The effects of diabetes on β-adrenoceptor mediated responsiveness of human and rat atria

Dinçer, Ü. Deniz; Onay, Arzu; Arı, Nuray; Özçeli̇kay, A.Tanju; Altan, V.Melih

doi:10.1016/s0168-8227(98)00034-5

Cited by 28 publications

(36 citation statements)

References 24 publications

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“…Figure 2C shows the summary of the changes in ϪdT/ dt max when hearts from 8C, 8D, and 6D-2I animals were challenged with 1, 10, and 100 nmol/l isoproterenol. These data are in agreement with those of Dincer et al (48) and Afzal et al (49) and clearly show that diabetes decreases relaxation rates. Taken together, data from in vivo ventricular function measurements and isobaric Langendorff procedure establish that after 8 weeks of diabetes left ventricular function was compromised and that 2 weeks of insulin treatment initiated after 6 weeks of diabetes prevented and/or reversed this dysfunction.…”

Section: Diabetes Vol 53 February 2004supporting

confidence: 93%

Diabetes Increases Formation of Advanced Glycation End Products on Sarco(endo)plasmic Reticulum Ca2+-ATPase

et al. 2004

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Prolongation of relaxation is a hallmark of diabetic cardiomyopathy. Most studies attribute this defect to decreases in sarco(endo)plasmic reticulum Ca 2؉ -ATPase (SERCA2a) expression and SERCA2a-to-phospholamban (PLB) ratio. Since its turnover rate is slow, SERCA2a is susceptible to posttranslational modifications during diabetes. These modifications could in turn compromise conformational rearrangements needed to translocate calcium ions, also leading to a decrease in SERCA2a activity. In the present study one such modification was investigated, namely advanced glycation end products (AGEs). Hearts from 8-week streptozotocin-induced diabetic (8D) rats showed typical slowing in relaxation, confirming cardiomyopathy. Hearts from 8D animals also expressed lower levels of SERCA2a protein and higher levels of PLB. Analysis of matrix-assisted laser desorption/ionization time-of-flight mass data files from trypsin-digested SERCA2a revealed several cytosolic SERCA2a peptides from 8D modified by single noncrosslinking AGEs. Crosslinked AGEs were also found. Lysine residues within actuator and phosphorylation domains were cross-linked to arginine residues within the nucleotide binding domain via pentosidine AGEs. Two weeks of insulin-treatment initiated after 6 weeks of diabetes attenuated these changes. These data demonstrate for the first time that AGEs are formed on SERCA2a during diabetes, suggesting a novel mechanism by which cardiac relaxation can be slowed during diabetes. Diabetes 53: [463][464][465][466][467][468][469][470][471][472][473] 2004 R eductions in rate and force of cardiac contractions are root causes for the increased incidence of morbidity and mortality among diabetic patients (1-3). Studies show that this "diabetic cardiomyopathy" is independent of coronary vascular diseases and is brought about by shifts in metabolism, cellular biochemistry, and structure (4 -8). At the molecular level, decreases in chronotropy and inotropy result from alterations in expression and/or function of several sarcolemmal membrane receptors and associated signal transduction proteins as well as other key proteins involved in regulating/maintaining intracellular ionic homeostasis (9 -11). Of particular interest is a transport protein on the sarcoplasmic reticular membrane that plays an integral role in cardiac relaxation. This protein, referred to as sarco(endo)plasmic reticulum Ca 2ϩ -ATPase (SERCA2a), is responsible for replenishing intracellular calcium stores following release and in so doing terminate contraction.SERCA2a is a member of a large family of P-type ATPase enzymes that utilizes the energy generated from hydrolysis of terminal phosphate bond of ATP to pump calcium against its electrochemical gradient (12,13). SERCA1a is the best studied of these single polypeptides. It consists of 10 transmembrane helixes (M1 through M10) and three cytoplasmic domains, referred to as A (actuator), N (nucleotide binding) and P (phosphorylation) domains (14). Translocation of calcium ions from the cytosol to the lumen of...

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Section: Diabetes Vol 53 February 2004supporting

confidence: 93%

Diabetes Increases Formation of Advanced Glycation End Products on Sarco(endo)plasmic Reticulum Ca2+-ATPase

et al. 2004

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“…These findings suggest that ␤ 1 -AR-but not ␤ 2 -AR-mediated chronotropic responses were reduced in the right atria of diabetic rats. On the other hand, it is important to note that in 14-week-STZ-induced diabetic rats, ␤ 1 -AR protein in heart was decreased by almost 55% in the present study, whereas the decrease in maximum chronotropic response of the right atria to ␤ 1 -AR stimulation was only 29% in our previous study (9). Taken together, these results suggest an abundance of spare receptors in this system.…”

Section: Discussionsupporting

confidence: 49%

“…Thus, in an attempt to gain insight into the role of ␤ 2 -ARs in diabetes, we previously studied the effect of diabetes on selective ␤ 1 -and ␤ 2 -AR stimulation in the DIABETES, VOL. 50, FEBRUARY 2001right atria of STZ-induced diabetic rats (9). We found a significant decrease in the chronotropic responses of the right atria from 14-week diabetic rats to noradrenaline, although the responsiveness to fenoterol was similar to that of controls.…”

Section: Discussionmentioning

confidence: 52%

“…However, in these studies, no attempt was made to distinguish between the various subtypes of ␤-ARs. In a recent study, we demonstrated that ␤ 1 -AR-mediated chronotropic responses in right atria of STZ-induced diabetic rats are impaired, but those mediated via ␤ 2 -ARs are preserved (9). It has also been demonstrated that in the human atrium, both ␤ 1 -and ␤ 2 -ARs are functionally coupled to the adenylate cyclase system (10), and both subtypes of ␤-ARs are reported to contribute to the cardiac responses of ␤-AR agonists (11).…”

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confidence: 92%

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The Effect of Diabetes on Expression of β1-,β2-, and β3-Adrenoreceptors in Rat Hearts

et al. 2001

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Diabetic hearts exhibit decreased responsiveness to stimulation by ␤-adrenoreceptor (␤-AR) agonists. This decrease in activity may be due to changes in expression and/or signaling of ␤-AR. Recently we showed that right atrial strips from 14-week streptozotocin (STZ)-induced diabetic rat hearts exhibit decreased responsiveness to ␤ 1 -AR agonist stimulation, but not to ␤ 2 -AR agonist. In the present study, we investigated the effects of long-term diabetes on the expression of cardiac ␤ 1 -, ␤ 2 -, and ␤ 3 -ARs and looked at whether these changes could be restored with insulin treatment. Using reverse transcription-polymerase chain reaction (RT-PCR), PAGE, and Western blot analysis, we found that ␤ 1 -AR mRNA and protein levels decreased by 34.9 ± 5.8 and 44.4 ± 5.8%, respectively, in 14 week-STZtreated diabetic rat hearts when compared with agematched controls. On the other hand, mRNA levels encoding ␤ 2 -and ␤ 3 -ARs increased by 72.5 ± 16.6 and 97.3 ± 26.1%, respectively. Although the latter translated into a proportional increase in ␤ 3 -AR protein levels (100.0 ± 17.0%), ␤ 2 -AR protein levels decreased to 82.6 ± 1.1% of control. Insulin treatment for 2 weeks, after 12 weeks of untreated diabetes, partially restored ␤ 1 -AR mRNA and protein levels to 60.1 ± 8.4 and 83.2 ± 5.0%, respectively, of control. Although insulin treatment minimally attenuated the rise in mRNA levels encoding ␤ 2 -and ␤ 3 -ARs, the steady-state levels of these proteins returned to near control values. These data suggest that the decreased responsiveness of diabetic hearts to stimulation of ␤-AR agonists may be due to a decrease in ␤ 1 -AR and an increase ␤ 3 -AR expression. Diabetes 50: [455][456][457][458][459][460][461] 2001

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“…A most signi�cant decrease was observed with noradrenaline acting preferably via 1 -AR undergoing considerable downregulation in T1DM [26], whereas AC effect of isoproterenol, nonselective -AR agonist, was reduced to a lesser extent (Figure 2(a) and Table 4(a)). In our view, this may be due to the fact that the signaling pathways mediated via 2 -AR, the main target of isoproterenol, in the heart of rats with T1DM, even short-term, were preserved or enhanced, this being a compensatory mechanism triggered by reducing the functional activity of 1 -AR [11,27]. us, in the heart of 14-week STZ rats, the content of 1 -AR protein as well as 1 -AR mRNA was decreased to 35 and 45%, respectively, and the decrease of maximal chronotropic response to selective 1 -AR agonists was 70% of that in control, whereas the number of 2 -AR and the chronotropic response to selective 2 -AR agonist fenoterol did not change [27].…”

Section: Groups Of Rats Heart Brain Testesmentioning

confidence: 95%

Alterations of Hormone-Sensitive Adenylyl Cyclase System in the Tissues of Rats with Long-Term Streptozotocin Diabetes and the Influence of Intranasal Insulin

Шпаков

Derkach

Moyseyuk

et al. 2013

Dataset Papers in Pharmacology

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One of the causes of complications in type 1 diabetes mellitus (T1DM) is the changes in adenylyl cyclase (AC) signaling system, identi�ed on the early stages of the disease. However, the most signi�cant disturbances in this system occur on the later stages of T1DM, which ultimately leads to severe complications, but functional state of the AC system in late T1DM is poorly understood. e aim of this work was to study alterations in AC system sensitive to biogenic amines and polypeptide hormones in the heart, brain, and testes of male rats with long-term, 7-month, streptozotocin T1DM and to assess the in�uence on them of 135-day therapy with intranasal insulin. It was shown that AC effects of -adrenergic agonists in the heart, serotonin receptor agonists and PACAP-38 in the brain, chorionic gonadotropin and PACAP-38 in the testes, and somatostatin in all investigated tissues in long-term T1DM were drastically decreased. e treatment with intranasal insulin (0.48 IU/day) signi�cantly restored these effects. e results were obtained suggesting that long-term T1DM induces signi�cant alterations in hormone-sensitive AC system in the heart, brain, and testes that are much more pronounced, compared with short-term T1DM, and include a large number of hormonal regulations.

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The effects of diabetes on β-adrenoceptor mediated responsiveness of human and rat atria

Cited by 28 publications

References 24 publications

Diabetes Increases Formation of Advanced Glycation End Products on Sarco(endo)plasmic Reticulum Ca2+-ATPase

Diabetes Increases Formation of Advanced Glycation End Products on Sarco(endo)plasmic Reticulum Ca2+-ATPase

The Effect of Diabetes on Expression of β1-,β2-, and β3-Adrenoreceptors in Rat Hearts

Alterations of Hormone-Sensitive Adenylyl Cyclase System in the Tissues of Rats with Long-Term Streptozotocin Diabetes and the Influence of Intranasal Insulin

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