Combined Inotropic and Bradycardic Effects of a Sodium Channel Enhancer in Conscious Dogs with Heart Failure: A Mechanism for Improved Myocardial Efficiency Compared with Dobutamine

2002 ◽  
Vol 303 (2) ◽  
pp. 673-680 ◽  
Author(s):  
Weiqun Shen ◽  
Robert M. Gill ◽  
Bonita D. Jones ◽  
Jian-Ping Zhang ◽  
Angela K. Corbly ◽  
...  
Keyword(s):  
Heart Failure ◽  
Sodium Channel ◽  
Conscious Dogs ◽  
Myocardial Efficiency

scholarly journals Propylbutyldopamine: hemodynamic effects in conscious dogs, normal human volunteers and patients with heart failure.

Circulation ◽  
1983 ◽  
Vol 67 (4) ◽  
pp. 829-836 ◽  
Author(s):  
W H Fennell ◽  
A A Taylor ◽  
J B Young ◽  
T A Brandon ◽  
J Z Ginos ◽  
...  
Keyword(s):  
Heart Failure ◽  
Conscious Dogs ◽  
Hemodynamic Effects ◽  
Human Volunteers ◽  
Patients With Heart Failure ◽  
Normal Human

Mechanisms of Nitrate Accumulation in Plasma during Pacing-Induced Heart Failure in Conscious Dogs

Nitric Oxide ◽  
1997 ◽  
Vol 1 (5) ◽  
pp. 386-396 ◽  
Author(s):  
Robert D. Bernstein ◽  
Xiaoping Zhang ◽  
Gong Zhao ◽  
Paul Forfia ◽  
Joshua Tuzman ◽  
...  
Keyword(s):  
Heart Failure ◽  
Conscious Dogs ◽  
Nitrate Accumulation

scholarly journals Short-term effects of naloxone hemodynamics and baroreflex function in conscious dogs with pacing-induced congestive heart failure

1994 ◽  
Vol 23 (1) ◽  
pp. 194-200 ◽  
Author(s):  
Yoshihiro Himura ◽  
Chang-Seng Liang ◽  
Naoaki Imai ◽  
Joseph M. Delehanty ◽  
Paul D. Woolf ◽  
...  
Keyword(s):  
Heart Failure ◽  
Congestive Heart Failure ◽  
Conscious Dogs ◽  
Short Term ◽  
Baroreflex Function ◽  
Short Term Effects

SCN10A-knock-out improves survival and proarrhythmia in a transgenic heart failure mouse model

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
P.R.F Bengel ◽  
C Krekeler ◽  
S Ahmad ◽  
N Hartmann ◽  
P Tirilomis ◽  
...  
Keyword(s):  
Heart Failure ◽  
Mouse Model ◽  
Sodium Channel ◽  
Structural Parameters ◽  
Left Ventricular ◽  
Heart Weight ◽  
Na Channel ◽  
Funding Source ◽  
Patch Clamp Technique ◽  
Knock Out

Abstract Background In heart failure (HF) both Ca2+/Calmodulin-dependent protein-kinase II (CaMKII) and late sodium current (INaL) are known to contribute to arrhythmogenesis as they contribute to action-potential (AP) prolongation and the occurrence of early- (EADs) and delayed afterdepolarizations (DADs). Further, augmented CaMKII and INaL maintain a vicious cycle as they both can activate each other. We recently found that the sodium channel isoform NaV1.8 is upregulated in HF and hypertrophy and that it is involved in INaL-generation. In the current study we investigated the effects of NaV1.8-knock-out (KO) on HF-progression and arrhythmogenesis in a CaMKII-overexpressing HF mouse model. Methods/Results CaMKII overexpressing mice (CaMKII+/T) were crossbred with NaV1.8-KO mice (SCN10A−/−). To our surprise knock-out of NaV1.8 in CaMKII+/T mice (SCN10A−/−/CaMKII+/T) significantly improved survival (median survival 103 days vs 74.5 CaMKII+/T, p<0.01). CaMKII+/T mice exhibited a strong HF phenotype compared to WT with increased heart-weight to tibia length ratio as well as reduced ejection fraction and left-ventricular end-diastolic diameter obtained by echocardiography. However, these structural parameters did not differ between SCN10A−/−/CaMKII+/T and CaMKII+/T. Therefore, cellular electrophysiology experiments were performed in isolated cardiomyocytes for a better understanding of the observed improvement in survival. INaL, measured by patch-clamp technique, was significantly augmented in CaMKII+/T vs WT and SCN10A−/−, while SCN10A−/−/CaMKII+/T showed significantly less INaL than CaMKII+/T alone. Further, AP-duration (APD) was significantly reduced in SCN10A−/−/CaMKII+/T vs CaMKII+/T while AP-amplitude, resting membrane-potential and upstroke velocity (dv/dtmax) remained unchanged. In addition, the occurrence of afterdepolarizations was significantly lower in SCN10A−/−/ CaMKII+/T vs CaMKII+/T. Confocal microscopy using the dye Fluo-4AM was performed and significantly less diastolic Ca2+-waves occurred in SCN10A−/−/CaMKII+/T compared to CaMKII+/T. In order to analyze an organ-specific SCN10A-KO, we generated homozygous SCN10A-KO lines of induced pluripotent stem cells by using CRISPR/Cas9 technology. 2-month old iPSC-cardiomyocytes lacking NaV1.8 were treated with low dose isoprenaline and showed significantly less INaL, thereby serving as a final proof of the relevant role of this Na+-channel on INaL-generation in the cardiomyocyte. Conclusion We found a survival benefit by selective knock-out of the neuronal sodium channel isoform NaV1.8 in a proarrhythmic HF mouse model with augmented CaMKII expression. However, in our model NaV1.8-knock-out showed no effects on HF progression, while cellular proarrhythmic triggers were attenuated. Taken together with our findings in IPS-cardiomyocytes treated with the CRSIPR/Cas9 technology NaV1.8 plays a significant role for the generation of INaL and cellular arrhythmogenic triggers in the cardiomyocyte. Funding Acknowledgement Type of funding source: Foundation. Main funding source(s): Deutsche Stiftung für Herzforschung

Mechanisms of desensitization to a PDE inhibitor (milrinone) in conscious dogs with heart failure

1999 ◽  
Vol 276 (5) ◽  
pp. H1699-H1705 ◽  
Author(s):  
Naoki Sato ◽  
Kuniya Asai ◽  
Satoshi Okumura ◽  
Gen Takagi ◽  
Richard P. Shannon ◽  
...  
Keyword(s):  
Heart Failure ◽  
Wall Stress ◽  
Major Effect ◽  
Left Ventricular ◽  
Conscious Dogs ◽  
Internal Diameter ◽  
Compensatory Mechanism ◽  
Before And After ◽  
Rapid Ventricular Pacing ◽  
Camp Levels

The goal of this study was to determine the extent to which the effects of milrinone were desensitized in heart failure (HF) and to determine the mechanisms, i.e., whether these effects could be ascribed to changes in cAMP or phosphodiesterase (PDE) activity in HF. Accordingly, we examined the effects of milrinone in seven conscious dogs before and after HF was induced by rapid ventricular pacing at 240 beats/min. The dogs were chronically instrumented for measurements of left ventricular (LV) pressure and first derivative of LV pressure (dP/d t), arterial pressure, LV internal diameter, and wall thickness. Milrinone (10 μg ⋅ kg−1 ⋅ min−1iv) increased LV dP/d t by 1,854 ± 157 from 2,701 ± 105 mmHg/s ( P < 0.05) before HF. After HF the increase in LV dP/d t in response to milrinone was attenuated significantly ( P < 0.05); it increased by 615 ± 67 from 1,550 ± 107 mmHg/s, indicating marked desensitization. In the presence of ganglionic blockade the increases in LV dP/d t (+445 ± 65 mmHg/s) in response to milrinone were markedly less ( P < 0.01), and milrinone increased LV dP/d t even less in HF (+240 ± 65 mmHg/s). cAMP and PDE activity were measured in endocardial and epicardial layers in normal and failing myocardium. cAMP was decreased significantly ( P < 0.05) in LV endocardium (−26%) but not significantly in LV epicardium (−14%). PDE activity was also decreased significantly ( P < 0.05) in LV endocardium (−18%) but not in LV epicardium (−4%). Thus significant desensitization to milrinone was observed in conscious dogs with HF. The major effect was autonomically mediated. The biochemical mechanism appears to be due in part to the modest reductions in PDE activity in failing myocardium, which, in turn, may be a compensatory mechanism to maintain cAMP levels in HF. Reductions in cAMP and PDE levels were restricted to the subendocardium, suggesting that the increased wall stress and reduced coronary reserve play a role in mediating these changes.

scholarly journals A randomised, double‐blind, placebo‐controlled trial of metformin on myocardial efficiency in insulin‐resistant chronic heart failure patients without diabetes

2019 ◽  
Vol 22 (9) ◽  
pp. 1628-1637 ◽  
Author(s):  
Anders Hostrup Larsen ◽  
Niels Jessen ◽  
Helene Nørrelund ◽  
Lars Poulsen Tolbod ◽  
Hendrik Johannes Harms ◽  
...  
Keyword(s):  
Heart Failure ◽  
Chronic Heart Failure ◽  
Controlled Trial ◽  
Double Blind ◽  
Double Blind Placebo ◽  
Heart Failure Patients ◽  
Insulin Resistant ◽  
Myocardial Efficiency
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