Trapidil (Triazolopyrimidine), a platelete derived growth factor(PDGF) antagonist in preventing restenosis after percutaneous transluminal coronary angioplasty

Okamoto, Shinya; Setuda, Morimichi; Inden, M; Konishi, Tokuji; Nakano, Takeshi

doi:10.1016/0735-1097(91)90974-e

Cited by 3 publications

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“…Several previous studies have shown antiproliferative actions of trapidil on SMC and fibroblasts in vitro and in vivo (Ohnishi et al, 1982;Tiell et al, 1983;Liu et al, 1990;Cercek et al, 1991). These data from animal experiments and/or cell culture studies were confirmed by clinical trials, demonstrating inhibition of restenosis after PTCA by the compound (Nishikawa et al, 1992;Okamoto et al, 1992;Maresta et al, 1994). The present study demonstrates that trapidil is a potent inhibitor of PDGF-induced mitogenesis in bovine coronary artery SMC.…”

Section: Discussionsupporting

confidence: 81%

“…The antimitogenic actions of trapidil have been explained by an antagonism of PDGF-mediated mitogenesis, putatively at the level of the PDGF receptor (Ohnishi et al, 1982;Nishikawa et al, 1992;Okamoto et al, 1992;Maresta et al, 1994). The present study shows that the effects of trapidil on SMC mitogenesis cannot be explained by PDGF receptor antagonism.…”

Section: Discussionmentioning

confidence: 99%

“…Clearly, the most exciting property of trapidil at the moment is its inhibition of PDGF-induced SMC proliferation in vitro (Ohnishi et al, 1982;Tiell et al, 1983;Cercek et al, 1991) and in vivo (Liu et al, 1990). A significant inhibition of restenosis after PTCA was also reported in clinical trials and was explained by PDGF receptor antagonism (Nishikawa et al, 1992;Okamoto et al, 1992;Maresta et al, 1994).…”

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confidence: 99%

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Antimitogenic Effects of Trapidil In Coronary Artery Smooth Muscle Cells by Direct Activation of Protein Kinase A

et al. 1998

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The triazolopyrimidine trapidil has been found in controlled clinical trials to prevent restenosis after vascular injury. Although trapidil is widely regarded as a platelet-derived growth factor receptor (PDGF) antagonist, its precise mode of action is still unknown. This study was designed to investigate the inhibition of mitogenesis by trapidil in cultured bovine coronary artery smooth muscle cells (SMC) and to identify major signal transduction pathways involved. Trapidil inhibited PDGF-BB-induced mitogenesis in SMC in a concentration-dependent manner. Comparable inhibitory effects were obtained after stimulation of smooth muscle cells by phorbol ester, which suggests that the action of trapidil was not restricted to PDGF receptor-mediated mechanisms. Trapidil also inhibited PDGF- and phorbol ester-induced mitogen-activated protein kinase as well as Raf-1 kinase activity. As a possible target of trapidil, stimulation of cellular protein kinase A (PKA) activity was detected. Trapidil also induced the phosphorylation of vasodilator-stimulated phosphoprotein in SMC. Antimitogenic effects of trapidil were completely abolished by PKA inhibitors. Neither a direct stimulation of cAMP formation nor a phosphodiesterase inhibition was observed at antimitogenic concentrations of trapidil. However, trapidil directly activated purified PKA holoenzyme in a cAMP-independent manner. In conclusion, trapidil exerts its antimitogenic effects on SMC by direct activation of PKA. Thus, PKA-mediated inhibition of the Raf-1/MAP kinase pathway may be involved in the antimitogenic actions of the compound.

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Section: Discussionsupporting

confidence: 81%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Antimitogenic Effects of Trapidil In Coronary Artery Smooth Muscle Cells by Direct Activation of Protein Kinase A

et al. 1998

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“…It has been hypothesized that a pertubation of the endothelial regulatory function may play a key role in the pathophysiologic process [3]. With the exception of individual reports on lovastatin, ciprostene, and trapidil [4,5,6], all pharmacological therapies have failed to reduce the restenosis rate significantly [7-161. Great attention was given to studies which seemed to demonstrate a beneficial effect of fish oil supplementation on the incidence of restenosis following PTCA [ 17-211. The rationale for the use of fish oil is based on several epidemiologic studies suggesting that diets rich in fish and fish oil are associated with a reduced risk of cardiovascular diseases and atherosclerosis.…”

Section: Introductionmentioning

confidence: 99%

A prospective, randomized, and double‐blind trial on the effect of fish oil on the incidence of restenosis following ptca

Franzen

Schannwell

Oette

et al. 1993

Cathet. Cardiovasc. Diagn.

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Restenosis after successful coronary angioplasty (PTCA) occurs in 25-35% of all procedures. To date, most pharmacologic strategies have failed to reduce the restenosis rate significantly. However, recent studies have suggested a potential benefit of dietary supplementation with omega-3 fatty acids (fish oil) on restenosis following PTCA. The benefit of omega-3 polyunsaturated fatty acids on the incidence of coronary artery restenosis following elective PTCA was assessed in 212 consecutive patients (41 female, 171 male). Following a successful angioplasty, 204 patients received a dietary supplementation with either nine capsules containing fish oil (3.15 g omega-3 fatty acids) or nine placebo capsules containing olive oil. Treatment was started immediately after PTCA and maintained over 4 mon. Compliance was assessed by analysis of lipid fatty acids prior to angioplasty and at 4 mon follow-up. The angiographically determined incidence of restenosis (stenosis diameter > 50%) was 31.2% per lesion in patients receiving fish oil and 33.7% in patients receiving olive oil. Gross progression of coronary artery disease in vessels not subjected to angioplasty was 17% and 16%, respectively. In conclusion, low dose fish oil supplementation begun on the day of a successful coronary angioplasty failed to demonstrate any effect on coronary artery restenosis.

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Pathophysiological mechanisms for restenosis following coronary angioplasty: possible preventive alternatives

Lövqvist

Emanuelsson

Nilsson

et al. 1993

Journal of Internal Medicine

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Restenosis after successful percutaneous transluminal coronary angioplasty (PTCA) remains an unsolved medical problem. The search for the underlying pathophysiological mechanisms have identified intimal proliferation of smooth muscle cells (SMC) to be the prevailing cause of late restenosis, with endothelial cells (EC) and platelets being important participators in the process. According to the most accepted present theory, SMC would be stimulated to migrate and proliferate shortly after the angioplasty by the release of growth factors from injured EC and accumulated platelets. However, clinical trials of agents interfering with these mechanisms have not significantly diminished the rate of restenosis, which suggest both that our knowledge of the process is incomplete, and that new ways of administering the agents may be required.

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Trapidil (Triazolopyrimidine), a platelete derived growth factor(PDGF) antagonist in preventing restenosis after percutaneous transluminal coronary angioplasty

Cited by 3 publications

References 0 publications

Antimitogenic Effects of Trapidil In Coronary Artery Smooth Muscle Cells by Direct Activation of Protein Kinase A

Antimitogenic Effects of Trapidil In Coronary Artery Smooth Muscle Cells by Direct Activation of Protein Kinase A

A prospective, randomized, and double‐blind trial on the effect of fish oil on the incidence of restenosis following ptca

Pathophysiological mechanisms for restenosis following coronary angioplasty: possible preventive alternatives

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