Tetrahydrobiopterin improves endothelial dysfunction in coronary microcirculation in patients without epicardial coronary artery disease

Soko Setoguchi Iwata, Masahiro Mohri, Hiroaki Shimokawa, Akira Takeshita

Research output: Contribution to journalArticle

66 Citations (Scopus)

Abstract

OBJECTIVES: We aimed to determine whether intracoronary supplementation with nitric oxide (NO) synthase co-factor tetrahydrobiopterin (BH4) improves NO-dependent coronary microvascular dilation in patients with coronary risk factors but no significant organic stenosis. BACKGROUND: Impaired coronary microvascular dilator reserve attributable to endothelial dysfunction plays an important role in the regulation of coronary blood flow (CBF). METHODS: Fifteen patients were measured for CBF (Doppler-wire and quantitative coronary angiography). Stimulated release of NO in the coronary microcirculation was evaluated by percent increase in CBF (%ΔCBF) at graded doses of intracoronary acetylcholine (1, 3, 10 and 30 μg/min). Measurements were repeated after intracoronary co-infusion of BH4 (4 mg/min) and acetylcholine. RESULTS: The patients were divided into two groups on the basis of CBF responses to acetylcholine: those with "diminished" (%ΔCBF <300%, n = 8) and "normal" (%ΔCBF >300%, n = 7) flow responses. Tetrahydrobiopterin significantly (p < 0.0001) improved acetylcholine-induced increases in CBF in patients with diminished flow responses, but exerted no effect in those with normal flow responses. Among the 15 studied patients, the magnitude of flow improvement by BH4 was inversely correlated with baseline flow responses (p < 0.02). Microvascular dilator response to direct NO donor (isosorbide dinitrate) was not affected by BH4. CONCLUSIONS: We demonstrated for the first time that intracoronary BH4 improved acetylcholine-induced microvascular dilator responses in patients with endothelial dysfunction in vivo. Thus, supplementation with BH4 may be a novel therapeutic means to increase NO availability for patients with coronary microvascular disease.

Original languageEnglish (US)
Pages (from-to)493-498
Number of pages6
JournalJournal of the American College of Cardiology
Volume38
Issue number2
DOIs
StatePublished - Aug 18 2001
Externally publishedYes

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Microcirculation
Coronary Artery Disease
Acetylcholine
Nitric Oxide
Isosorbide Dinitrate
Nitric Oxide Donors
sapropterin
Coronary Angiography
Nitric Oxide Synthase
Coronary Disease
Dilatation
Pathologic Constriction

All Science Journal Classification (ASJC) codes

  • Nursing(all)

Cite this

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title = "Tetrahydrobiopterin improves endothelial dysfunction in coronary microcirculation in patients without epicardial coronary artery disease",
abstract = "OBJECTIVES: We aimed to determine whether intracoronary supplementation with nitric oxide (NO) synthase co-factor tetrahydrobiopterin (BH4) improves NO-dependent coronary microvascular dilation in patients with coronary risk factors but no significant organic stenosis. BACKGROUND: Impaired coronary microvascular dilator reserve attributable to endothelial dysfunction plays an important role in the regulation of coronary blood flow (CBF). METHODS: Fifteen patients were measured for CBF (Doppler-wire and quantitative coronary angiography). Stimulated release of NO in the coronary microcirculation was evaluated by percent increase in CBF ({\%}ΔCBF) at graded doses of intracoronary acetylcholine (1, 3, 10 and 30 μg/min). Measurements were repeated after intracoronary co-infusion of BH4 (4 mg/min) and acetylcholine. RESULTS: The patients were divided into two groups on the basis of CBF responses to acetylcholine: those with {"}diminished{"} ({\%}ΔCBF <300{\%}, n = 8) and {"}normal{"} ({\%}ΔCBF >300{\%}, n = 7) flow responses. Tetrahydrobiopterin significantly (p < 0.0001) improved acetylcholine-induced increases in CBF in patients with diminished flow responses, but exerted no effect in those with normal flow responses. Among the 15 studied patients, the magnitude of flow improvement by BH4 was inversely correlated with baseline flow responses (p < 0.02). Microvascular dilator response to direct NO donor (isosorbide dinitrate) was not affected by BH4. CONCLUSIONS: We demonstrated for the first time that intracoronary BH4 improved acetylcholine-induced microvascular dilator responses in patients with endothelial dysfunction in vivo. Thus, supplementation with BH4 may be a novel therapeutic means to increase NO availability for patients with coronary microvascular disease.",
author = "{Setoguchi Iwata}, Soko and Masahiro Mohri and Hiroaki Shimokawa and Akira Takeshita",
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Tetrahydrobiopterin improves endothelial dysfunction in coronary microcirculation in patients without epicardial coronary artery disease. / Setoguchi Iwata, Soko; Mohri, Masahiro; Shimokawa, Hiroaki; Takeshita, Akira.

In: Journal of the American College of Cardiology, Vol. 38, No. 2, 18.08.2001, p. 493-498.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Tetrahydrobiopterin improves endothelial dysfunction in coronary microcirculation in patients without epicardial coronary artery disease

AU - Setoguchi Iwata, Soko

AU - Mohri, Masahiro

AU - Shimokawa, Hiroaki

AU - Takeshita, Akira

PY - 2001/8/18

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N2 - OBJECTIVES: We aimed to determine whether intracoronary supplementation with nitric oxide (NO) synthase co-factor tetrahydrobiopterin (BH4) improves NO-dependent coronary microvascular dilation in patients with coronary risk factors but no significant organic stenosis. BACKGROUND: Impaired coronary microvascular dilator reserve attributable to endothelial dysfunction plays an important role in the regulation of coronary blood flow (CBF). METHODS: Fifteen patients were measured for CBF (Doppler-wire and quantitative coronary angiography). Stimulated release of NO in the coronary microcirculation was evaluated by percent increase in CBF (%ΔCBF) at graded doses of intracoronary acetylcholine (1, 3, 10 and 30 μg/min). Measurements were repeated after intracoronary co-infusion of BH4 (4 mg/min) and acetylcholine. RESULTS: The patients were divided into two groups on the basis of CBF responses to acetylcholine: those with "diminished" (%ΔCBF <300%, n = 8) and "normal" (%ΔCBF >300%, n = 7) flow responses. Tetrahydrobiopterin significantly (p < 0.0001) improved acetylcholine-induced increases in CBF in patients with diminished flow responses, but exerted no effect in those with normal flow responses. Among the 15 studied patients, the magnitude of flow improvement by BH4 was inversely correlated with baseline flow responses (p < 0.02). Microvascular dilator response to direct NO donor (isosorbide dinitrate) was not affected by BH4. CONCLUSIONS: We demonstrated for the first time that intracoronary BH4 improved acetylcholine-induced microvascular dilator responses in patients with endothelial dysfunction in vivo. Thus, supplementation with BH4 may be a novel therapeutic means to increase NO availability for patients with coronary microvascular disease.

AB - OBJECTIVES: We aimed to determine whether intracoronary supplementation with nitric oxide (NO) synthase co-factor tetrahydrobiopterin (BH4) improves NO-dependent coronary microvascular dilation in patients with coronary risk factors but no significant organic stenosis. BACKGROUND: Impaired coronary microvascular dilator reserve attributable to endothelial dysfunction plays an important role in the regulation of coronary blood flow (CBF). METHODS: Fifteen patients were measured for CBF (Doppler-wire and quantitative coronary angiography). Stimulated release of NO in the coronary microcirculation was evaluated by percent increase in CBF (%ΔCBF) at graded doses of intracoronary acetylcholine (1, 3, 10 and 30 μg/min). Measurements were repeated after intracoronary co-infusion of BH4 (4 mg/min) and acetylcholine. RESULTS: The patients were divided into two groups on the basis of CBF responses to acetylcholine: those with "diminished" (%ΔCBF <300%, n = 8) and "normal" (%ΔCBF >300%, n = 7) flow responses. Tetrahydrobiopterin significantly (p < 0.0001) improved acetylcholine-induced increases in CBF in patients with diminished flow responses, but exerted no effect in those with normal flow responses. Among the 15 studied patients, the magnitude of flow improvement by BH4 was inversely correlated with baseline flow responses (p < 0.02). Microvascular dilator response to direct NO donor (isosorbide dinitrate) was not affected by BH4. CONCLUSIONS: We demonstrated for the first time that intracoronary BH4 improved acetylcholine-induced microvascular dilator responses in patients with endothelial dysfunction in vivo. Thus, supplementation with BH4 may be a novel therapeutic means to increase NO availability for patients with coronary microvascular disease.

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