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 Ca(2+) 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 microgram kg(-1). min(-1) SC) with an osmotic pump. Analysis of PDE activities showed an increased function of Ca(2+)/calmodulin (CaM)-stimulated PDE (PDE1A1), which preferentially hydrolyzes cGMP after NTG treatment. Western blot analysis for the Ca(2+)/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 Ca(2+)-mediated vasoconstriction is supersensitized. Inhibiting PDE1A1 expression and/or activity could be a novel therapeutic approach to limit nitrate tolerance.
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 Ca(2+) 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 microgram kg(-1). min(-1) SC) with an osmotic pump. Analysis of PDE activities showed an increased function of Ca(2+)/calmodulin (CaM)-stimulated PDE (PDE1A1), which preferentially hydrolyzes cGMP after NTG treatment. Western blot analysis for the Ca(2+)/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 Ca(2+)-mediated vasoconstriction is supersensitized. Inhibiting PDE1A1 expression and/or activity could be a novel therapeutic approach to limit nitrate tolerance.
Authors: Pedro Cabrales; George Han; Parimala Nacharaju; Adam J Friedman; Joel M Friedman Journal: Am J Physiol Heart Circ Physiol Date: 2010-11-05 Impact factor: 4.733
Authors: David Schairer; Luis R Martinez; Karin Blecher; Jason Chouake; Parimala Nacharaju; Philip Gialanella; Joel M Friedman; Joshua D Nosanchuk; Adam Friedman Journal: Virulence Date: 2012-01-01 Impact factor: 5.882
Authors: Fernanda R Giachini; Victor V Lima; Fernando S Carneiro; Rita C Tostes; R Clinton Webb Journal: Hypertension Date: 2011-01-31 Impact factor: 10.190
Authors: Nazish Sayed; David D Kim; Xavier Fioramonti; Toru Iwahashi; Walter N Durán; Annie Beuve Journal: Circ Res Date: 2008-07-31 Impact factor: 17.367