Antioxidant is a useful supportive agent for the treatment of coronary vasospasm with endothelial dysfunction in pig.

OBJECTIVES: Recently, many antioxidants have been tested in cardiovascular disease. The effect of antioxidants on alleviation of coronary vasospasm, however, remains unclear. We investigated whether chronic administration of ascorbic acid and glutathione prevents coronary vasospasm in pigs. MATERIALS AND METHODS: Balloon-induced endothelial injury in the left anterior descending coronary artery was performed every 2 weeks until 6 weeks (0, 2, 4, 6 weeks). Ten micrograms per kilogram serotonin-induced vasoconstriction was assessed before each endothelial injury and at eighth week by coronary angiography. RESULTS: In endothelial injury without antioxidant group (ED group, n=12), serotonin-induced left anterior descending coronary artery vasoconstriction was augmented from 7+/-4% (0 week) to 88+/-8% (8th week, P<0.01) with electrocardiogram-ST elevation, and an increase of cyclooxygenase-2 expression and a decrease of endothelial nitric oxide synthase expression was observed at the spasm portion removed from the endothelial denuded site. In the endothelial injury group with oral administration of ascorbic acid 3 g/day and glutathione 1 g/day after the first endothelial injury (ASC+GSH group, n=12), serotonin-induced vasoconstriction was suppressed (8th week, 60+/-6%, P<0.01 vs. ED group) and endothelial nitric oxide synthase expression was fairly well maintained. Intimal thickening was observed at the left anterior descending artery spasm portion in the endothelial injury without antioxidant group but not at the corresponding portion in the ASC+GSH group. CONCLUSION: Antioxidant therapy was partially effective to prevent coronary vasospasm, whereas intimal thickening after endothelial injury was nearly restored. From these results, chronic antioxidant therapy may well be a useful supportive therapy for the treatment of coronary vasospasm, although it has limited availability despite amelioration of endothelial dysfunction.

Differing effects of metoprolol and propranolol on large vessel and microvessel responsiveness in a porcine model of coronary spasm.

OBJECTIVES: The purpose of this study is to assess the effect of beta1-selective blocker on coronary vasospasm. MATERIALS AND METHODS: Balloon epicardial coronary artery endothelial denudation was performed at the left anterior descending coronary artery every 2 weeks for a total of 4 times in pigs. Changes in denuded site diameter and left anterior descending coronary artery blood flow caused by acetylcholine or serotonin were assessed before each endothelial denudation and at week 8 in untreated pigs (ED group) and in those treated with metoprolol (Meto group) or propranolol (Pro group). RESULTS: In the ED group, decreased blood flow response to acetylcholine enhanced from -20+/-10% before the first ED to -100% (i.e. zero flow) at week 8 without denuded site narrowing, suggesting microvascular spasm, and serotonin-induced left anterior descending coronary artery diameter reduction at week 8 was -92+/-15%. In the Pro group, blood flow reduction by acetylcholine and left anterior descending coronary artery diameter reduction by serotonin did not change compared with those of the ED group. In the Meto group however, blood flow reduction by acetylcholine (week 8, -70+/-16%) and left anterior descending coronary artery diameter reduction by serotonin (week 8, -64+/-15%) were blunted (P<0.01) compared with those of ED and Pro groups. CONCLUSION: The beta1-selective blocker metoprolol was effective to prevent coronary vasospasm.

Effects of antioxidants on coronary microvascular spasm induced by epicardial coronary artery endothelial injury in pigs.

OBJECTIVES: The effect of oxidative stress on coronary microvascular disease is unknown. We investigated whether chronic administration of ascorbic acid (ASC) or glutathione (GSH) prevents microvascular dysfunction and remodeling induced by upstream repeated coronary artery endothelial injury. METHODS: Balloon endothelial injury was repeated at the left anterior descending coronary artery (LAD), just distal to an implanted flow meter, every 2 weeks for 6 weeks in pigs. Changes in LAD blood flow induced by acetylcholine (ACh) and 5-hydroxytryptamine were assessed before each endothelial injury and at 8 weeks after the first endothelial injury in pigs without treatment (endothelial injury group, n = 12) and in pigs treated with oral ASC (3 g/day) (ASC group, n = 12) and ASC (3 g/day) plus GSH (1 g/day) (ASC + GSH group, n = 12). RESULTS: In the endothelial injury group, reduced blood flow in response to ACh was augmented from a decrease of 18 +/- 17% to a decrease of 100% (that is, zero flow, 8 weeks, P < 0.01), accompanied by an increase of ascorbyl free radicals (AFRs) in coronary sinus blood. In contrast, in the ASC + GSH group, blood flow response to ACh was altered to a decrease of 45 +/- 17% (8 weeks, P < 0.01 compared with the endothelial injury group), coronary sinus blood AFRs did not change (8 weeks, 21.4 +/- 12.5 signal intensities, P < 0.01 compared with the endothelial injury group) and the rate of platelet aggregation induced by adenosine diphosphate was small (8 weeks, 56 +/- 17%, P < 0.01 compared with the endothelial injury group). CONCLUSIONS: Chronic administration of antioxidants suppressed microvascular hypercontraction, suggesting that it may be a promising therapeutic strategy for treating coronary microvessel disorders, including microvascular angina.

Repeated epicardial coronary artery endothelial injuries lead to a global spontaneous coronary artery spasm.

OBJECTIVES: This study was conducted to develop a spontaneous coronary spasm model. MATERIALS AND METHODS: Balloon endothelial denudation was carried out in the epicardial left anterior descending coronary artery (LAD) every 2 weeks, for a total of four times, in 12 pigs. Changes in the denuded site diameter and LAD blood flow caused by acetylcholine or serotonin were assessed before each denudation and at week 8. Blood pressure, electrocardiogram (ECG) from the LAD area and LAD blood flow were monitored continuously in conscious and unrestrained pigs. RESULTS: Spontaneous ECG ST depression with a decrease in LAD blood flow appeared at around 2 weeks. In accordance with this, 0.5 microg/kg acetylcholine induced similar ECG and LAD blood flow changes without denuded site narrowing, suggesting microvascular spasm. Thereafter, ECG ST depression or elevation by serotonin via a denuded site spasm was found after 6 weeks and spontaneous ECG ST changes due to epicardial coronary artery spasm were observed. CONCLUSION: Epicardial coronary artery endothelial injury may induce spontaneous vasospasticity in the downstream coronary microvessels as well as in the denuded portion, suggesting functional abnormality through the entire coronary arterial tree.