Rho-kinase inhibition with intracoronary fasudil prevents myocardial ischemia in patients with coronary microvascular spasm.

OBJECTIVES: We sought to determine whether a potent Rho-kinase inhibitor fasudil prevents the occurrence of myocardial ischemia in patients with microvascular angina attributable to coronary microvascular spasm. BACKGROUND: Effective treatment of patients with angina who have normal coronary arteriograms (microvascular angina) has not yet been established. Rho-kinase-mediated calcium sensitization of the myosin light chain in smooth muscle cells has been implicated as substantially contributing to vascular hyperconstriction. METHODS: We studied consecutive 18 patients with angina and normal epicardial coronaries in whom intracoronary acetylcholine (ACh) induced myocardial ischemia (ischemic electrocardiographic changes, myocardial lactate production, or both) without angiographically demonstrable epicardial coronary vasospasm. All patients underwent a second ACh challenge test after pretreatment with either saline (n = 5) or fasudil (4.5 mg intracoronarily, n = 13). RESULTS: Myocardial ischemia was reproducibly induced by ACh in the saline group. In contrast, 11 of the 13 patients pretreated with fasudil had no evidence of myocardial ischemia during the second infusion of ACh (p < 0.01). The lactate extraction ratio (median value [interquartile range]) during ACh infusion was improved by fasudil pretreatment, from -0.16 (-0.25 to 0.04) to 0.09 (0.05 to 0.18) (p = 0.0125). CONCLUSIONS: Fasudil ameliorated myocardial ischemia in patients who were most likely having coronary microvascular spasm. The inhibition of Rho-kinase may be a novel therapeutic strategy for this group of patients with microvascular angina.

Electron spin resonance detection of hydrogen peroxide as an endothelium-derived hyperpolarizing factor in porcine coronary microvessels.

OBJECTIVE: Endothelium-derived hyperpolarizing factor (EDHF) plays an important role in modulating vascular tone, especially in microvessels, although its nature has yet to be elucidated. This study was designed to examine whether hydrogen peroxide (H2O2) is an EDHF in porcine coronary microvessels with use of an electron spin resonance (ESR) method to directly detect H2O2 production from the endothelium. METHODS AND RESULTS: Isometric tension and membrane-potential recordings demonstrated that bradykinin and substance P caused EDHF-mediated relaxations and hyperpolarizations of porcine coronary microvessels in the presence of indomethacin and Nomega-nitro-L-arginine. The contribution of H2O2 to the EDHF-mediated responses was demonstrated by the inhibitory effect of catalase and by the relaxing and hyperpolarizing effects of exogenous H2O2. Endothelial production of H2O2 was quantified in bradykinin- or substance P-stimulated intact blood vessels by ESR spectroscopy. Tiron, a superoxide scavenger that facilitates H2O2 formation, enhanced bradykinin-induced production of H2O2, as well as the EDHF-mediated relaxations and hyperpolarizations. By contrast, cytochrome P-450 inhibitors (sulfaphenazole or 17-octadecynoic acid) or a gap junction inhibitor (18alpha-glycyrrhetinic acid) failed to inhibit the EDHF-mediated relaxations. Involvement of endothelium-derived K+ was not evident in experiments with ouabain plus Ba2+ or exogenous K+. CONCLUSIONS: These results provide ESR evidence that H2O2 is an EDHF in porcine coronary microvessels.

Anti-ischemic effects of fasudil, a specific Rho-kinase inhibitor, in patients with stable effort angina.

Epicardial coronary stenosis causes myocardial ischemia; however, the role of coronary microvessels is poorly understood in the pathogenesis of effort angina. We have previously demonstrated that Rho-kinase pathway is substantially involved in coronary arterial hyperconstriction in patients with vasospastic angina and those with microvascular angina. In the present study, we tested our hypothesis that Rho-kinase is involved in coronary microvascular constriction in patients with effort angina. Intracoronary administration of fasudil (300 microg/min for 15 min), a specific Rho-kinase inhibitor, significantly increased oxygen saturation in coronary sinus vein from 37 +/- 3% to 41 +/- 3% (P < 0.05) but not in six age-matched controls (from 42 +/- 3% to 43 +/- 3%, P = NS). Furthermore, the fasudil treatment significantly ameliorated pacing-induced myocardial ischemia in patients with effort angina (magnitudes of symptom: 1.5 +/- 0.6 to 0.6 +/- 0.4, P < 0.01; ischemic ST-segment depression, 1.8 +/- 0.3 to 1.0 +/- 0.2 mm, P < 0.01; percent lactate production, 50 +/- 17% to 0.4 +/- 7%, P < 0.01) without significant hemodynamic changes. These results provide the first evidence that Rho-kinase is substantially involved in coronary microvascular dysfunction associated with myocardial ischemia in patients with effort angina, suggesting that Rho-kinase can be a novel therapeutic target in ischemic heart disease.

Hydrogen peroxide is an endothelium-derived hyperpolarizing factor in human mesenteric arteries.

The endothelium plays an important role in maintaining vascular homeostasis by synthesizing and releasing several vasodilating factors, including prostacyclin, nitric oxide, and endothelium-derived hyperpolarizing factor (EDHF). We have recently identified that endothelium-derived hydrogen peroxide (H(2)O(2)) is an EDHF in mice. The present study was designed to examine whether this is also the case in humans. Bradykinin elicited endothelium-dependent relaxations and hyperpolarizations in the presence of indomethacin and N(omega)-nitro-l-arginine, which thus were attributed to EDHF, in human mesenteric arteries. The EDHF-mediated relaxations were significantly inhibited by catalase, an enzyme that specifically decomposes H(2)O(2), whereas catalase did not affect endothelium-independent hyperpolarizations to levcromakalim. Exogenous H(2)O(2) elicited relaxations and hyperpolarizations in endothelium-stripped arteries. Gap junction inhibitor 18alpha-glycyrrhetinic acid partially inhibited, whereas inhibitors of cytochrome P450 did not affect the EDHF-mediated relaxations. These results indicate that H(2)O(2) is also a primary EDHF in human mesenteric arteries with some contribution of gap junctions.

Postprandial increase in plasma concentrations of remnant-like particles: an independent risk factor for restenosis after percutaneous coronary intervention.

Postprandial increase in remnant lipoprotein concentrations has been suggested as an important atherogenic factor. However, the influence of these remnants on the development of restenosis after percutaneous coronary intervention (PCI) remains to be examined. The present study was designed to address this point. In 60 consecutive patients with successful PCI, the influences of possible risk factors on the development of restenosis, including remnant-like particles (RLP) cholesterol (RLP-C) and triglyceride (RLP-TG), were examined. While mean concentrations of RLP-C and RLP-TG were normal in fasting state, postprandial change in RLP-C concentrations was a significant and independent risk factor for restenosis after PCI. The calculated cut-off index (COI) for the change was +64%. When the patients were divided into 2 groups according to this COI, minimal lumen diameter (MLD) and reference coronary diameter were comparable before and immediately after PCI between the high- (COI < 64%) and the low- (COI < 64%) responders. However, follow-up coronary angiography 3 to 6 months after PCI demonstrated that MLD, late loss, and loss index were all worse in the high responders compared with the low responders. These results indicate that post-prandial increase in RLP-C concentrations is an independent risk factor for restenosis after successful PCI, even in patients with normal fasting RLP-C levels.