Upregulation of phosphodiesterase 1A1 expression is associated with the development of nitrate tolerance

Dongsoo Kim, Sergei D. Rybalkin, Xinchun Pi, Yining Wang, Changxi Zhang, Thomas Munzel, Joseph A. Beavo, Bradford C. Berk, Chen Yan

Research output: Contribution to journalArticle

155 Citations (Scopus)

Abstract

Background - The efficacy of nitroglycerin (NTG) as a vasodilator is limited by tolerance, which develops shortly after treatment begins. In vascular smooth muscle cells (VSMCs), NTG is denitrated to form nitric oxide (NO), which activates guanylyl cyclase and generates cGMP. cGMP plays a key role in nitrate-induced vasodilation by reducing intracellular Ca2+ concentration. Therefore, one possible mechanism for development of nitrate tolerance would be increased activity of the cGMP phosphodiesterase (PDE), which decreases cGMP levels. Methods and Results-To test this hypothesis, rats were made tolerant by continuous infusion of NTG for 3 days (10 μg · kg-1 · min-1 SC) with an osmotic pump. Analysis of PDE activities showed an increased function of Ca2+/calmodulin (CaM)-stimulated PDE (PDE1A1), which preferentially hydrolyzes cGMP after NTG treatment. Western blot analysis for the Ca2+/CaM-stimulated PDE revealed that PDE1A1 was increased 2.3-fold in NTG-tolerant rat aortas. Increased PDE1A1 was due to mRNA upregulation as measured by relative quantitative reverse transcription-polymerase chain reaction. The PDE1-specific inhibitor vinpocetine partially restored the sensitivity of the tolerant vasculature to subsequent NTG exposure. In cultured rat aortic VSMCs, angiotensin II (Ang II) increased PDE1A1 activity, and vinpocetine blocked the effect of Ang II on decrease in cGMP accumulation. Conclusions - Induction of PDE1A1 in nitrate-tolerant vessels may be one mechanism by which NO/cGMP-mediated vasodilation is desensitized and Ca2+-mediated vasoconstriction is supersensitized. Inhibiting PDE1A1 expression and/or activity could be a novel therapeutic approach to limit nitrate tolerance.

Original languageEnglish (US)
Pages (from-to)2338-2343
Number of pages6
JournalCirculation
Volume104
Issue number19
DOIs
StatePublished - Nov 6 2001

Fingerprint

Phosphoric Diester Hydrolases
Nitroglycerin
Nitrates
Up-Regulation
vinpocetine
Type 1 Cyclic Nucleotide Phosphodiesterases
Vascular Smooth Muscle
Vasodilation
Angiotensin II
Smooth Muscle Myocytes
Nitric Oxide
Guanylate Cyclase
Vasoconstriction
Vasodilator Agents
Reverse Transcription
Aorta
Western Blotting
Polymerase Chain Reaction
Messenger RNA

Keywords

  • Nitrates
  • Phosphodiesterase
  • Vasculature

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Upregulation of phosphodiesterase 1A1 expression is associated with the development of nitrate tolerance. / Kim, Dongsoo; Rybalkin, Sergei D.; Pi, Xinchun; Wang, Yining; Zhang, Changxi; Munzel, Thomas; Beavo, Joseph A.; Berk, Bradford C.; Yan, Chen.

In: Circulation, Vol. 104, No. 19, 06.11.2001, p. 2338-2343.

Research output: Contribution to journalArticle

Kim, D, Rybalkin, SD, Pi, X, Wang, Y, Zhang, C, Munzel, T, Beavo, JA, Berk, BC & Yan, C 2001, 'Upregulation of phosphodiesterase 1A1 expression is associated with the development of nitrate tolerance', Circulation, vol. 104, no. 19, pp. 2338-2343. https://doi.org/10.1161/hc4401.098432
Kim, Dongsoo ; Rybalkin, Sergei D. ; Pi, Xinchun ; Wang, Yining ; Zhang, Changxi ; Munzel, Thomas ; Beavo, Joseph A. ; Berk, Bradford C. ; Yan, Chen. / Upregulation of phosphodiesterase 1A1 expression is associated with the development of nitrate tolerance. In: Circulation. 2001 ; Vol. 104, No. 19. pp. 2338-2343.
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AU - Kim, Dongsoo

AU - Rybalkin, Sergei D.

AU - Pi, Xinchun

AU - Wang, Yining

AU - Zhang, Changxi

AU - Munzel, Thomas

AU - Beavo, Joseph A.

AU - Berk, Bradford C.

AU - Yan, Chen

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AB - Background - The efficacy of nitroglycerin (NTG) as a vasodilator is limited by tolerance, which develops shortly after treatment begins. In vascular smooth muscle cells (VSMCs), NTG is denitrated to form nitric oxide (NO), which activates guanylyl cyclase and generates cGMP. cGMP plays a key role in nitrate-induced vasodilation by reducing intracellular Ca2+ concentration. Therefore, one possible mechanism for development of nitrate tolerance would be increased activity of the cGMP phosphodiesterase (PDE), which decreases cGMP levels. Methods and Results-To test this hypothesis, rats were made tolerant by continuous infusion of NTG for 3 days (10 μg · kg-1 · min-1 SC) with an osmotic pump. Analysis of PDE activities showed an increased function of Ca2+/calmodulin (CaM)-stimulated PDE (PDE1A1), which preferentially hydrolyzes cGMP after NTG treatment. Western blot analysis for the Ca2+/CaM-stimulated PDE revealed that PDE1A1 was increased 2.3-fold in NTG-tolerant rat aortas. Increased PDE1A1 was due to mRNA upregulation as measured by relative quantitative reverse transcription-polymerase chain reaction. The PDE1-specific inhibitor vinpocetine partially restored the sensitivity of the tolerant vasculature to subsequent NTG exposure. In cultured rat aortic VSMCs, angiotensin II (Ang II) increased PDE1A1 activity, and vinpocetine blocked the effect of Ang II on decrease in cGMP accumulation. Conclusions - Induction of PDE1A1 in nitrate-tolerant vessels may be one mechanism by which NO/cGMP-mediated vasodilation is desensitized and Ca2+-mediated vasoconstriction is supersensitized. Inhibiting PDE1A1 expression and/or activity could be a novel therapeutic approach to limit nitrate tolerance.

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