Increased availability of angiotensin AT 1 receptors leads to sustained arterial constriction to angiotensin II in diabetes - Role for Rho-kinase activation

Zsolt Bagi, Attila Feher, James Cassuto, Komala Akula, Nazar Labinskyy, Gabor Kaley, Akos Koller

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

BACKGROUND AND PURPOSE Antagonists of angiotensin AT 1 receptors elicit beneficial vascular effects in diabetes mellitus. We hypothesized that diabetes induces sustained availability of AT 1 receptors, causing enhanced arterial constriction to angiotensin II. EXPERIMENTAL APPROACH To assess functional availability of AT 1 receptors, constrictions to successive applications of angiotensin II were measured in isolated skeletal muscle resistance arteries (∼150 μm) of Zucker diabetic fatty (ZDF) rats and of their controls (+/Fa), exposed acutely to high glucose concentrations (HG, 25 mM, 1 h). AT 1 receptors on cell membrane surface were measured by immunofluorescence. KEY RESULTS Angiotensin II-induced constrictions to first applications were greater in arteries of ZDF rats (maximum: 82 ± 3% original diameter) than in those from +/Fa rats (61 ± 5%). Constrictions to repeated angiotensin II administration were decreased in +/Fa arteries (20 ± 6%), but were maintained in ZDF arteries (67 ± 4%) and in +/Fa arteries vessels exposed to HG (65 ± 6%). In ZDF arteries and in HG-exposed +/Fa arteries, Rho-kinase activities were enhanced. The Rho-kinase inhibitor, Y27632 inhibited sustained constrictions to angiotensin II in ZDF arteries and in +/Fa arteries exposed to HG. Levels of surface AT 1 receptors on cultured vascular smooth muscle cells (VSMCs) were decreased by angiotensin II but were maintained in VSMCs exposed to HG. In VSMCs exposed to HG and treated with Y27632, angiotensin II decreased surface AT 1 receptors. CONCLUSIONS AND IMPLICATIONS In diabetes, elevated glucose concentrations activate Rho-kinase which inhibits internalization or facilitates recycling of AT 1 receptors, leading to increased functional availability of AT 1 receptors and sustained angiotensin II-induced arterial constriction.

Original languageEnglish (US)
Pages (from-to)1059-1068
Number of pages10
JournalBritish Journal of Pharmacology
Volume163
Issue number5
DOIs
StatePublished - Jul 1 2011
Externally publishedYes

Fingerprint

rho-Associated Kinases
Angiotensins
Constriction
Angiotensin II
Arteries
Vascular Smooth Muscle
Smooth Muscle Myocytes
Glucose
Angiotensin Receptors
Recycling
Fluorescent Antibody Technique
Blood Vessels
Diabetes Mellitus
Skeletal Muscle
Cell Membrane

Keywords

  • AT receptor
  • Rho-kinase
  • arteriolar constriction
  • diabetes mellitus
  • hyperglycaemia

ASJC Scopus subject areas

  • Pharmacology

Cite this

Increased availability of angiotensin AT 1 receptors leads to sustained arterial constriction to angiotensin II in diabetes - Role for Rho-kinase activation. / Bagi, Zsolt; Feher, Attila; Cassuto, James; Akula, Komala; Labinskyy, Nazar; Kaley, Gabor; Koller, Akos.

In: British Journal of Pharmacology, Vol. 163, No. 5, 01.07.2011, p. 1059-1068.

Research output: Contribution to journalArticle

Bagi, Zsolt ; Feher, Attila ; Cassuto, James ; Akula, Komala ; Labinskyy, Nazar ; Kaley, Gabor ; Koller, Akos. / Increased availability of angiotensin AT 1 receptors leads to sustained arterial constriction to angiotensin II in diabetes - Role for Rho-kinase activation. In: British Journal of Pharmacology. 2011 ; Vol. 163, No. 5. pp. 1059-1068.
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AU - Bagi, Zsolt

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AU - Akula, Komala

AU - Labinskyy, Nazar

AU - Kaley, Gabor

AU - Koller, Akos

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AB - BACKGROUND AND PURPOSE Antagonists of angiotensin AT 1 receptors elicit beneficial vascular effects in diabetes mellitus. We hypothesized that diabetes induces sustained availability of AT 1 receptors, causing enhanced arterial constriction to angiotensin II. EXPERIMENTAL APPROACH To assess functional availability of AT 1 receptors, constrictions to successive applications of angiotensin II were measured in isolated skeletal muscle resistance arteries (∼150 μm) of Zucker diabetic fatty (ZDF) rats and of their controls (+/Fa), exposed acutely to high glucose concentrations (HG, 25 mM, 1 h). AT 1 receptors on cell membrane surface were measured by immunofluorescence. KEY RESULTS Angiotensin II-induced constrictions to first applications were greater in arteries of ZDF rats (maximum: 82 ± 3% original diameter) than in those from +/Fa rats (61 ± 5%). Constrictions to repeated angiotensin II administration were decreased in +/Fa arteries (20 ± 6%), but were maintained in ZDF arteries (67 ± 4%) and in +/Fa arteries vessels exposed to HG (65 ± 6%). In ZDF arteries and in HG-exposed +/Fa arteries, Rho-kinase activities were enhanced. The Rho-kinase inhibitor, Y27632 inhibited sustained constrictions to angiotensin II in ZDF arteries and in +/Fa arteries exposed to HG. Levels of surface AT 1 receptors on cultured vascular smooth muscle cells (VSMCs) were decreased by angiotensin II but were maintained in VSMCs exposed to HG. In VSMCs exposed to HG and treated with Y27632, angiotensin II decreased surface AT 1 receptors. CONCLUSIONS AND IMPLICATIONS In diabetes, elevated glucose concentrations activate Rho-kinase which inhibits internalization or facilitates recycling of AT 1 receptors, leading to increased functional availability of AT 1 receptors and sustained angiotensin II-induced arterial constriction.

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KW - hyperglycaemia

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