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(Circulation. 2001;104:2338.)
© 2001 American Heart Association, Inc.

Basic Science Reports

Upregulation of Phosphodiesterase 1A1 Expression Is Associated With the Development of Nitrate Tolerance

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

From the Department of Medicine (D.K., X.P., C.Z., B.C.B., C.Y.) and Department of Surgery (Y.W.), University of Rochester, Rochester, NY; the Department of Pharmacology, University of Washington, Seattle (S.D.R., J.A.B.); and the Division of Cardiology, University of Eppendorf, Hamburg, Germany (T.M.).

Correspondence to Chen Yan, PhD, Center for Cardiovascular Research, University of Rochester, 601 Elmwood Ave, Box 679, Rochester, NY 14642-8679. E-mail chen_yan{at}urmc.rochester.edu

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.

Key Words: nitrates • phosphodiesterase • vasculature

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