Effect of systemic insulin and angiotensin II receptor subtype-1 antagonist on endothelin-1 receptor subtype(s) regulation and binding in diabetic rat heart

Chehade N. Karam; Nuha Nuwayri-Salti; Julnar A. Usta; Darine S. Zwainy; Roy E. Abrahamian; Wael A. Al Jaroudi; Malek J. Baasisri; Samer M. Abdallah; Khalil M. Bitar; Anwar B. Bikhazi

doi:10.1080/10623320500476450

Effect of systemic insulin and angiotensin II receptor subtype-1 antagonist on endothelin-1 receptor subtype(s) regulation and binding in diabetic rat heart

Chehade N. Karam, Nuha Nuwayri-Salti, Julnar A. Usta, Darine S. Zwainy, Roy E. Abrahamian, Wael A. Al Jaroudi, Malek J. Baasisri, Samer M. Abdallah, Khalil M. Bitar, Anwar B. Bikhazi

Research output: Contribution to journal › Article › peer-review

8 Scopus citations

Abstract

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 (τ = 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 τ on CE but not on CMs in diabetic rats. In diabetics treated with losartan, an increase in τ value on CE but not on CMs was noted. Cotreatment of diabetic rats with insulin and losartan normalized τ 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.

Original language	English (US)
Pages (from-to)	225-231
Number of pages	7
Journal	Endothelium: Journal of Endothelial Cell Research
Volume	12
Issue number	5-6
DOIs	https://doi.org/10.1080/10623320500476450
State	Published - Sep 2005
Externally published	Yes

Keywords

Diabetes
Endothelin-1
Heart
Insulin/ARB treatment(s)
Receptor subtypes

ASJC Scopus subject areas

Physiology
Cell Biology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1080/10623320500476450

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Karam, C. N., Nuwayri-Salti, N., Usta, J. A., Zwainy, D. S., Abrahamian, R. E., Al Jaroudi, W. A., Baasisri, M. J., Abdallah, S. M., Bitar, K. M., & Bikhazi, A. B. (2005). Effect of systemic insulin and angiotensin II receptor subtype-1 antagonist on endothelin-1 receptor subtype(s) regulation and binding in diabetic rat heart. Endothelium: Journal of Endothelial Cell Research, 12(5-6), 225-231. https://doi.org/10.1080/10623320500476450

Effect of systemic insulin and angiotensin II receptor subtype-1 antagonist on endothelin-1 receptor subtype(s) regulation and binding in diabetic rat heart. / Karam, Chehade N.; Nuwayri-Salti, Nuha; Usta, Julnar A. et al.
In: Endothelium: Journal of Endothelial Cell Research, Vol. 12, No. 5-6, 09.2005, p. 225-231.

Research output: Contribution to journal › Article › peer-review

Karam, CN, Nuwayri-Salti, N, Usta, JA, Zwainy, DS, Abrahamian, RE, Al Jaroudi, WA, Baasisri, MJ, Abdallah, SM, Bitar, KM & Bikhazi, AB 2005, 'Effect of systemic insulin and angiotensin II receptor subtype-1 antagonist on endothelin-1 receptor subtype(s) regulation and binding in diabetic rat heart', Endothelium: Journal of Endothelial Cell Research, vol. 12, no. 5-6, pp. 225-231. https://doi.org/10.1080/10623320500476450

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title = "Effect of systemic insulin and angiotensin II receptor subtype-1 antagonist on endothelin-1 receptor subtype(s) regulation and binding in diabetic rat heart",

abstract = "This study reports on the regulation and remodeling role of endothelin-1 (ET-1) and its receptor subtypes, ETA-Rs/ETB-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 ETA-Rs/ETB-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 (τ = 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 τ on CE but not on CMs in diabetic rats. In diabetics treated with losartan, an increase in τ value on CE but not on CMs was noted. Cotreatment of diabetic rats with insulin and losartan normalized τ on CE but decreased it on CMs. Western blot, using snap-frozen heart tissues, revealed increase in ETA-R density in all diabetic groups. However, significant decrease in ETB-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.",

keywords = "Diabetes, Endothelin-1, Heart, Insulin/ARB treatment(s), Receptor subtypes",

author = "Karam, {Chehade N.} and Nuha Nuwayri-Salti and Usta, {Julnar A.} and Zwainy, {Darine S.} and Abrahamian, {Roy E.} and {Al Jaroudi}, {Wael A.} and Baasisri, {Malek J.} and Abdallah, {Samer M.} and Bitar, {Khalil M.} and Bikhazi, {Anwar B.}",

note = "Funding Information: The authors would like to acknowledge the generous contribution of Dr. Mounir Y. Obeid to the Basic Medical Science Research Fund, and the financial support of the Medical Practice Plan and the University Research Board of the American University of Beirut (AUB). In addition, the authors acknowledge the assistance of Dr. Abla Mehio-Sibai in the statistical analysis of the data as well as the Central Research Science Laboratory (AUB) for making use of their facilities.",

year = "2005",

month = sep,

doi = "10.1080/10623320500476450",

language = "English (US)",

volume = "12",

pages = "225--231",

journal = "Endothelium: Journal of Endothelial Cell Research",

issn = "1062-3329",

publisher = "Taylor and Francis Ltd.",

number = "5-6",

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T1 - Effect of systemic insulin and angiotensin II receptor subtype-1 antagonist on endothelin-1 receptor subtype(s) regulation and binding in diabetic rat heart

AU - Karam, Chehade N.

AU - Nuwayri-Salti, Nuha

AU - Usta, Julnar A.

AU - Zwainy, Darine S.

AU - Abrahamian, Roy E.

AU - Al Jaroudi, Wael A.

AU - Baasisri, Malek J.

AU - Abdallah, Samer M.

AU - Bitar, Khalil M.

AU - Bikhazi, Anwar B.

N1 - Funding Information: The authors would like to acknowledge the generous contribution of Dr. Mounir Y. Obeid to the Basic Medical Science Research Fund, and the financial support of the Medical Practice Plan and the University Research Board of the American University of Beirut (AUB). In addition, the authors acknowledge the assistance of Dr. Abla Mehio-Sibai in the statistical analysis of the data as well as the Central Research Science Laboratory (AUB) for making use of their facilities.

PY - 2005/9

Y1 - 2005/9

N2 - This study reports on the regulation and remodeling role of endothelin-1 (ET-1) and its receptor subtypes, ETA-Rs/ETB-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 ETA-Rs/ETB-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 (τ = 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 τ on CE but not on CMs in diabetic rats. In diabetics treated with losartan, an increase in τ value on CE but not on CMs was noted. Cotreatment of diabetic rats with insulin and losartan normalized τ on CE but decreased it on CMs. Western blot, using snap-frozen heart tissues, revealed increase in ETA-R density in all diabetic groups. However, significant decrease in ETB-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.

AB - This study reports on the regulation and remodeling role of endothelin-1 (ET-1) and its receptor subtypes, ETA-Rs/ETB-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 ETA-Rs/ETB-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 (τ = 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 τ on CE but not on CMs in diabetic rats. In diabetics treated with losartan, an increase in τ value on CE but not on CMs was noted. Cotreatment of diabetic rats with insulin and losartan normalized τ on CE but decreased it on CMs. Western blot, using snap-frozen heart tissues, revealed increase in ETA-R density in all diabetic groups. However, significant decrease in ETB-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.

KW - Diabetes

KW - Endothelin-1

KW - Heart

KW - Insulin/ARB treatment(s)

KW - Receptor subtypes

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JO - Endothelium: Journal of Endothelial Cell Research

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Effect of systemic insulin and angiotensin II receptor subtype-1 antagonist on endothelin-1 receptor subtype(s) regulation and binding in diabetic rat heart

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

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