk (1.34 ± 0.06 vs. 2.70 ± 0.29 ms/mmHg, P < 0.01). Coherence between interbeat interval and mean arterial blood pressure variability in the LF domain was reduced in CHF rats at 3 (0.12 ± 0.03 vs. 0.26 ± 0.05 k2, P < 0.05) and 7 (0.16 ± 0.02 vs. 0.31 ± 0.05 k2, P < 0.05) wk. CHF rats invariably entered the open arm of the elevated plus maze first and spent more time in the open arms (36.0 ± 15% vs. 4.6 ± 1.9%, P < 0.05). CHF rats also showed a tendency to jump head first off the apparatus, whereas controls did not. Together the data indicate that severe autonomic dysfunction is accompanied by escape-seeking behaviors in rats with verified CHF.

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.

Normal contractions triggered by I Ca,L in ventricular myocytes from rats with postinfarction CHF

2002 ◽  
Vol 283 (3) ◽  
pp. H1225-H1236 ◽  
Author(s):  
Ivar Sjaastad ◽  
Janny Bøkenes ◽  
Fredrik Swift ◽  
J. Andrew Wasserstrom ◽  
Ole M. Sejersted
Keyword(s):  
Heart Failure ◽  
Congestive Heart Failure ◽  
Coronary Artery ◽  
Sarcoplasmic Reticulum ◽  
Ventricular Myocytes ◽  
Cardiac Contractility ◽  
Left Ventricular ◽  
Coronary Artery Ligation ◽  
Artery Ligation ◽  
Fractional Shortening

Attenuated L-type Ca2+ current ( I Ca,L), or current-contraction gain have been proposed to explain impaired cardiac contractility in congestive heart failure (CHF). Six weeks after coronary artery ligation, which induced CHF, left ventricular myocytes from isoflurane-anesthetized rats were current or voltage clamped from −70 mV. In both cases, contraction and contractility were attenuated in CHF cells compared with cells from sham-operated rats when cells were only minimally dialyzed using high-resistance microelectrodes. With patch pipettes, cell dialysis caused attenuation of contractions in sham cells, but not CHF cells. Stepping from −50 mV, the following variables were not different between sham and CHF, respectively: peak I Ca,L (4.5 ± 0.3 vs. 3.8 ± 0.3 pApF−1 at 23°C and 9.4 ± 0.5 vs. 8.4 ± 0.5 pApF−1 at 37°C), the bell-shaped voltage-contraction relationship in Cs+ solutions (fractional shortening, 15.2 ± 1.0% vs. 14.3 ± 0.7%, respectively, at 23°C and 7.5 ± 0.4% vs. 6.7 ± 0.5% at 37°C) and the sigmoidal voltage-contraction relationship in K+ solutions. Caffeine-induced Ca2+ release and sarcoplasmic reticulum Ca2+-ATPase-to-phospholamban ratio were not different. Thus CHF contractions triggered by I Ca,L were normal, and the contractile deficit was only seen in undialyzed cardiomyocytes stimulated from −70 mV.

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