Zaprinast, but not dipyridamole, reverses hemodynamic tolerance to nitroglycerin in vivo

Garavilla, Lawrence de; Pagani, Edward D.; Buchholz, Richard; Dundore, Ronald L.; Bode, Donald C.; Volberg, Marlo L.; Jackson, Keith N.; Pratt, Phillip F.; Silver, Paul J.

doi:10.1016/0014-2999(96)00505-5

Cited by 17 publications

(12 citation statements)

References 23 publications

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“…We chose to use zaprinast in the intact animal to allow comparison with previous in vivo studies that assessed the role of PDEs in nitrate tolerance (Silver et al, 1991;de Garavilla et al, 1996). Consistent with the data obtained in the in vitro experiments, administration of this cGMP PDE inhibitor at the dose chosen (1 mg/kg) selectively increased Phosphodiesterase 5 and Nitrate Tolerance the sensitivity to the venodilator effects of GTN in GTNtolerant animals (Fig.…”

Section: Discussionmentioning

confidence: 67%

“…In heart failure, the nitrate-induced decrease in ventricular end diastolic pressure improves endocardial perfusion, and in angina, decreased preload reduces myocardial oxygen demand. Of the many mechanisms proposed to explain the phenomenon of nitrate tolerance, several studies have suggested a role of the cGMP-hydrolyzing PDEs, PDE1A1 (Kim et al, 2001) and PDE5 (Silver et al, 1991;Pagani et al, 1993;de Garavilla et al, 1996). Increased cGMP PDE activity would be expected to decrease cGMP levels and attenuate cGMP signaling.…”

Section: Discussionmentioning

confidence: 99%

“…Several studies have provided evidence for a role of PDEs (e.g., PDE1A1 and PDE5) in nitrate tolerance (Axelsson and Andersson, 1983;Ahlner et al, 1986;Silver et al, 1991;Pagani et al, 1993;de Garavilla et al, 1996;Kim et al, 2001). Most studies investigating nitrate tolerance have used arterial tissue, mainly thoracic aorta tissue preparations, or have assessed changes in mean arterial pressure when this phenomenon has been studied in vivo.…”

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confidence: 99%

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Inhibition of Phosphodiesterase 5 Selectively Reverses Nitrate Tolerance in the Venous Circulation

MacPherson¹,

Gillespie²,

Dunkerley³

et al. 2005

J Pharmacol Exp Ther

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An important component of the antianginal efficacy of glyceryl trinitrate (GTN) is attributable to its selective venodilator effect, resulting in decreased cardiac preload and myocardial oxygen demand. Tolerance to nitrates occurs during chronic exposure, and the current study assessed whether this was due to increased phosphodiesterase (PDE) activity in the venous circulation. Tolerance was induced in rats by continuous exposure to 0.4 mg/h GTN for 48 h. Tension recordings of isolated femoral artery and vein indicated that tolerance was more pronounced in femoral vein. 4-[[3,4-(Methylenedioxy)benzyl]amino]-6-chloroquinazoline (MBCQ), a selective PDE5 inhibitor, significantly decreased the EC 50 values for GTN-induced relaxation in both tolerant and nontolerant tissues, but with the greatest relative shift occurring in tolerant veins. MBCQ also increased the vasodilator potency of 1,1-diethyl-2-hydroxy-2-nitrosohydrazine (DEA/NO), a nitric oxide donor; however, cross-tolerance between DEA/NO and GTN was not observed. A significant increase in cGMP PDE activity was observed in tolerant femoral vein, whereas PDE activity was unchanged in femoral artery. Conscious rats treated with hexamethonium (30 mg/kg) to induce ganglionic blockade exhibited blunted central venous pressure (CVP) and mean arterial pressure (MAP) responses to bolus i.v. doses of GTN in GTNtolerant animals. The cGMP PDE inhibitor zaprinast (1 mg/kg) selectively reversed the blunted CVP response to GTN in tolerant animals but had no effect on the CVP response to GTN in nontolerant animals or on the MAP response in either group. These results suggest that increased PDE5 activity in the venous circulation contributes to the altered hemodynamic response to GTN following chronic GTN exposure.

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Section: Discussionmentioning

confidence: 67%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Inhibition of Phosphodiesterase 5 Selectively Reverses Nitrate Tolerance in the Venous Circulation

MacPherson¹,

Gillespie²,

Dunkerley³

et al. 2005

J Pharmacol Exp Ther

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“…11 Aortic rings were stretched with a preload of 2 g, equilibrated, and then preconstricted with phenylephrine. Preconstricted aortic rings were pretreated with vehicle or 100 mol/L vinpocetine for 10 minutes, followed by exposure to ascending concentrations of NTG.…”

Section: Contraction Studymentioning

confidence: 99%

“…Zaprinast, which inhibits both PDE1 and PDE5 isoforms with higher sensitivity to PDE5, has been shown to be able to reverse NTG tolerance in vitro and in vivo. 11,25 The effect of zaprinast on the reversal of nitrate tolerance may be due to the inhibition of both PDE1A1 and PDE5A1. Inhibition of PDE5A1 activity is able to diminish nitrate tolerance because of augmentation of the response to organic nitrates, even though PDE5A1 expression is not altered in the setting of nitrate tolerance.…”

Section: Effects Of Pde Inhibition On Tolerancementioning

confidence: 99%

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

et al. 2001

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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 2ϩ 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 g · kg Ϫ1 · min Ϫ1 SC) with an osmotic pump. Analysis of PDE activities showed an increased function of Ca 2ϩ /calmodulin (CaM)-stimulated PDE (PDE1A1), which preferentially hydrolyzes cGMP after NTG treatment. Western blot analysis for the Ca 2ϩ /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 2ϩ -mediated vasoconstriction is supersensitized. Inhibiting PDE1A1 expression and/or activity could be a novel therapeutic approach to limit nitrate tolerance.

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Treating Acute Decompensated Heart Failure in Patients with COVID-19 Using Intravenous Nitroglycerin in 5% Glutathione

Kaesemeyer¹,

Suvorava

2021

Am J Cardiovasc Drugs

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The purpose of this current opinion article is to illustrate a novel approach to the treatment of acute decompensated heart failure (ADHF) in coronavirus disease 2019 (COVID-19) patients. The approach described herein relies on a reformulation of intravenous nitroglycerin in 5% glutathione, itself novel, and is felt to have the potential to not only improve the rate of resolution of ADHF, but also reduce the risk of complications of heart failure seen in patients with COVID-19. Key Points This paper continues our approach to treating coronavirus disease 2019 (COVID-19) as a disease of the vascular endothelium with a focus on heart failure.

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Zaprinast, but not dipyridamole, reverses hemodynamic tolerance to nitroglycerin in vivo

Cited by 17 publications

References 23 publications

Inhibition of Phosphodiesterase 5 Selectively Reverses Nitrate Tolerance in the Venous Circulation

Inhibition of Phosphodiesterase 5 Selectively Reverses Nitrate Tolerance in the Venous Circulation

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

Treating Acute Decompensated Heart Failure in Patients with COVID-19 Using Intravenous Nitroglycerin in 5% Glutathione

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