Enhanced coronary vasodilation in isolated Langendorff‐perfused hearts of asthmatic mice

Abstract Background Voltage-gated K+ (Kv) channels in coronary artery smooth muscle cells (CSMCs), especially the major specific Kv1 subfamily, contribute to coronary artery vasodilation. Advanced glycation end products (AGEs) have been strongly implicated in diabetes-related cardiovascular complications. Our previous study showed AGEs can impair Kv channel-mediated coronary vasodilation by reducing Kv channel activity. However, its underlying mechanism remains unclear. Purpose Here, we used isolated rat small coronary arteries (RSCAs) and primary CSMCs to investigate the effect of AGEs on Kv channel-mediated coronary vasodilation and the possible involvement of peroxisome proliferators-activated receptor (PPAR)-γ pathway. Methods RSCAs and primary CSMCs were isolated, cultured and treated with bovine serum albumin (BSA), AGE-BSA, alagrebrium (ALA, AGE cross-linking breaker), pioglitazone (PIO) and/or GW9662, and then divided into the following groups: DMEM, BSA, AGE, AGE+ALA, AGE+PIO, and AGE+PIO+GW9662. Kv channel-mediated coronary vasodilation was analyzed using wire myograph. Histology and immunohistochemistry of RSCAs were performed. Western blot was used to detect the protein expression of RAGE, the major Kv1 channel subunits expressed in CSMCs (Kv1.2/1.5), PPAR-γ, and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase-2 (NOX-2). Results AGEs markedly reduced forskolin-induced Kv channel-mediated vasodilation of RSCAs by interacting with the receptor for AGEs (RAGE), and ALA or PIO significantly reversed this effect. In both RSCAs and primary CSMCs, AGEs decreased Kv1.2 and Kv1.5 channel protein expression, inhibited PPAR-γ expression, increased RAGE and NOX-2 expression. Treatment with ALA or PIO partially reversed the effects of AGEs on Kv1.2/Kv1.5 expression, accompanied by elevation of PPAR-γ level and diminished oxidative stress. Conclusion AGE/RAGE axis-induced inhibition of PPAR-γ pathway and enhancement of oxidative stress may contribute to AGEs-mediated Kv channel dysfunction and coronary vasodilation in RSCAs. Our results may provide new insights into developing therapeutic strategies to manage diabetic vasculature. Funding Acknowledgement Type of funding source: Foundation. Main funding source(s): National Natural Science Foundation of China; Natural Science Foundation of Beijing (7172059)

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Effects of genetic background, sex, and age on murine atrial electrophysiology

EP Europace ◽

10.1093/europace/euaa369 ◽

2021 ◽

Author(s):

Julius Obergassel ◽

Molly O’Reilly ◽

Laura C Sommerfeld ◽

S Nashitha Kabir ◽

Christopher O’Shea ◽

...

Keyword(s):

Genetic Background ◽

Monophasic Action Potential ◽

Atrial Arrhythmias ◽

Activation Time ◽

Factors Influencing ◽

Normal Ranges ◽

Atrial Electrophysiology ◽

Cycle Lengths ◽

Perfused Hearts ◽

Atrial Effective Refractory Period

Abstract Aims Genetically altered mice are powerful models to investigate mechanisms of atrial arrhythmias, but normal ranges for murine atrial electrophysiology have not been robustly characterized. Methods and results We analyzed results from 221 electrophysiological (EP) studies in isolated, Langendorff-perfused hearts of wildtype mice (114 female, 107 male) from 2.5 to 17.7 months (mean 7 months) with different genetic backgrounds (C57BL/6, FVB/N, MF1, 129/Sv, Swiss agouti). Left atrial monophasic action potential duration (LA-APD), interatrial activation time (IA-AT), and atrial effective refractory period (ERP) were summarized at different pacing cycle lengths (PCLs). Factors influencing atrial electrophysiology including genetic background, sex, and age were determined. LA-APD70 was 18 ± 0.5 ms, atrial ERP was 27 ± 0.8 ms, and IA-AT was 17 ± 0.5 ms at 100 ms PCL. LA-APD was longer with longer PCL (+17% from 80 to 120 ms PCL for APD70), while IA-AT decreased (−7% from 80 to 120 ms PCL). Female sex was associated with longer ERP (+14% vs. males). Genetic background influenced atrial electrophysiology: LA-APD70 (−20% vs. average) and atrial ERP (−25% vs. average) were shorter in Swiss agouti background compared to others. LA-APD70 (+25% vs. average) and IA-AT (+44% vs. average) were longer in 129/Sv mice. Atrial ERP was longer in FVB/N (+34% vs. average) and in younger experimental groups below 6 months of age. Conclusion This work defines normal ranges for murine atrial EP parameters. Genetic background has a profound effect on these parameters, at least of the magnitude as those of sex and age. These results can inform the experimental design and interpretation of murine atrial electrophysiology.

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Treatment of type 2 diabetic db/db mice with a novel PPARγ agonist improves cardiac metabolism but not contractile function

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00329.2003 ◽

2004 ◽

Vol 286 (3) ◽

pp. E449-E455 ◽

Cited By ~ 70

Author(s):

Andrew N. Carley ◽

Lisa M. Semeniuk ◽

Yakhin Shimoni ◽

Ellen Aasum ◽

Terje S. Larsen ◽

...

Keyword(s):

Contractile Function ◽

Ex Vivo ◽

Metabolic Changes ◽

Pparγ Agonist ◽

Perfused Hearts ◽

Type 2 Diabetic ◽

Contractile Performance ◽

Exogenous Substrates

Hearts from insulin-resistant type 2 diabetic db/db mice exhibit features of a diabetic cardiomyopathy with altered metabolism of exogenous substrates and reduced contractile performance. Therefore, the effect of chronic oral administration of 2-(2-(4-phenoxy-2-propylphenoxy)ethyl)indole-5-acetic acid (COOH), a novel ligand for peroxisome proliferator-activated receptor-γ that produces insulin sensitization, to db/db mice (30 mg/kg for 6 wk) on cardiac function was assessed. COOH treatment reduced blood glucose from 27 mM in untreated db/db mice to a normal level of 10 mM. Insulin-stimulated glucose uptake was enhanced in cardiomyocytes from COOH-treated db/db hearts. Working perfused hearts from COOH-treated db/db mice demonstrated metabolic changes with enhanced glucose oxidation and decreased palmitate oxidation. However, COOH treatment did not improve contractile performance assessed with ex vivo perfused hearts and in vivo by echocardiography. The reduced outward K+ currents in diabetic cardiomyocytes were still attenuated after COOH. Metabolic changes in COOH-treated db/db hearts are most likely indirect, secondary to changes in supply of exogenous substrates in vivo and insulin sensitization.

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The dark side of the moon of coronary vasodilation

European Journal of Nuclear Medicine and Molecular Imaging ◽

10.1007/s00259-016-3416-3 ◽

2016 ◽

Vol 43 (8) ◽

pp. 1491-1492

Author(s):

Raffaele Giubbini ◽

Francesco Bertagna

Keyword(s):

Dark Side ◽

The Moon ◽

Coronary Vasodilation

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Coronary vasodilation and positive inotropism by urocortin in the isolated rat heart

Journal of Endocrinology ◽

10.1677/joe.0.1690177 ◽

2001 ◽

Vol 169 (1) ◽

pp. 177-183 ◽

Cited By ~ 64

Author(s):

K Terui ◽

A Higashiyama ◽

N Horiba ◽

KI Furukawa ◽

S Motomura ◽

...

Keyword(s):

Rat Heart ◽

Isolated Rat Heart ◽

Coronary Vasodilation ◽

Duration Of Action ◽

Inotropic Effects ◽

Vasodilator Effect ◽

Cardiac Effects ◽

Positive Inotropic Effects ◽

Isolated Rat

Corticotropin-releasing factor (CRF) has a coronary vasodilator effect and a positive inotropic effect on the isolated rat heart. Recently, expression of CRF receptor type 2 (CRF-R2) has been demonstrated in the heart. In addition, urocortin (Ucn), a new member of the CRF family, has been reported to have much greater affinity for CRF-R2 than CRF. It is suggested that the cardiac effects of Ucn may be more potent than those of CRF. We compared the effect of Ucn with that of CRF on isolated rat heart. The effects of Ucn were then analyzed to determine whether these effects were mediated by CRF receptors and/or any other mediators under the following conditions: perfusion buffer containing (1) alpha-helical CRF 9-41, (2) indomethacin, (3) N(G)-nitro-l -arginine methylester and (4) propranolol. Ucn exhibited a greater effect with a longer duration of action than CRF. Indomethacin significantly attenuated the vasodilator effects of Ucn (P<0.05). CRF receptor antagonist diminished both coronary vasodilation and the positive inotropic effects of Ucn (P<0.05). These results suggest that the cardiac effects of Ucn may be mediated by a CRF receptor, and prostaglandins may be involved in the vasodilator effect.

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