Background-Several nonpharmacological interventions, including exercise, are recommended in primary prevention of hypertension and other cardiovascular diseases in which the pathogenetic role of endothelial dysfunction has been suggested. We studied the effects of long-term aerobic exercise on endothelial function in patients with essential hypertension. Methods and Results-The forearm blood flow was measured by strain-gauge plethysmography. The responses of forearm vasculature to acetylcholine were smaller in the hypertensive patients than in the normotensive subjects. There was no significant difference in forearm vascular responses to isosorbide dinitrate in the normotensive and hypertensive subjects. We evaluated the effects of physical exercise for 12 weeks on forearm hemodynamics in untreated patients with mild essential hypertension who were divided randomly into an exercise group (nϭ10) and a control group (nϭ7). After 12 weeks, the forearm blood flow response to acetylcholine increased significantly, from 25.8Ϯ9.8 to 32.3Ϯ11.2 mL ⅐ min Ϫ1 ⅐ 100 mL tissue Ϫ1 (PϽ0.05), in the exercise group but not in the control group. The increase in the forearm blood flow after isosorbide dinitrate was similar before and after 12 weeks of follow-up in both groups. The infusion of N G -monomethyl-L-arginine abolished the exercise-induced enhancement of forearm vasorelaxation evoked by acetylcholine in the exercising group. In normotensive subjects also, long-term aerobic exercise augmented acetylcholine-stimulated nitric oxide release. Conclusions-These findings suggest that long-term physical exercise improves endothelium-dependent vasorelaxation through an increase in the release of nitric oxide in normotensive as well as hypertensive subjects. (Circulation. 1999;100:1194-1202.)

These findings suggest that excessive oxidative stress is involved, at least in part, in impaired endothelium-dependent vasodilatation in patients with renovascular hypertension.

Background-Patients with limb ischemia were associated with endothelial dysfunction. The purpose of this study was to determine whether autologous bone-marrow mononuclear cell (BM-MNC) implantation improves endothelial dysfunction in patients with limb ischemia. Methods and Results-We evaluated the leg blood flow (LBF) response to acetylcholine (ACh), an endotheliumdependent vasodilator, and sodium nitroprusside (SNP), an endothelium-independent vasodilator, before and after BM-MNC implantation in 7 patients with limb ischemia. LBF was measured with a mercury-filled Silastic strain-gauge plethysmograph. The number of BM-MNCs implanted into ischemic limbs was 1.6ϫ10 9 Ϯ0.3ϫ10 9 . The number of CD34 ϩ cells included in the implanted BM-MNCs was 3.8ϫ10 7 Ϯ1.6ϫ10 7 . BM-MNC implantation improved the ankle-brachial pressure index (0.33Ϯ0.21 to 0.39Ϯ0.17, Pϭ0.06), transcutaneous oxygen pressure (28.4Ϯ11.5 to 36.6Ϯ5.2 mm Hg, Pϭ0.03), and pain-free walking time (0.8Ϯ0.6 to 2.9Ϯ2.2 minutes, Pϭ0.02). After BM-MNC implantation, LBF response to ACh was enhanced (19.3Ϯ6.8 versus 29.6Ϯ7.1 mL/min per 100 mL; Pϭ0.002). The vasodilatory effect of SNP was similar before and after BM-MNC implantation. Conclusions-These findings suggest that BM-MNC implantation augments endothelium-dependent vasodilation in patients with limb ischemia.

Abstract-We have previously demonstrated that stimulation of the angiotensin (Ang) II type 2 receptor in vascular smooth muscle cells caused bradykinin production by activating kininogenase in transgenic mice. The aim of this study was to determine whether overexpression of AT 2 receptors in cardiomyocytes attenuates Ang II-induced cardiomyocyte hypertrophy or interstitial fibrosis through a kinin/nitric oxide (NO)-dependent mechanism in mice. Ang II (1.4 mg/kg per day) or vehicle was subcutaneously infused into transgenic mice and wild-type mice for 14 days. The amount of cardiac AT 2 receptor relative to AT 1 receptor in transgenic mice was 22% to 37%. Ang II caused similar elevations in systolic blood pressure (by Ϸ45 mm Hg) in transgenic mice and wild-type mice. Myocyte hypertrophy assessed by an increase in myocyte cross-sectional area, left ventricular mass, and atrial natriuretic peptide mRNA levels were similar in transgenic and wild-type mice. Ang II induced prominent perivascular fibrosis of the intramuscular coronary arteries, the extent of which was significantly less in transgenic mice than in wild-type mice. Inhibition of perivascular fibrosis in transgenic mice was abolished by cotreatment with HOE140, a bradykinin B 2 receptor antagonist, or L-NAME, an inhibitor of NO synthase. Cardiac kininogenase activity was markedly increased (Ϸ2.6-fold, PϽ0.001) after Ang II infusion in transgenic mice but not in wild-type mice. Immunohistochemistry indicated that both bradykinin B 2 receptors and endothelial NO synthase were expressed in the vascular endothelium, whereas only B 2 receptors were present in fibroblasts. These results suggest that stimulation of AT 2 receptors present in cardiomyocytes attenuates perivascular fibrosis by a kinin/NO-dependent mechanism. However, the effect on the development of cardiomyocyte hypertrophy was not detected in this experimental setting. Key Words: receptors, angiotensin II Ⅲ kinins Ⅲ mice Ⅲ fibrosis Ⅲ hypertrophy A ngiotensin (Ang) II is an important humoral factor responsible for cardiomyocyte hypertrophy as well as interstitial hyperplasia. 1 Both of the major Ang II receptor subtypes, AT 1 and AT 2 , are expressed in the heart. 2 The AT 2 receptor (AT 2 R) has been implicated in suppression of myocardial hypertrophy, 3-5 fibroblast proliferation, 6,7 and vascular cell hyperplasia. 8,9 However, little is known about the mechanisms by which this receptor subtype exerts such antigrowth effects and the role of the cardiac AT 2 R in cardiac diseases in vivo. Previous studies have suggested possible involvement of the bradykinin/nitric oxide (NO)/cGMP system in AT 2 R-mediated physiological functions in the rat aorta, 10 canine coronary artery, 11 a rat model of heart failure caused by myocardial infarction, 12,13 hypertrophied rat heart caused by aortic coarctation, 4 and in the kidney. 14 We have recently demonstrated that AT 2 R overexpression in vascular smooth muscle cells activates the vascular kinin system and causes vasodilation in transgenic mice. 15 However,...