Aliskiren, exendin-4, and insulin: their impact on endothelin receptor subtype(s) regulation/binding in type 1 diabetic rat hearts

2013 ◽  
Vol 91 (10) ◽  
pp. 830-838 ◽  
Author(s):  
Sawsan M. Al Lafi ◽  
Shushan B. Artinian ◽  
Suzan S. Boutary ◽  
Nadine S. Zwainy ◽  
Khalil M. Bitar ◽  
...  
Keyword(s):  
Binding Affinity ◽  
Diabetic Rat ◽  
Receptor Subtype ◽  
Receptor Subtypes ◽  
Rat Hearts ◽  
Heart Perfusion ◽  
Glucagon Like Peptide 1 ◽  
Coronary Endothelium ◽  
The Impact

This study focuses on the impact of aliskiren and (or) glucagon-like peptide-1 analogue on the binding affinity/regulation of endothelin-1 (ET-1) to its receptor subtypes A (ETAR) and B (ETBR) at the level of the coronary endothelium and the cardiomyocytes in a type-1 diabetic rat model. Seven groups were used: (i) normal rats, (ii) rats with induced diabetes, (iii) rats with induced diabetes that were treated with insulin, (iv) rats with induced diabetes that were treated with exendin-4, (v) rats with induced diabetes that were treated with aliskiren, (vi) rats with induced diabetes that were co-treated with insulin plus aliskiren, and (vii) rats with induced diabetes that were co-treated with exendin-4 plus aliskiren. Heart perfusion with [125I]-ET-1 was employed to estimate ET-1 binding affinity (τ = 1/K–n) to ETAR and ETBR at the level of the coronary endothelium and the cardiomyocytes. Plasma ET-1 levels were measured using enzyme immunoassay, whereas densities of ETAR and ETBR were detected using Western blot. No significance differences were detected in the τ of ETAR and ETBR between normal and diabetic in cardiomyocytes and the coronary endothelium. Exendin-4 normalized the τ value for ETAR and ETBR on coronary endothelium, while aliskiren normalized it on cardiomyocytes. Furthermore, ETAR and ETBR densities were normalized with monotreatments of aliskiren and exendin-4, compared with up-regulated ETAR and down-regulated ETBR band densities in the diabetic animals. Our data indicate that aliskiren alleviates diabetes-associated hypertrophy in type 1 diabetes mellitus.

scholarly journals Assessment of Glucagon-Like Peptide-1 Analogue and Renin Inhibitor on the Binding and Regulation of GLP-1 Receptor in Type 1 Diabetic Rat Hearts

2011 ◽  
Vol 2011 ◽  
pp. 1-7 ◽  
Author(s):  
Shushan B. Artinian ◽  
Sawsan M. Al Lafi ◽  
Suzan S. Boutary ◽  
Khalil M. Bitar ◽  
Nadine S. Zwainy ◽  
...  
Keyword(s):  
Binding Affinity ◽  
Renin Angiotensin System ◽  
Diabetic Rat ◽  
Enzyme Linked Immunosorbent Assay ◽  
Sprague Dawley ◽  
Sprague Dawley Rats ◽  
Rat Hearts ◽  
Glucagon Like Peptide 1 ◽  
Coronary Endothelium

This study focuses on the effects of long-term renin-angiotensin system suppression and/or incretin mimetic therapies on the regulation and binding affinity of GLP-1 to its receptor in the coronary endothelium (CE) and cardiomyocytes (CMs) of type 1 diabetic male Sprague-Dawley rats. The groups assessed are normal (N), streptozotocin-induced diabetic (D), Insulin treated (DI), Exendin-4 treated (DE), Aliskiren treated (DA), cotreated with Insulin and Aliskiren (DIA) and cotreated with exendin-4 and Aliskiren (DEA). Heart perfusion with125I-GLP-1 was performed to estimate GLP-1 binding affinity () to its receptor in the heart. Western Blotting was assessed to determine the expression variation of GLP-1 receptor in the heart. Plasma GLP-1 levels were measured using Enzyme-Linked Immunosorbent Assay (ELISA). Diabetes decreased the value on CE and increased it on CMs compared to normal. The combination of Exendin-4 with Aliskiren showed a normalizing effect on the binding affinity of GLP-1 at the coronary endothelium, while at the cardiomyocyte level Exendin-4 treatment alone was the most effective.

Abstract 36: Acute Inhibition Of O-GlcNAc Signaling Rescues Inotropic Responsiveness In Type 1 Diabetic Rat Hearts

2014 ◽  
Vol 115 (suppl_1) ◽  
Author(s):  
Chengxue Qin ◽  
Rochelle S S Sleaby ◽  
Lea M Delbridge ◽  
Amy J Davidoff ◽  
John C Chatham ◽  
...  
Keyword(s):  
Left Ventricular ◽  
Male Rats ◽  
Diabetic Heart ◽  
Diabetic Rat ◽  
Lv Function ◽  
Diabetic Patients ◽  
Cardiac Phenotype ◽  
Rat Hearts ◽  
The Impact

Metabolism of excess glucose is an important component of the aetiology of type 1 diabetes. The cardiac phenotype includes left ventricular (LV) remodelling and LV dysfunction. Increased hexosamine biosythesis (HBP) and downstream upregulation of protein O-GlcNAcylation has been linked to diabetic complications in many organs. Its impact on LV contractile responsiveness is however not well understood. This study aimed to test the hypothesis that acute inhibition of O-GlcNAc signaling protects inotropic responsiveness in type 1 diabetic heart. Hearts isolated from adult Sprague-Dawley male rats were Langendorff-perfused (constant flow, 10ml/min). Baseline and phenylephrine-stimulated (PE, 10μmol/L) LV function was determined in diabetic (8wks post-streptozotocin diabetes, 55mg/kg i.v.) versus non-diabetic sham rats in the presence of pharmacological inhibitors of HBP/O-GlcNAc including 6-diazo-5-oxo-L-norleucine (DON, 20μM) and alloxan (5mM). Diabetic rats exhibited a marked reduction in inotropic responsiveness to PE (Table, mean±SEM, one-way ANOVA, #P<0.05 vs non-diabetic vehicle rats, *P<0.05 vs diabetic vehicle, at 40 mins). Acute interruption of cardiac HBP/O-GlcNAc by DON and Alloxan significantly rescued LV responsiveness to PE in type 1 diabetic rat hearts. These results support further assessment of the impact of upregulated protein O-GlcNAcylation on LV function, particularly in the diabetic heart. Treatment strategies that target HBP may provide significant benefits alone or in combination with current standard treatments, to reduce progression of heart failure and death in type 1 diabetic patients.

scholarly journals Role of glucagon-like peptide-1 and its agonists on early prevention of cardiac remodeling in type 1 diabetic rat hearts

2011 ◽  
Vol 30 (1) ◽  
pp. 34-44 ◽  
Author(s):  
G. Barakat ◽  
N. Nuwayri-Salti ◽  
L. Kadi ◽  
K. Bitar ◽  
W. Al-Jaroud ◽  
...  
Keyword(s):  
Cardiac Remodeling ◽  
Diabetic Rat ◽  
Early Prevention ◽  
Rat Hearts ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1

scholarly journals Characterisation of the Contribution of the GABA-Benzodiazepine α1 Receptor Subtype to [11C]Ro15-4513 PET Images

2012 ◽  
Vol 32 (4) ◽  
pp. 731-744 ◽  
Author(s):  
James FM Myers ◽  
Lula Rosso ◽  
Ben J Watson ◽  
Sue J Wilson ◽  
Nicola J Kalk ◽  
...  
Keyword(s):  
Spectral Analysis ◽  
A Priori ◽  
Benzodiazepine Receptor ◽  
Brain Regions ◽  
Complex Model ◽  
Receptor Subtype ◽  
Receptor Subtypes ◽  
Time Activity ◽  
Positron Emission ◽  
The Impact

This positron emission tomography (PET) study aimed to further define selectivity of [11C]Ro15-4513 binding to the GABARα5 relative to the GABARα1 benzodiazepine receptor subtype. The impact of zolpidem, a GABARα1-selective agonist, on [11C]Ro15-4513, which shows selectivity for GABARα5, and the nonselective benzodiazepine ligand [11C]flumazenil binding was assessed in humans. Compartmental modelling of the kinetics of [11C]Ro15-4513 time-activity curves was used to describe distribution volume ( VT) differences in regions populated by different GABA receptor subtypes. Those with low α5 were best fitted by one-tissue compartment models; and those with high α5 required a more complex model. The heterogeneity between brain regions suggested spectral analysis as a more appropriate method to quantify binding as it does not a priori specify compartments. Spectral analysis revealed that Zolpidem caused a significant VT decrease (~10%) in [11C]flumazenil, but no decrease in [11C]Ro15-4513 binding. Further analysis of [11C]Ro15-4513 kinetics revealed additional frequency components present in regions containing both α1 and α5 subtypes compared with those containing only α1. Zolpidem reduced one component (mean ± s.d.: 71% ± 41%), presumed to reflect α1-subtype binding, but not another (13% ± 22%), presumed to reflect α5. The proposed method for [11C]Ro15-4513 analysis may allow more accurate selective binding assays and estimation of drug occupancy for other nonselective ligands.

Distribution and function of cardiac angiotensin AT1- and AT2-receptor subtypes in hypertrophied rat hearts

1994 ◽  
Vol 267 (2) ◽  
pp. H844-H852 ◽  
Author(s):  
J. J. Lopez ◽  
B. H. Lorell ◽  
J. R. Ingelfinger ◽  
E. O. Weinberg ◽  
H. Schunkert ◽  
...  
Keyword(s):  
Dissociation Constants ◽  
Diastolic Pressure ◽  
Binding Capacity ◽  
Pressure Overload ◽  
Left Ventricular ◽  
Receptor Subtype ◽  
Receptor Subtypes ◽  
Ang Ii ◽  
Rat Hearts ◽  
And Function

To determine distribution and function of cardiac angiotensin (ANG) II receptor AT1 and AT2 subtypes in left ventricular (LV) hypertrophy (LVH), ANG II (10(-8) M) was infused into isolated rat hearts with hypertrophy from aortic banding and into sham-operated controls. ANG II was infused alone or in the presence of AT1 inhibitor [losartan (10(-5) M) or CL-329167 (10(-7) M)] or AT2 inhibitor [CG-42112A (10(-8) M]. ANG II alone caused less increase in coronary vascular resistance (CVR) in LVH compared with control hearts (19 vs. 39%; P < 0.01), although baseline CVR was higher in LVH hearts. This was prevented by AT1 but not AT2 antagonists. ANG II also increased LV end-diastolic pressure in LVH hearts, signifying decreased diastolic relaxation that was prevented by AT1 but not AT2 inhibition. Characterization of ANG II binding sites in LV membrane preparations revealed similar dissociation constants between groups (1.6 +/- 0.95 vs. 2.2 +/- 2.0 nM; not significant) but lower maximum binding capacity in the LVH group (21.1 +/- 5.9 vs. 33.5 +/- 3.0 fmol/mg protein; P < 0.05). Competition assays demonstrated that control left ventricles contain predominantly the AT1 subtype (68.8 +/- 20%), whereas LVH ventricles contain primarily the putative AT2 subtype (59.8% +/- 10.8%; P < 0.05). This suggests that receptor subtype redistribution occurs in LVH with AT1 subtype down-regulation. Nonetheless, the AT1 subtype mediates the effects of ANG II on coronary tone and diastolic dysfunction in pressure-overload hypertrophy.

scholarly journals Type 3 inositol trisphosphate receptors in RINm5F cells are biphasically regulated by cytosolic Ca2+ and mediate quantal Ca2+ mobilization

1999 ◽  
Vol 344 (1) ◽  
pp. 55-60 ◽  
Author(s):  
Jane E. SWATTON ◽  
Stephen A. MORRIS ◽  
Thomas J. A. CARDY ◽  
Colin W. TAYLOR
Keyword(s):  
Single Type ◽  
Receptor Subtype ◽  
Receptor Subtypes ◽  
Rinm5f Cells ◽  
Intact Cells ◽  
Single Receptor ◽  
Insp3 Receptors ◽  
Type 3 ◽  
Insp3 Receptor

There are three subtypes of mammalian Ins(1,4,5)P3 (InsP3) receptor, each of which forms an intracellular Ca2+ channel. Biphasic regulation of InsP3 receptors by cytosolic Ca2+ is well documented in cells expressing predominantly type 1 or type 2 InsP3 receptors and might contribute to the regenerative recruitment of Ca2+ release events and to limiting their duration in intact cells. The properties of type 3 receptors are less clear. Bilayer recording from InsP3 receptors of RIN-5F cells, cells in which the InsP3 receptors are likely to be largely type 3, recently suggested that the receptors are not inhibited by Ca2+ [Hagar, Burgstahler, Nathanson and Ehrlich (1998) Nature (London) 296, 81-84]. By using antipeptide antisera that either selectively recognized each InsP3 receptor subtype or interacted equally well with all subtypes, together with membranes from Spodoptera frugiperda (Sf9) cells expressing only single receptor subtypes to calibrate the immunoblotting, we quantified the relative levels of expression of type 1 (17%) and type 3 (77%) InsP3 receptors in RINm5F cells. In unidirectional 45Ca2+ efflux experiments from permeabilized RINm5F cells, submaximal concentrations of InsP3 released only a fraction of the InsP3-sensitive Ca2+ stores, indicating that responses to InsP3 are quantal. Increasing the cytosolic free [Ca2+] ([Ca2+]i) from approx. 4 to 186 nM increased the sensitivity of the Ca2+ stores to InsP3: the EC50 decreased from 281±15 to 82±2 nM. Further increases in [Ca2+]i massively decreased the sensitivity of the stores to InsP3, by almost 10-fold when [Ca2+]i was 2.4 μM, and by more than 3000-fold when it was 100 μM. The inhibition caused by 100 μM Ca2+ was fully reversed within 60 s of the restoration of [Ca2+]i to 186 nM. The effect of submaximal InsP3 concentrations on Ca2+ mobilization from permeabilized RINm5F cells is therefore biphasically regulated by cytosolic Ca2+. We conclude that type 3 InsP3 receptors of RINm5F cells mediate quantal Ca2+ release and they are biphasically regulated by cytosolic Ca2+, either because a single type 1 subunit within the tetrameric receptor confers the Ca2+ inhibition or because the type 3 subtype is itself directly inhibited by Ca2+.

scholarly journals Effect of Omega‐3 PUFA on Endothelin‐1 Receptors in Normal and Type 1 Diabetic Rat Hearts

2012 ◽  
Vol 26 (S1) ◽  
Author(s):  
Anwar B Bikhazi ◽  
Mohamad Imad El Chami ◽  
Nadine S Zwainy ◽  
Asdghig H Der-Boghossian
Keyword(s):  
Diabetic Rat ◽  
Omega 3 ◽  
Endothelin 1 ◽  
Rat Hearts

scholarly journals Expression of type 1 angiotensin II receptor subtypes and angiotensin II-induced calcium mobilization along the rat nephron.

1997 ◽  
Vol 8 (11) ◽  
pp. 1658-1667 ◽  
Author(s):  
N Bouby ◽  
A Hus-Citharel ◽  
J Marchetti ◽  
L Bankir ◽  
P Corvol ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Collecting Duct ◽  
At1 Receptor ◽  
Receptor Subtype ◽  
Receptor Subtypes ◽  
Thick Ascending Limb ◽  
Ang Ii ◽  
Angiotensin Ii Receptor ◽  
Nephron Segments

The localization of two type 1 angiotensin II receptor subtype mRNA, AT1A and AT1B, was determined by reverse transcription-PCR on microdissected glomeruli and nephron segments. The coupling sensitivity of these two receptor subtypes was evaluated by measuring variations in intracellular calcium ([Ca2+]i) elicited by angiotensin II (Ang II) in structures expressing either AT1A or AT1B mRNA, using Fura-2 fluorescence. The highest expression of AT1 mRNA was found in glomerulus, proximal tubule, and thick ascending limb. In glomerulus, AT1A and AT1B mRNA were similarly expressed, whereas in all nephron segments AT1A mRNA expression was dominant (approximately 84%). The increase in [Ca2+]i elicited by 10(-7) mol/L Ang II was highest in proximal segments (delta [Ca2+]i is approximately equivalent to 300 to 400 nmol/L) and thick ascending limb (delta [Ca2+]i is approximately equivalent to 200 nmol/L). In glomerulus and collecting duct, the response was lower (delta < 100 nmol/L). The median effective concentrations for Ang II were of the same order of magnitude in glomerulus (12.2 nmol/L), in which both AT1A and AT1B are expressed, and in cortical thick ascending limb (10.3 nmol/ L), in which AT1A is almost exclusively expressed. The Ang II-induced calcium responses were totally abolished by the AT1 receptor antagonist losartan (1 mumol/L) but not by the AT2 antagonist PD 123319 (1 mumol/L). In the absence of external Ca2+, the peak phase of the response induced by 10(-7) mol/L Ang II was reduced and shortened, suggesting that a part of the [Ca2+]i increase originated from the mobilization of the intracellular Ca2+ pool. In conclusion, these results demonstrate that in the rat kidney: (1) AT1A is the predominant AT1 receptor subtype expressed in the nephron segments, (2) glomerulus is the only structure with a relatively high AT1B mRNA content, and (3) AT1A and AT1B receptor subtypes do not differ in their efficiency for the activation of calcium second-messenger system.

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