Prevention of vascular nitroglycerin tolerance by inhibition of protein kinase C

Zierhut, Wolfgang; Ball, Howard

doi:10.1111/j.1476-5381.1996.tb15669.x

Cited by 30 publications

(21 citation statements)

References 3 publications

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“…Our experiments, which showed that the combination of tempol and chelerythrine similarly reduced GTN tolerance, suggest that both agents are working through reduction of oxidant levels; tempol is scavenging superoxide and other ROS, and chelerythrine is reducing oxidant formation by preventing PKC activation. Our findings confirm previous reports of involvement of oxidative stress and PKC activity in GTN tolerance (Zierhut and Ball, 1996;Munzel et al, 2000). Our finding that O 2…”

Section: Discussionsupporting

confidence: 93%

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Roles of Superoxide, Peroxynitrite, and Protein Kinase C in the Development of Tolerance to Nitroglycerin

Abou-Mohamed

Johnson

Jin

et al. 2003

J Pharmacol Exp Ther

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A current hypothesis states that tolerance to nitroglycerin (GTN) involves increased formation of superoxide (O 2 . ). Studies showing that inhibitors of protein kinase C (PKC) prevent tolerance to GTN suggest the involvement of PKC activation, which can also increase O 2 . . We examined the roles of O 2 . , peroxynitrite (ONOO Ϫ ), and PKC activation in GTN tolerance. Pre-exposure of rat aortic rings to GTN (5 ϫ 10 Ϫ4 M) for 2 h caused tolerance to the vasodilating effect of GTN, as evidenced by a substantial rightward shift of GTN concentration-relaxation curves. This shift was reduced by treatment of the rings with the antioxidants uric acid, vitamin C, or tempol or the PKC inhibitor chelerythrine. We also found that O 2 . generation via xanthine/ xanthine oxidase in the bath induced tolerance to GTN. However, responses to nitroprusside were not affected. In vivo tolerance produced in rats by 3-day i.v. infusion of GTN was also almost completely prevented by coinfusion of tempol. In bovine aortic endothelial cells (EC), addition of GTN produced a marked increase in tyrosine nitrosylation, indicating increased ONOO Ϫ formation. This action was blocked by prior treatment with uric acid, superoxide dismutase, N G -nitro-L-arginine methyl ester, or chelerythrine. We also demonstrated that GTN translocates the ␣-and ⑀PKC isoforms in EC. However, PKC was not affected by GTN treatment. In conclusion, tolerance to GTN involves enhanced production of O 2 . and ONOO Ϫ and activation of NO synthase. Furthermore, sustained activation of ␣-and ⑀PKC isozymes in EC by GTN may play a role in development of tolerance.

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Section: Discussionsupporting

confidence: 93%

“…A previous study has reported that a protein kinase C (PKC) inhibitor can prevent tolerance to GTN (Zierhut and Ball, 1996). The PKC family includes at least 11 isozymes (Nishizuka, 1986).…”

mentioning

confidence: 99%

Roles of Superoxide, Peroxynitrite, and Protein Kinase C in the Development of Tolerance to Nitroglycerin

Abou-Mohamed

Johnson

Jin

et al. 2003

J Pharmacol Exp Ther

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“…64 In addition, PKC-mediated phosphorylation causes inhibition of NOS, 65 and a recent report demonstrated that angiotensin II, via an ·O 2 Ϫ -and PKC-mediated mechanism, can trigger NOS uncoupling. 14 Inhibition of PKC prevented tolerance in a rat model, 66 but the effect of endothelin-1 receptor or PKC inhibition in the response to nitrates in humans has not yet been tested.…”

Section: Neurohormonal Activation and The Control Of ·O 2 ؊ Productionmentioning

confidence: 99%

The Puzzle of Nitrate Tolerance

Gori

Parker

2002

Circulation

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“…Peroxynitrite, O2 -, or both might be responsible for the development of nitrate tolerance. 21 In addition, NTG is a potent stimulus for PKC activation in cultured endothelial cells, and inhibition of PKC prevents in vivo nitrate tolerance. 21 Because PKC activation is induced by O2 -and peroxynitrite, 22 NTG might initiate a vicious cycle that involves activation of PKC, increased O2 -and peroxynitrite, depletion of BH4, and uncoupling of eNOS.…”

Section: Discussionmentioning

confidence: 99%

“…21 In addition, NTG is a potent stimulus for PKC activation in cultured endothelial cells, and inhibition of PKC prevents in vivo nitrate tolerance. 21 Because PKC activation is induced by O2 -and peroxynitrite, 22 NTG might initiate a vicious cycle that involves activation of PKC, increased O2 -and peroxynitrite, depletion of BH4, and uncoupling of eNOS. NTG-induced increases in oxidative stress could also lead to increased production of endothelin-1 within endothelial and smooth muscle cells, leading to PKC activation, which in turn may trigger enhanced constrictor responses to almost every receptor-dependent agonist.…”

Section: Discussionmentioning

confidence: 99%

Effect of Pioglitazone on Nitroglycerin-Induced Impairment of Nitric Oxide Bioavailability by a Catheter-Type Nitric Oxide Sensor

Ikejima

Imanishi

Tsujioka

et al. 2008

Circ J

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everal clinical and basic studies have shown that chronic treatment with nitroglycerin (NTG) causes endothelial dysfunction. [1][2][3] However, the limitation of these data is that the release of nitric oxide (NO) from the endothelium was estimated on the basis of the comparison of vessel relaxation. We have very recently shown that longterm treatment of New Zealand White rabbits with NTG decreases basal, as well as acetylcholine (ACh)-induced plasma NO concentrations by using a catheter-type NO sensor, accompanied with augmentation of nitrosative stress. 4 In addition, we have shown that the negative effects of NTG could be prevented by co-treatment with drugs attenuating nitrosative stress, such as, angiotensin-converting enzyme inhibitors and angiotensin II type 1 receptor blockers (ARB). 4 The peroxisome proliferator-activated receptor (PPAR) is a nuclear receptor that has recently emerged as a pivotal intracellular controller of systemic and vascular processes, including inflammation and atherosclerosis. 5 PPAR is expressed in all major cell types involved in the initiation and evolution of the atherosclerotic plaque, including endothelial cells, vascular smooth muscle cells, macrophages, and T lymphocytes, where it might exert anti-inflammatory and potentially anti-atherogenic effects. 6 Interestingly, PPAR stimulation improves insulin resistance as well as endothelial function in patients with type 2 diabetes. 7 However, it is unknown whether this beneficial effect of PPAR stimulation on endothelial function could extend to NTG-induced endothelial dysfunction. It is clinically important because patients with diabetes mellitus have frequently accompanied with ischemic heart disease.By using the catheter-type NO sensor we investigated to clarify the effect of PPAR agonist on the impairment of bioavailability of NO induced by chronic treatment with NTG patches. The present study has shown that the NTGinduced impairment of NO bioavailability is significantly reversed by the co-treatment with a PPAR agonist, pioglitazone. Methods A Catheter Type NO SensorIntegrated architecture and performance of the cathetertype NO sensor have been described previously. [8][9][10] In brief, an NO sensor (amino-700 XL, Innovative Instruments, 700 m in diameter at the detection tip) was mounted in a 4-Fr catheter (1,200 mm long; Hirakawa Hewtech, Tokyo, Japan) and fixed with silicon adhesive. The oxidative current of NO was monitored by with an NO monitor (model inNO-T, Innovative Instruments). Each sensor was calibrated by using an NO-saturated pure water as previously described. [8][9][10] Briefly, NO-saturated pure water was prepared by bubbling pure NO gas in oxygen-free pure water. Using a gas-tight syrindge, 5 l was injected into a well Background We examined whether nitroglycerin (NTG)-induced impairment of nitric oxide (NO) bioavailability could be modified by a peroxisome proliferator-activated receptor (PPAR) agonist. Methods and ResultsMale New Zealand White rabbits were treated for 7 days with NTG patches, either al...

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Prevention of vascular nitroglycerin tolerance by inhibition of protein kinase C

Cited by 30 publications

References 3 publications

Roles of Superoxide, Peroxynitrite, and Protein Kinase C in the Development of Tolerance to Nitroglycerin

Roles of Superoxide, Peroxynitrite, and Protein Kinase C in the Development of Tolerance to Nitroglycerin

The Puzzle of Nitrate Tolerance

Effect of Pioglitazone on Nitroglycerin-Induced Impairment of Nitric Oxide Bioavailability by a Catheter-Type Nitric Oxide Sensor

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