Kosuke Inokuchi

Rho-Kinase Inhibitor Improves Increased Vascular Resistance and Impaired Vasodilation of the Forearm in Patients With Heart Failure

Background—Rho-kinase is suggested to have an important role in enhanced vasoconstriction in animal models of heart failure (HF). Patients with HF are characterized by increased vasoconstriction and reduced vasodilator responses to reactive hyperemia and exercise. The aim of the present study was to examine whether Rho-kinase is involved in the peripheral circulation abnormalities of HF in humans with the Rho-kinase inhibitor fasudil. Methods and Results—Studies were performed in patients with HF (HF group, n=26) and an age-matched control group (n=26). Forearm blood flow was measured with a strain-gauge plethysmograph during intra-arterial infusion of graded doses of fasudil or sodium nitroprusside. Resting forearm vascular resistance (FVR) was significantly higher in the HF group than in the control group. The increase in forearm blood flow evoked by fasudil was significantly greater in the HF group than in the control group. The increased FVR was decreased by fasudil in the HF group toward the level of the control group. By contrast, FVR evoked by sodium nitroprusside was comparable between the 2 groups. Fasudil significantly augmented the impaired ischemic vasodilation during reactive hyperemia after arterial occlusion of the forearm in the HF group but not in the control group. Fasudil did not augment the increased FVR evoked by phenylephrine in the control group significantly. Conclusions—These results indicate that Rho-kinase is involved in increased FVR and impaired vasodilation of the forearm in patients with HF.

Role of Endothelium-Derived Hyperpolarizing Factor in Human Forearm Circulation

Abstract—Endothelium-derived hyperpolarizing factor (EDHF) contributes to endothelium-dependent relaxation of isolated arteries, but it is not known whether this also occurs in the case of humans in vivo. The present study examined the role of EDHF in human forearm circulation. Forearm blood flow (FBF) was measured by strain-gauge plethysmography in 31 healthy, normal subjects (mean±SE age, 23±2 years; 24 men and 7 women). After oral administration of aspirin (486 mg), we infused NG-monomethyl-l-arginine (8 &mgr;mol/min for 5 minutes) into the brachial artery. We used tetraethylammonium chloride (TEA, 1 mg/min for 20 minutes), a KCa channel blocker, as an EDHF inhibitor, and nicorandil as a direct K+ channel opener. TEA significantly reduced FBF (P <0.05) but did not change systemic arterial blood pressure. Furthermore, TEA significantly inhibited the FBF increase in response to substance P (0.8, 1.6, 3.2, and 6.4 ng/min, n=8) and bradykinin (12.5, 25, 50, and 100 ng/min, n=8; both P <0.001), whereas it did not affect the FBF increase in response to acetylcholine (4, 8, 16, and 32 &mgr;g/min, n=8), sodium nitroprusside (0.4, 0.8, 1.6, and 3.2 &mgr;g/min, n=8), or nicorandil (0.128, 0.256, 0.512, and 1.024 mg/min, n=8). These results suggest that EDHF contributes substantially to basal forearm vascular resistance, as well as to forearm vasodilatation evoked by substance P and bradykinin in humans in vivo.

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 μg/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.

Wandering ST-Segment Elevation

A 52-year-old man with a history of surgical repair of an abdominal aortic aneurysm 9 years earlier had a sudden onset of chest and back pain. His primary physician diagnosed acute myocardial infarction on the basis of ST elevation in leads V2 and V3 (Figure 1A). ST segments in leads I and aVL became elevated 30 minutes later, when chest pain worsened (Figure 2B). On arrival at our hospital, the patient had a blood pressure of 70/50 mm Hg in both arms and a heart rate of 54 bpm. Both femoral and dorsal arteries …