Binding of 125I-Insulin on Capillary Endothelial and Myofiber Cell Membranes in Normal and Streptozotocin-Induced Diabetic Perfused Rat Hearts

Haddad, R.; Jurjus, Abdu R.; Ibrahim, M. Z. M.; Nahlé, Zaher; El-Kasti, Muna M.; Bitar, Khalil M.; Kreydiyyeh, Sawsan Ibrahim; Saadeh, Faysal A.; Bikhazi, Anwar B.

doi:10.1016/s0300-9629(96)00399-4

Cited by 18 publications

(33 citation statements)

References 17 publications

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“…The dissected part of the animal and the exposed heart were soaked with saline at 37°C throughout the experiment. All these perfusion experiments were carried out following the procedures reported in previous studies performed in our laboratory (Haddad et al 1997). …”

Section: Rat Heart Perfusionmentioning

confidence: 99%

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

Barakat

Nuwayri-Salti

Kadi

et al. 2011

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Abstract. Glucagon-like peptide-1 (GLP-1) is an incretin hormone secreted from intestinal L cells upon nutrients ingestion, and is currently used for treating diabetes mellitus. It plays an important role in receptor modulation and cross talk with insulin at the coronary endothelium (CE) and cardiomyocytes (CM) in diabetic type 1 rat heart model. We studied the effects of insulin, GLP-1 analogues (exendin-4), and dipeptidyl peptidase-IV (DPP-IV) inhibitor on GLP-1 cardiac receptor modulation. The binding affinity of GLP-1 to its receptor on CE and CM was calculated using a rat heart perfusion model with [125 I]-GLP-1(7-36). Tissue samples from the heart were used for immunostaining and Western blot analyses. GLP-1 systemic blood levels were measured using ELISA. GLP-1 binding affinity (τ) increased on the CE (0.33 ± 0.01 vs. 0.25 ± 0.01 min; p < 0.001) and decreased on the CM (0.29 ± 0.02 vs. 0.43 ± 0.02 min; p < 0.001) in the diabetic non-treated rats when compared to normal. There was normalization of τ back to baseline on the CE and CM levels with insulin and DPP-IV inhibitor treatment, respectively. Histological sections and immunofluorescence showed receptor upregulation in diabetic rats with significant decrease and even normalization with the different treatment strategies. Systemic GLP-1 levels increased after 14 days of diabetes induction (10 ± 3.7 vs. 103 ± 58 pM; p = 0.0005). In conclusion, there is a significant GLP-1 receptor affinity modulation on the CE and CM levels in rats with diabetes type 1, and a cross talk with GLP-1 analogues in early prevention of cardiac remodeling.

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Section: Rat Heart Perfusionmentioning

confidence: 99%

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

Barakat

Nuwayri-Salti

Kadi

et al. 2011

gpb

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“…Using a mathematical physical model [20], timedependent radioactive IGF-1 ([ 125 I]-IGF-1) concentration curves were exploited to determine the IGF-1 forward binding constant (k n ), reversal constant (k -n ), dissociation constant (k d = k -n /k n ), and affinity (residency-time) constant ( =1/k -n ) with its receptor subtype IGF-1R. These derived binding and affinity constants of IGF-1 to its receptor subtype on coronary endothelial cells (CE) and CM are shown in Tables 2 and 3 respectively.…”

Section: Heart Perfusion Resultsmentioning

confidence: 99%

“…Using a physical-mathematical model [20,21], heart perfusion results show that IGF-1 affinity to its receptor subtype increased in all diabetic groups at the CE level (Table 2) and that the co-treatment with insulin and losartan in the DIL group managed to decrease this affinity but not to the normal level seen in N. Taking these data into consideration, we could say that the interaction between insulin and AT 1 -R blockade is needed to modify the IGF-1R binding affinity at the CE level. Therefore, the cross-talk between insulin and the AT 1 -R seems to have an influence to IGF-1 binding kinetics on coronary endothelial cells.…”

Section: Discussionmentioning

confidence: 99%

Effect of Insulin and Losartan on Modulation of Insulin-Like Growth Factor 1 Receptor at Heart Level in Diabetic Rats

Bikhazi¹,

Maharsy²,

Kadi³

et al. 2007

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This study investigates insulin-like growth factor-1 receptor (IGF-1R) modulation in hearts of streptozotocininduced diabetic rats treated with insulin/angiotensin-II receptor subtype-1 blocker (AR 1 B), losartan. Male rats were divided into: normal (N), losartan-treated normal (NL), diabetic (D), insulin-treated diabetic (DI), losartan-treated diabetic (DL), and insulin/losartan co-treated diabetic (DIL) groups. Thirty days post-treatment, rats underwent heart perfusion using [I 125 ]-labeled IGF-1 to assess receptor-binding affinity on coronary endothelial cells (CE) and cardiomyocytes (CM). This revealed an increase in binding affinity of IGF-1 to its receptor on CE in all groups compared to N. On CM, binding affinity increased in D, DI, and DL compared to N, but was almost normalized in DIL. Western blot analyses and immunohistochemistry done on heart tissues showed decrease in IGF-1R density in DIL versus remaining groups. These results demonstrate a complex interaction between insulin, angiotensin-II, and IGF-1, and mass blockade of myocardial remodeling by AR 1 B treatment in diabetic state.

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“…The surgical procedure and perfusion model (Haddad et al 1997) were followed to determine the binding kinetics of [ 125 I]endothelin-1 ([ 125 I]ET-1) (specific activity, 2200 Ci/mmol; Amersham International plc, Buckinghamshire, UK) to its receptor subtypes at the level of ECs and CMs.…”

Section: Perfusion Of Rat Heart With Radioactive Endothelin-1mentioning

confidence: 99%

“…Time-dependent tracer ET-1 concentration curves of all animal groups were plotted using a Dirac delta and/or impulse function and a first-order Bessel function (1:1 binding stoiciometry), from which the derived binding (k n , k −n , K d ) and affinity (τ = 1/k −n ) constants for ET-1 receptor subtypes on CE cells and CMs were obtained (Haddad et al 1997;Bikhazi et al 2003;Al Jaroudi et al 2005). At the level of the CE (Table 2A), there were no significant changes in the values of the residency-time constant (τ values) among N, NL, and D groups, respectively.…”

Section: Binding Kinetics Of Endothelin-1 To Its Receptor Subtypes Onmentioning

confidence: 99%

Effect of Systemic Insulin and Angiotensin II Receptor Subtype-1 Antagonist on Endothelin-1 Receptor Subtype(s) Regulation and Binding in Diabetic Rat Heart

et al. 2005

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This study reports on the regulation and remodeling role of endothelin-1 (ET-1) and its receptor subtypes, ET(A)-Rs/ET(B)-Rs, at the coronary endothelium (CE) and cardiomyocyte (CM) sites. It is carried out in normal and normotensive rats with streptozotocin-induced diabetes mellitus receiving different treatment modalities. Normal rats were divided into two groups, namely a placebo (N) and a losartan-treated (NL), and diabetic rats into four groups receiving placebo (D), insulin-treated (DI), losartan-treated (DL), and insulin/losartan-treated (DIL) respectively. Binding kinetics of ET-1 to ET(A)-Rs/ET(B)-Rs on CE and CMs were assessed in the above groups to try to explain the effect of therapeutic doses of an angiotensin II receptor subtype-1 blocker on the dynamics of this ligand and its receptor in insulin supplemented diabetic animals. Each group was divided into two subgroups: CHAPS-untreated and CHAPS-treated rat hearts perfused with [125I]ET-1 to respectively estimate ET-1 binding affinity (tau = 1/k-n) to its receptor subtype(s) on CE and CMs using mathematical modeling describing a 1:1 reversible binding stoichiometry. Heart perfusion results revealed that insulin treatment significantly decreased tau on CE but not on CMs in diabetic rats. In diabetics treated with losartan, an increase in tau value on CE but not on CMs was noted. Cotreatment of diabetic rats with insulin and losartan normalized tau on CE but decreased it on CMs. Western blot, using snap-frozen heart tissues, revealed increase in ET(A)-R density in all diabetic groups. However, significant decrease in ET(B)-R density was observed in all groups compared to the normal, and was reconfirmed by immunohistochemical analysis. In conclusion, coadministration of insulin and losartan in nonhypertensive animals suffering from diabetes type 1 may offer new cardiac protection benefits by improving coronary blood flow and cardiomyocyte contractility through modulating ET-1 receptor subtypes density and affinity at CE and CM sites.

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Binding of 125I-Insulin on Capillary Endothelial and Myofiber Cell Membranes in Normal and Streptozotocin-Induced Diabetic Perfused Rat Hearts

Cited by 18 publications

References 17 publications

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

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

Effect of Insulin and Losartan on Modulation of Insulin-Like Growth Factor 1 Receptor at Heart Level in Diabetic Rats

Effect of Systemic Insulin and Angiotensin II Receptor Subtype-1 Antagonist on Endothelin-1 Receptor Subtype(s) Regulation and Binding in Diabetic Rat Heart

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