scholarly journals Enhanced activation of RVLM-projecting PVN neurons in rats with chronic heart failure

2012 ◽  
Vol 302 (8) ◽  
pp. H1700-H1711 ◽  
Author(s):  
Bo Xu ◽  
Hong Zheng ◽  
Kaushik P. Patel
Keyword(s):  
Heart Failure ◽  
Chronic Heart Failure ◽  
Internal Carotid ◽  
Discharge Rate ◽  
Nmda Receptor Antagonist ◽  
Ventrolateral Medulla ◽  
Coronary Artery Ligation ◽  
Artery Ligation ◽  
The Mean ◽  
Hypertonic Stimulation

Previous studies have indicated that there is increased activation of the paraventricular nucleus (PVN) in rats with chronic heart failure (CHF); however, it is not clear if the preautonomic neurons within the PVN are specifically overactive. Also, it is not known if these neurons have altered responses to baroreceptor or osmotic challenges. Experiments were conducted in rats with CHF (6–8 wk after coronary artery ligation). Spontaneously active neurons were recorded in the PVN, of which 36% were antidromically activated from the rostral ventrolateral medulla (RVLM). The baseline discharge rate in RVLM-projecting PVN (PVN-RVLM) neurons from CHF rats was significantly greater than in sham-operated (sham) rats (6.0 ± 0.6 vs. 2.6 ± 0.3 spikes/s, P < 0.05). Picoinjection of the N-methyl-d-aspartate (NMDA) receptor antagonist d,l-2-amino-5-phosphonovaleric acid significantly decreased the basal discharge of PVN-RVLM neurons by 80% in CHF rats compared with 37% in sham rats. Fifty-two percent of spontaneously active PVN-RVLM neurons responded to changes in the mean arterial pressure (MAP). The changes in discharge rate in PVN-RVLM neurons after a reduction in MAP (+52 ± 7% vs. +184 ± 61%) or an increase in MAP (−42 ± 8% vs. −71 ± 6%) were significantly attenuated in rats with CHF compared with sham rats. Most PVN-RVLM neurons (63%), including all barosensitive PVN-RVLM neurons, were excited by an internal carotid artery injection of hypertonic NaCl (2.1 osmol/l), whereas a smaller number (7%) were inhibited. The increase in discharge rate in PVN-RVLM neurons to hypertonic stimulation was significantly enhanced in rats with CHF compared with sham rats (134 ± 15% vs. 92 ± 13%). Taken together, these data suggest that PVN-RVLM neurons are more active under basal conditions and this overactivation is mediated by an enhanced glutamatergic tone in rats with CHF. Furthermore, this enhanced activation of PVN-RVLM neurons may contribute to the altered responses to baroreceptor and osmotic challenges observed during 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.

Impairment of cGMP- and cAMP-mediated vasorelaxations in rats with chronic heart failure

1996 ◽  
Vol 271 (6) ◽  
pp. H2228-H2237 ◽  
Author(s):  
Y. Nasa ◽  
H. Toyoshima ◽  
H. Ohaku ◽  
Y. Hashizume ◽  
A. Sanbe ◽  
...  
Keyword(s):  
Heart Failure ◽  
Chronic Heart Failure ◽  
Water Soluble ◽  
Cgmp Level ◽  
Coronary Artery Ligation ◽  
No Production ◽  
Vascular Relaxation ◽  
Artery Ligation ◽  
Reduction Of No ◽  
Cyclic Monophosphate

To elucidate pathophysiological alterations in vascular relaxation in rats with chronic heart failure (CHF), guanosine 3',5'-cyclic monophosphate (cGMP)- and adenosine 3',5'-cyclic monophosphate (cAMP)-mediated vasorelaxations in pulmonary artery (PA) and thoracic aorta (TA) of rats were examined 12 wk after coronary artery ligation. Acetylcholine (ACh)-induced relaxation was attenuated in endothelium-intact segments of both arteries, whereas sodium nitroprusside-induced relaxation was attenuated only in endothelium-intact TA segments of rats with CHF. Vasorelaxations elicited by isoproterenol and NKH-477, a water-soluble forskolin analogue, were diminished mainly in PA segments of the CHF rat. NG-nitro-L-arginine methyl ester (L-NAME)-induced decrease in cGMP level was less in endothelium-intact TA segments of the rat with CHF (0.20 +/- 0.06 vs. 0.99 +/- 0.26 pmol/mg protein in control), suggesting that basal nitric oxide (NO) production is reduced in CHF. Treatment with L-NAME attenuated the isoproterenol-induced relaxation only in endothelium-intact TA segments in control rats but not in CHF rats. The results suggest that both cGMP- and cAMP-mediated relaxations are impaired in CHF, and a reduction of NO synthesis, presumably in endothelial cells, plays a significant role in pathophysiological alterations in vessels of rats with CHF.

scholarly journals Effects of nitrite infusion on skeletal muscle vascular control during exercise in rats with chronic heart failure

2015 ◽  
Vol 309 (8) ◽  
pp. H1354-H1360 ◽  
Author(s):  
Angela A. Glean ◽  
Scott K. Ferguson ◽  
Clark T. Holdsworth ◽  
Trenton D. Colburn ◽  
Jennifer L. Wright ◽  
...  
Keyword(s):  
Heart Failure ◽  
Skeletal Muscle ◽  
Chronic Heart Failure ◽  
Myocardial Infarct ◽  
Muscle Blood Flow ◽  
Coronary Artery Ligation ◽  
Myocardial Infarct Size ◽  
Sprague Dawley ◽  
Vascular Control ◽  
Artery Ligation

Chronic heart failure (CHF) reduces nitric oxide (NO) bioavailability and impairs skeletal muscle vascular control during exercise. Reduction of NO2− to NO may impact exercise-induced hyperemia, particularly in muscles with pathologically reduced O2 delivery. We tested the hypothesis that NO2− infusion would increase exercising skeletal muscle blood flow (BF) and vascular conductance (VC) in CHF rats with a preferential effect in muscles composed primarily of type IIb + IId/x fibers. CHF (coronary artery ligation) was induced in adult male Sprague-Dawley rats. After a >21-day recovery, mean arterial pressure (MAP; carotid artery catheter) and skeletal muscle BF (radiolabeled microspheres) were measured during treadmill exercise (20 m/min, 5% incline) with and without NO2− infusion. The myocardial infarct size (35 ± 3%) indicated moderate CHF. NO2− infusion increased total hindlimb skeletal muscle VC (CHF: 0.85 ± 0.09 ml·min−1·100 g−1·mmHg−1 and CHF + NO2−: 0.93 ± 0.09 ml·min−1·100 g−1·mmHg−1, P < 0.05) without changing MAP (CHF: 123 ± 4 mmHg and CHF + NO2−: 120 ± 4 mmHg, P = 0.17). Total hindlimb skeletal muscle BF was not significantly different (CHF: 102 ± 7 and CHF + NO2−: 109 ± 7 ml·min−1·100 g−1 ml·min−1·100 g−1, P > 0.05). BF increased in 6 (∼21%) and VC in 8 (∼29%) of the 28 individual muscles and muscle parts. Muscles and muscle portions exhibiting greater BF and VC after NO2− infusion comprised ≥63% type IIb + IId/x muscle fibers. These data demonstrate that NO2− infusion can augment skeletal muscle vascular control during exercise in CHF rats. Given the targeted effects shown herein, a NO2−-based therapy may provide an attractive “needs-based” approach for treatment of the vascular dysfunction in CHF.

scholarly journals The effects of dietary fish oil on exercising skeletal muscle vascular and metabolic control in chronic heart failure rats

2014 ◽  
Vol 39 (3) ◽  
pp. 299-307 ◽  
Author(s):  
Clark T. Holdsworth ◽  
Steven W. Copp ◽  
Daniel M. Hirai ◽  
Scott K. Ferguson ◽  
Gabrielle E. Sims ◽  
...  
Keyword(s):  
Heart Failure ◽  
Chronic Heart Failure ◽  
Fish Oil ◽  
Blood Lactate ◽  
Diastolic Pressure ◽  
Muscle Blood Flow ◽  
Left Ventricular ◽  
Coronary Artery Ligation ◽  
Artery Ligation ◽  
Pufa Supplementation

Impaired vasomotor control in chronic heart failure (CHF) is due partly to decrements in nitric oxide synthase (NOS) mediated vasodilation. Exercising muscle blood flow (BF) is augmented with polyunsaturated fatty acid (PUFA) supplementation via fish oil (FO) in healthy rats. We hypothesized that FO would augment exercising muscle BF in CHF rats via increased NO-bioavailability. Myocardial infarction (coronary artery ligation) induced CHF in Sprague–Dawley rats which were subsequently randomized to dietary FO (20% docosahexaenoic acid, 30% eicosapentaenoic acid, n = 15) or safflower oil (SO, 5%, n = 10) for 6–8 weeks. Mean arterial pressure (MAP), blood [lactate], and hindlimb muscles BF (radiolabeled microspheres) were determined at rest, during treadmill exercise (20 m·min−1, 5% incline) and exercise + NG-nitro-l-arginine-methyl-ester (l-NAME) (a nonspecific NOS inhibitor). FO did not change left ventricular end-diastolic pressure (SO: 14 ± 2; FO: 11 ± 1 mm Hg, p > 0.05). During exercise, MAP (SO: 128 ± 3; FO: 132 ± 3 mm Hg) and blood [lactate] (SO: 3.8 ± 0.4; FO: 4.6 ± 0.5 mmol·L−1) were not different (p > 0.05). Exercising hindlimb muscle BF was lower in FO than SO (SO: 120 ± 11; FO: 93 ± 4 mL·min−1·100 g−1, p < 0.05) but was not differentially affected by l-NAME. Specifically, 17 of 28 individual muscle BF’s were lower (p < 0.05) in FO demonstrating that PUFA supplementation with FO in CHF rats does not augment muscle BF during exercise but may lower metabolic cost.

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

AIM2-driven inflammasome activation in chronic heart failure

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
M Ruppert ◽  
Z.S Onodi ◽  
P Leszek ◽  
V.E Toth ◽  
G Koncsos ◽  
...  
Keyword(s):  
Heart Failure ◽  
Chronic Heart Failure ◽  
Animal Models ◽  
Left Ventricular ◽  
Inflammasome Activation ◽  
Coronary Artery Ligation ◽  
Funding Source ◽  
Human Cardiomyocytes ◽  
Pannexin 1 ◽  
End Stage

Abstract Background Inflammation and cytokine release have been implicated in the pathogenesis of chronic heart failure (CHF). Of particular interest, Canakinumab, a monoclonal antibody against interleukin-1b (IL-1β), had provided benefit against cardiovascular events, suggesting that blockade of IL-1β secretion and signaling might be a promising new therapeutic target. Although, recent studies have provided evidence that inflammasome activation is the main contributor to IL-1β maturation, the role of inflammasome activation in CHF remains unknown. Objective Therefore, we aimed to assess inflammasome activation in myocardial samples from end-stage failing hearts. Methods Inflammasome activation was assessed by immunoblotting in left ventricular myocardial specimens harvested from patients with end-stage CHF. Furthermore, immunoblot measurements were also performed on translational animal models of CHF (e.g. rat models of permanent coronary artery ligation and transverse aortic constriction). Left ventricular monocyte and macrophage infiltration was detected by immunohistochemistry. To investigate the molecular background of inflammasome activation, a series of cell culture experiments were performed on AC16 human cardiomyocytes and THP-1 human monocytic cell lines. Results Out of the 4 major inflammasome sensors tested, expression of the inflammasome protein absent in melanoma 2 (AIM2) and NLR family CARD domain-containing protein 4 (NLRC4) increased in human CHF while the NLRP1 and NLRP3 (NLR family, pyrin domain containing 1 and 3) inflammasome showed no change. A similar expression pattern in AIM2 and NLRC4 was also noted in CHF animal models. Furthermore, robust infiltration of Iba1+ monocytes/macrophages was observed in human failing hearts as well as in different animal models of CHF. In vitro AIM2 inflammasome activation, as induced by transfection with double-stranded DNA [poly(deoxyadenylic-deoxythymidylic)] was reduced significantly by the pharmacological blockade of pannexin-1 channels. Conclusions AIM2 and NLRC4 inflammasome activation might contribute to chronic inflammation in CHF. Our findings suggest that pannexin-1 channels might be a promising novel target to reduce inflammasome activation. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): NVKP_16-1-2016-0017

scholarly journals Altered Na/Ca exchange distribution in ventricular myocytes from failing hearts

2016 ◽  
Vol 310 (2) ◽  
pp. H262-H268 ◽  
Author(s):  
Hanne C. Gadeberg ◽  
Simon M. Bryant ◽  
Andrew F. James ◽  
Clive H. Orchard
Keyword(s):  
Heart Failure ◽  
Ventricular Myocytes ◽  
Cell Voltage ◽  
Coronary Artery Ligation ◽  
Sham Operation ◽  
Ca Current ◽  
Artery Ligation ◽  
Whole Cell ◽  
Rat Hearts ◽  
T Tubules

In mammalian cardiac ventricular myocytes, Ca efflux via Na/Ca exchange (NCX) occurs predominantly at T tubules. Heart failure is associated with disrupted t-tubular structure, but its effect on t-tubular function is less clear. We therefore investigated t-tubular NCX activity in ventricular myocytes isolated from rat hearts ∼18 wk after coronary artery ligation (CAL) or corresponding sham operation (Sham). NCX current ( INCX) and l-type Ca current ( ICa) were recorded using the whole cell, voltage-clamp technique in intact and detubulated (DT) myocytes; intracellular free Ca concentration ([Ca]i) was monitored simultaneously using fluo-4. INCX was activated and measured during application of caffeine to release Ca from sarcoplasmic reticulum (SR). Whole cell INCX was not significantly different in Sham and CAL myocytes and occurred predominantly in the T tubules in Sham myocytes. CAL was associated with redistribution of INCX and ICa away from the T tubules to the cell surface and an increase in t-tubular INCX/ ICa density from 0.12 in Sham to 0.30 in CAL myocytes. The decrease in t-tubular INCX in CAL myocytes was accompanied by an increase in the fraction of Ca sequestered by SR. However, SR Ca content was not significantly different in Sham, Sham DT, and CAL myocytes but was significantly increased by DT of CAL myocytes. In Sham myocytes, there was hysteresis between INCX and [Ca]i, which was absent in DT Sham but present in CAL and DT CAL myocytes. These data suggest altered distribution of NCX in CAL myocytes.

Abstract P237: Is Ischemia/Reperfusion an Efficient Method for Producing Heart Failure in Rats?

Hypertension ◽  
2016 ◽  
Vol 68 (suppl_1) ◽  
Author(s):  
Ana Carolina M Omoto ◽  
Fábio N Gava ◽  
Mauro de Oliveira ◽  
Carlos A Silva ◽  
Rubens Fazan ◽  
...  
Keyword(s):  
Heart Failure ◽  
Diastolic Pressure ◽  
Histopathological Examination ◽  
Ischemia Reperfusion ◽  
Mitral Annulus ◽  
Mortality Rates ◽  
Tissue Doppler ◽  
Left Ventricular ◽  
Coronary Artery Ligation ◽  
Artery Ligation

Myocardium infarction (MI) elicited by coronary artery ligation (CAL) is commonly used to induce chronic heart failure (HF) in rats. However, CAL shows high mortality rates. Given that ischemia-reperfusion (IR) may cause the development of HF, this approach may be useful for obtaining a model of HF with low mortality rates. Therefore, it was compared the model of CAL vs. IR in rats, evaluating the mortality and cardiac morphological and functional aspects. The IR consisted of 30 minutes of cardiac ischemia. Wistar rats were assigned into three groups: CAL: n=18; IR: n=7; SHAM (fictitious IR): n=7. After four weeks of CAL, the subjects were evaluated by echocardiography and ventriculography as well. The statistical analysis consisted of ANOVA combined with Tukey’s posthoc test (p<0.05). There were no deaths in the IR and SHAM groups, whereas in the CAL group the mortality rate was 33.33% (6 out of 18). In the CAL group echocardiography showed increased left ventricular (LV) cavity during systole (8.3 ± 1mm) and diastole (10.5 ± 1mm); decreased LV free wall during systole (1.4 ± 0.5 mm); increased left atrium/aorta (2.3 ± 0.4) ratio. These changes were not significant in IR (4.8 ± 0.5mm, 7.6 ± 0.6mm, 2.6 ± 0.3 mm, 1.6 ± 0.2) and SHAM (4.6 ± 0.6 mm, 7.7 ± 0.8mm, 2.8 ± 0.4mm, 1.5 ± 0.2) groups. There was also the reduction in the ejection fraction in the CAL group (41 ± 12 %) when compared with IR (65 ± 9%) and SHAM (69 ± 7%) groups. The tissue Doppler analysis from the lateral mitral annulus showed reduction in E′ in CAL (-29 ± 8 mm/s) and IR (-31± 9 mm/s) groups when compared with the SHAM (-48 ± 11 mm/s) group. The ventriculography in the CAL group showed smaller maximum dP/dt (6519 ± 1062) and greater end-diastolic pressure (33 ± 8 mmHg) when compared with IR (8716 ± 756 mmHg/s; 9 ± 9 mmHg) and SHAM (7989 ± 1230 mmHg/s; 9 ± 7 mmHg) groups. The CAL group presented transmural infarct size of 40% of the left ventricular wall, measured under histopathological examination. In conclusion, IR for 30 minutes caused only small changes in LV diastolic function, assessed by tissue Doppler; however, the IR was not effective for promoting HF, as observed with CAL. Thus, it is possible that prolonged IR is necessary for promoting significant HF in rats.

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