Effect of chronic and selective endothelin receptor antagonism on microvascular function in Type 2 diabetes

Kamakshi Sachidanandam, Mostafa M. Elgebaly, Alex K. Harris, Jim R. Hutchinson, Erin M. Mezzetti, Vera Portik-Dobos, Adviye Ergul

Research output: Contribution to journalArticle

25 Citations (Scopus)

Abstract

Vascular dysfunction, which presents either as an increased response to vasoconstrictors or an impaired relaxation to dilator agents, results in worsened cardiovascular outcomes in diabetes. We have established that the mesenteric circulation in Type 2 diabetes is hyperreactive to the potent vasoconstrictor endothelin-1 (ET-1) and displays increased nitric oxide-dependent vasodilation. The current study examined the individual and/or the relative roles of the ET receptors governing vascular function in the Goto-Kakizaki rat, a mildly hyperglycemic, normotensive, and nonobese model of Type 2 diabetes. Diabetic and control rats received an antagonist to either the ET type A (ETA; atrasentan; 5 mg·kg -1·day-1) or type B (ETB; A-192621; 15 or 30 mg·kg-1·day-1) receptors for 4 wk. Third-order mesenteric arteries were isolated, and vascular function was assessed with a wire myograph. Maximum response to ET-1 was increased in diabetes and attenuated by ETA antagonism. ETB blockade with 15 mg/kg A-192621 augmented vasoconstriction in controls, whereas it had no further effect on ET-1 hyperreactivity in diabetes. The higher dose of A-192621 showed an ETA-like effect and decreased vasoconstriction in diabetes. Maximum relaxation to acetylcholine (ACh) was similar across groups and treatments. ETB antagonism at either dose had no effect on vasorelaxation in control rats, whereas in diabetes the dose-response curve to ACh was shifted to the right, indicating a decreased relaxation at 15 mg/kg A-192621. These results suggest that ETA receptor blockade attenuates vascular dysfunction and that ETB receptor antagonism exhibits differential effects depending on the dose of the antagonists and the disease state.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume294
Issue number6
DOIs
StatePublished - Jun 1 2008

Fingerprint

A 192621
Endothelin Receptors
Type 2 Diabetes Mellitus
Blood Vessels
Endothelin-1
Vasoconstrictor Agents
Vasoconstriction
Vasodilation
Acetylcholine
Splanchnic Circulation
Mesenteric Arteries
Nitric Oxide

Keywords

  • Goto-Kakizaki rats
  • Microvessel
  • Vascular dysfunction

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Effect of chronic and selective endothelin receptor antagonism on microvascular function in Type 2 diabetes. / Sachidanandam, Kamakshi; Elgebaly, Mostafa M.; Harris, Alex K.; Hutchinson, Jim R.; Mezzetti, Erin M.; Portik-Dobos, Vera; Ergul, Adviye.

In: American Journal of Physiology - Heart and Circulatory Physiology, Vol. 294, No. 6, 01.06.2008.

Research output: Contribution to journalArticle

Sachidanandam, Kamakshi ; Elgebaly, Mostafa M. ; Harris, Alex K. ; Hutchinson, Jim R. ; Mezzetti, Erin M. ; Portik-Dobos, Vera ; Ergul, Adviye. / Effect of chronic and selective endothelin receptor antagonism on microvascular function in Type 2 diabetes. In: American Journal of Physiology - Heart and Circulatory Physiology. 2008 ; Vol. 294, No. 6.
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AB - Vascular dysfunction, which presents either as an increased response to vasoconstrictors or an impaired relaxation to dilator agents, results in worsened cardiovascular outcomes in diabetes. We have established that the mesenteric circulation in Type 2 diabetes is hyperreactive to the potent vasoconstrictor endothelin-1 (ET-1) and displays increased nitric oxide-dependent vasodilation. The current study examined the individual and/or the relative roles of the ET receptors governing vascular function in the Goto-Kakizaki rat, a mildly hyperglycemic, normotensive, and nonobese model of Type 2 diabetes. Diabetic and control rats received an antagonist to either the ET type A (ETA; atrasentan; 5 mg·kg -1·day-1) or type B (ETB; A-192621; 15 or 30 mg·kg-1·day-1) receptors for 4 wk. Third-order mesenteric arteries were isolated, and vascular function was assessed with a wire myograph. Maximum response to ET-1 was increased in diabetes and attenuated by ETA antagonism. ETB blockade with 15 mg/kg A-192621 augmented vasoconstriction in controls, whereas it had no further effect on ET-1 hyperreactivity in diabetes. The higher dose of A-192621 showed an ETA-like effect and decreased vasoconstriction in diabetes. Maximum relaxation to acetylcholine (ACh) was similar across groups and treatments. ETB antagonism at either dose had no effect on vasorelaxation in control rats, whereas in diabetes the dose-response curve to ACh was shifted to the right, indicating a decreased relaxation at 15 mg/kg A-192621. These results suggest that ETA receptor blockade attenuates vascular dysfunction and that ETB receptor antagonism exhibits differential effects depending on the dose of the antagonists and the disease state.

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