Mechanism of β-Adrenergic Receptor Upregulation Induced by ACE Inhibition in Cultured Neonatal Rat Cardiac Myocytes

Yonemochi, Hidetoshi; Yasunaga, Seikoh; Teshima, Yasushi; Iwao, Tetsu; Akiyoshi, Kumiko; Nakagawa, Mikiko; Saikawa, Tetsunori; Ito, Morio

doi:10.1161/01.cir.97.22.2268

Cited by 36 publications

(25 citation statements)

References 27 publications

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“…Alternatively, a low ACE activity could enhance substrate mobilisation by interference with hormonal counterregulation, e.g. the response of [28,33] or sensitivity to [34,35] catecholamines that constitute the primary hormonal defence against hypoglycaemia in Type 1 diabetes when the glucagon response is lost.…”

Section: Discussionmentioning

confidence: 99%

Prediction of Severe Hypoglycaemia by Angiotensin-Converting Enzyme Activity and Genotype in Type 1 Diabetes

et al. 2003

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Aims/hypothesis. We have previously shown a strong relationship between high angiotensin-converting enzyme (ACE) activity, presence of the deletion (D) allele of the ACE gene and recall of severe hypoglycaemic events in patients with Type 1 diabetes. This study was carried out to assess this relationship prospectively. Methods. We followed 171 adult outpatients with Type 1 diabetes in a one-year observational study with the recording of severe hypoglycaemia. Participants were characterised by serum ACE activity and ACE genotype and not treated with ACE inhibitors or angiotensin II receptor antagonists.Results. There was a positive relationship between serum ACE activity and rate of severe hypoglycaemia with a 2.7 times higher rate in the fourth quartile of ACE activity compared to the first quartile (p=0.0007). A similar relationship was observed for the subset of episodes with coma (2.9 times higher rate in fourth quartile compared to first quartile; p=0.048). The impact of serum ACE activity was most pronounced in C-peptide negative subjects (4.2 times higher rate in fourth quartile compared to first quartile; p=0.003), and in this subgroup carriers of the D allele of the ACE gene had higher rates of severe hypoglycaemia compared to the group homozygous for the insertion (I) allele. In a multiple regression analysis high serum ACE activity and impaired awareness of hypoglycaemia were identified as the only significant predictors of severe hypoglycemia. To avoid progression of these frequent episodes into severe hypoglycaemia patients rely on maintenance of performance capacity [3] until hypoglycaemic symptoms are recognised and self-treated or until the next pre-scheduled meal is ingested.Risk of severe hypoglycaemia is a major limiting factor for the achievement of good metabolic control [4] rendering prediction of individual risk of severe hypoglycaemia increasingly important. Loss of hypoglycaemic warning symptoms and blunted hormonal counterregulatory response are the most important known predictors of severe hypoglycaemia [4,5]. However, even patients at high risk according to these paFollowing the Diabetes Control and Complications Trial [1] a growing demand for strict glycaemic control has emerged to avoid late diabetic complications in Type 1 diabetes. As a consequence the majority of patients with Type 1 diabetes experience mild hypoglycaemia on a regular basis and recent studies applying continuous glucose monitoring indicate that pa-

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Section: Discussionmentioning

confidence: 99%

Prediction of Severe Hypoglycaemia by Angiotensin-Converting Enzyme Activity and Genotype in Type 1 Diabetes

et al. 2003

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“…Cardiac myocytes were prepared from 3-to 5-day-old Wistar rats, as described previously. 10,11 Briefly, hearts removed under ether anesthesia were minced into 1-mm 3 pieces in PBS. After treatment with 0.02% EDTA, the pieces were incubated in 5 mL of HBSS containing 2 mg/mL collagenase (type IV; Cooper Biochemical) for 10 minutes at 37°C, and then in 5 mL of Ca 2ϩ -and Mg 2ϩ -free HBSS containing 1000 IU/mL dispase (Godo Shusei) for 20 minutes at 37°C.…”

Section: Cell Culturementioning

confidence: 99%

“…As previously described, 10 15 We also evaluated the frequency-and time-dependent effects of rapid pacing on ␤-AR density and inhibitory effects of BDM and taxol on rapid pacing-induced reduction in ␤-AR density in the presence of 10 nmol/L [ 3 H]CGP-12177. Agonist competition binding curves were constructed with 5 nmol/L [ 3 H]CGP-12177 and ISP (10 Ϫ10 to 5ϫ10 Ϫ4 mol/L) at 14 different concentrations.…”

Section: Measurement Of Cardiac ␤-Ar Densitymentioning

confidence: 99%

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Rapid Electrical Stimulation of Contraction Reduces the Density of β-Adrenergic Receptors and Responsiveness of Cultured Neonatal Rat Cardiomyocytes

et al. 2000

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Background-Although tachycardia is commonly present in patients with congestive heart failure, its role in the development of congestive heart failure remains unclear. We studied the effect of rapid electrical stimulation of contraction on ␤-adrenergic receptor (␤-AR) signal pathway in cultured cardiomyocytes of neonatal rats. Methods and Results-Contraction of cardiomyocytes was induced by electrical stimulation at 50 V with twice the threshold pulse width. ␤-ARs were identified by [ 3 H]CGP-12177 and [ 3 H]dihydroalprenolol. Electrical stimulation reduced cell-surface but not total ␤-AR density; the effect was dependent on pacing frequency (a reduction of 11%, 28%, and 18% in cells paced at 2.5, 3.0, and 3.3 Hz, respectively). This reduction was apparent at 3 hours, in contrast to reduced ␤-AR density after exposure to isoproterenol (ISP) for 1 hour. The fraction and inhibition constant of ␤-AR binding agonist with high affinity were not affected by rapid electrical stimulation. In cardiomyocytes paced at 3.0 Hz for 24 hours, the response to ISP decreased compared with unpaced cells, 142% versus 204% of baseline with 1 mol/L ISP, whereas the responses to forskolin or acetylcholine were not different. Treatment of cardiomyocytes with 2,3-butanedione monoxime (10 mmol/L) or taxol (10 mol/L) inhibited the rapid pacing-induced reduction in ␤-AR density. Conclusions-Our results suggest that contractile activity is involved in regulation of cardiac function by modulating the ␤-AR system independently of hemodynamic and neurohormonal factors. This may help to elucidate the role of mechanical stress in the development of heart failure.

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“…Culture of neonatal rat ventricular myocytes Ventricular myocytes were cultured as described previously [20,21] . Briefly, one-day-old Sprague-Dawley rats were sacrificed and their hearts were isolated, and the ventricles were dissected and digested with a buffer solution containing 0.125% trypsin and 1% collagenase for 10 min at 37 °C.…”

Section: Introductionmentioning

confidence: 99%

Breviscapine ameliorates hypertrophy of cardiomyocytes induced by high glucose in diabetic rats via the PKC signaling pathway

et al. 2009

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Aim: To investigate the influence of breviscapine on high glucose-induced hypertrophy of cardiomyocytes and the relevant mechanism in vitro and in vivo. Methods: Cultured neonatal cardiomyocytes were divided into i) control; ii) high glucose concentrations; iii) high glucose+PKC inhibitor Ro-31-8220; iv) high glucose+breviscapine; or v) high glucose+NF-κB inhibitor BAY11-7082. Cellular contraction frequency and volumes were measured; the expression of protein kinase C (PKC), NF-κB, TNF-α, and c-fos were assessed by Western blot or reverse transcription-polymerase chain reaction (RT-PCR). Diabetic rats were induced by a single intraperitoneal injection of streptozotocin, and randomly divided into i) control rats; ii) diabetic rats; or iii) diabetic rats administered with breviscapine (10 or 25 mg·kg -1 ·d -1 ). After treatment with breviscapine for six weeks, the echocardiographic parameters were measured. All rats were then sacrificed and heart tissue was obtained for microscopy. The expression patterns of PKC, NF-κB, TNF-α, and c-fos were measured by Western blot or RT-PCR. Results: Cardiomyocytes cultured in a high concentration of glucose showed an increased pulsatile frequency and cellular volume, as well as a higher expression of PKC, NF-κB, TNF-α, and c-fos compared with the control group. Breviscapine could partly prevent these changes. Diabetic rats showed relative cardiac hypertrophy and a higher expression of PKC, NF-κB, TNF-α, and c-fos; treatment with breviscapine could ameliorate these changes in diabetic cardiomyopathy. Conclusion: Breviscapine prevented cardiac hypertrophy in diabetic rats by inhibiting the expression of PKC, which may have a protective effect in the pathogenesis of diabetic cardiomyopathy via the PKC/NF-κB/c-fos signal transduction pathway.

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Mechanism of β-Adrenergic Receptor Upregulation Induced by ACE Inhibition in Cultured Neonatal Rat Cardiac Myocytes

Cited by 36 publications

References 27 publications

Prediction of Severe Hypoglycaemia by Angiotensin-Converting Enzyme Activity and Genotype in Type 1 Diabetes

Prediction of Severe Hypoglycaemia by Angiotensin-Converting Enzyme Activity and Genotype in Type 1 Diabetes

Rapid Electrical Stimulation of Contraction Reduces the Density of β-Adrenergic Receptors and Responsiveness of Cultured Neonatal Rat Cardiomyocytes

Breviscapine ameliorates hypertrophy of cardiomyocytes induced by high glucose in diabetic rats via the PKC signaling pathway

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