Tetsuya Oshima

Regular Aerobic Exercise Augments Endothelium-Dependent Vascular Relaxation in Normotensive As Well As Hypertensive Subjects Role of Endothelium-Derived Nitric Oxide

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 (n=10) and a control group (n=7). After 12 weeks, the forearm blood flow response to acetylcholine increased significantly, from 25.8+/-9.8 to 32.3+/-11.2 mL. min(-1). 100 mL tissue(-1) (P<0.05), 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.

Autologous Bone-Marrow Mononuclear Cell Implantation Improves Endothelium-Dependent Vasodilation in Patients With Limb Ischemia

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 endothelium-dependent 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 1.6×109±0.3×109. The number of CD34+ cells included in the implanted BM-MNCs was 3.8×107±1.6×107. BM-MNC implantation improved the ankle-brachial pressure index (0.33±0.21 to 0.39±0.17, P =0.06), transcutaneous oxygen pressure (28.4±11.5 to 36.6±5.2 mm Hg, P =0.03), and pain-free walking time (0.8±0.6 to 2.9±2.2 minutes, P =0.02). After BM-MNC implantation, LBF response to ACh was enhanced (19.3±6.8 versus 29.6±7.1 mL/min per 100 mL; P =0.002). 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.

Daily Aerobic Exercise Improves Reactive Hyperemia in Patients With Essential Hypertension

The effects of long-term aerobic exercise on endothelial function in patients with essential hypertension remain unclear. To determine whether endothelial function relating to forearm hemodynamics in these patients differs from normotensive subjects and whether endothelial function can be modified by continued physical exercise, we randomized patients with essential hypertension into a group that engaged in 30 minutes of brisk walking 5 to 7 times weekly for 12 weeks (n=20) or a group that underwent no activity modifications (control group, n=7). Forearm blood flow was measured using strain-gauge plethysmography during reactive hyperemia to test for endothelium-dependent vasodilation and after sublingual nitroglycerin administration to test endothelium-independent vasodilation. Forearm blood flow in hypertensive patients during reactive hyperemia was significantly less than that in normotensive subjects (n=17). Increases in forearm blood flow after nitroglycerin were similar between hypertensive and normotensive subjects. Exercise lowered mean blood pressure from 115.7+/-5.3 to 110.2+/-5.1 mm Hg (P<0.01) and forearm vascular resistance from 25.6+/-3.2 to 23. 2+/-2.8 mm Hg/mL per minute per 100 mL tissue (P<0.01); no change occurred in controls. Basal forearm blood flow, body weight, and heart rate did not differ with exercise. After 12 weeks of exercise, maximal forearm blood flow response during reactive hyperemia increased significantly, from 38.4+/-4.6 to 47.1+/-4.9 mL/min per 100 mL tissue (P<0.05); this increase was not seen in controls. Changes in forearm blood flow after sublingual nitroglycerin administration were similar before and after 12 weeks of exercise. Intra-arterial infusion of the nitric oxide synthase inhibitor NG-monomethyl-L-arginine abolished the enhancement of reactive hyperemia induced by 12 weeks of exercise. These findings suggest that through increased release of nitric oxide, continued physical exercise alleviates impairment of reactive hyperemia in patients with essential hypertension.

Cardiac Angiotensin II Type 2 Receptor Activates the Kinin/NO System and Inhibits Fibrosis

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 AT2 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 AT2 receptor relative to AT1 receptor in transgenic mice was 22% to 37%. Ang II caused similar elevations in systolic blood pressure (by ≈45 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 B2 receptor antagonist, or L-NAME, an inhibitor of NO synthase. Cardiac kininogenase activity was markedly increased (≈2.6-fold, P <0.001) after Ang II infusion in transgenic mice but not in wild-type mice. Immunohistochemistry indicated that both bradykinin B2 receptors and endothelial NO synthase were expressed in the vascular endothelium, whereas only B2 receptors were present in fibroblasts. These results suggest that stimulation of AT2 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.

A comparison of angiotensin-converting enzyme inhibitors, calcium antagonists, beta-blockers and diuretic agents on reactive hyperemia in patients with essential hypertension: a multicenter study

OBJECTIVES The purpose of this study was to compare the effect of different antihypertensive agents, calcium antagonists, angiotensin-converting enzyme (ACE) inhibitors, beta-blockers and diuretic agents on endothelial function. BACKGROUND Endothelial dysfunction is a component of essential hypertension, and various antihypertensive drugs may be able to restore normal function. METHODS Forearm blood flow (FBF) was measured in 296 patients with essential hypertension, including 46 untreated subjects using strain-gauge plethysmography during reactive hyperemia and after sublingual administration of nitroglycerin (NTG). Forty-seven normotensive subjects were similarly evaluated as control subjects. RESULTS The FBF during reactive hyperemia in the 296 hypertensive patients was significantly less than that in age-matched normotensive subjects. The increase in FBF after administration of sublingual NTG was similar in both groups. Systolic and diastolic blood pressures and forearm vascular resistance were greater in the untreated group than in the four treated groups and did not differ with respect to the antihypertensive agent used. The maximal FBF response from reactive hyperemia was significantly greater in the ACE inhibitor-treated group than in the group treated with calcium antagonists, beta-blockers, diuretic agents, or nothing (40.5 +/- 5.2 vs. 32.9 +/- 5.8, 34.0 +/- 5.6, 32.1 +/- 5.9, and 31.9 +/- 5.8 ml/min per 100 ml tissue, p < 0.05, respectively). Reactive hyperemia was similar in the calcium antagonist, beta-blocker, diuretic and untreated groups, and changes in FBF after sublingual NTG administration were similar in all groups. The infusion of NG-monomethyl-L-arginine, a nitric oxide (NO) synthase inhibitor, abolished the enhancement of reactive hyperemia in hypertensive patients treated with ACE inhibitors. CONCLUSIONS These findings suggest that ACE inhibitors augment reactive hyperemia, an index of endothelium-dependent vasorelaxation, in patients with essential hypertension. This augmentation may be due to increases in NO.

Tetrahydrobiopterin enhances forearm vascular response to acetylcholine in both normotensive and hypertensive individuals.

BACKGROUND A deficiency of tetrahydrobiopterin (BH4), an essential cofactor for nitric oxide (NO) synthase, decreases NO synthesis and increases superoxide production. Supplementation of BH4 has been postulated to improve endothelial function in atherosclerotic patients. The purpose of this study was to determine whether BH4 restores endothelium-dependent vasodilation in patients with essential hypertension. METHODS We evaluated the effects of BH4 on forearm vascular responses to acetylcholine (ACh), an endothelium-dependent vasodilator, and isosorbide dinitrate (ISDN), an endothelium-independent vasodilator, both in patients with essential hypertension and in age- and sex-matched normal control subjects. Forearm blood flow (FBF) was measured using strain gauge plethysmography. RESULTS The response of FBF to ACh was less in hypertensive patients (n = 8) than in normal control subjects (n = 8). There was no significant difference in FBF response to ISDN in the two groups. During coinfusion of BH4 (500 mg/min), the FBF response to ACh in hypertensive patients increased significantly (14.8 +/- 4.6 to 25.6 +/- 7.3 mL/min/100 mL tissue, P < .05) to the level of normal control subjects. In the control subjects, also, BH4 augmented the FBF response to ACh (27.8 +/- 8.7 to 36.1 +/- 9.6 mL/min/100 mL tissue, P < .05). The increase in FBF after ISDN was not altered by BH4 in either group (each group, n = 6). CONCLUSION Supplementation of BH4 augments endothelium-dependent vasodilation in both normotensive and hypertensive individuals.

Circadian Variation of Blood Pressure and Endothelial Function in Patients With Essential Hypertension: A Comparison of Dippers and Non-Dippers

OBJECTIVES The purpose of this study was to evaluate the relationship between the circadian blood pressure (BP) rhythm and endothelial function in patients with essential hypertension. BACKGROUND Hypertension is associated with alterations in resistance artery endothelial function. Patients with a non-dipper circadian pattern of BP have a greater risk of cerebrovascular and cardiovascular complications than do patients with a dipper circadian pattern. METHODS We evaluated the forearm blood flow (FBF) response to intra-arterial acetylcholine (ACh), an endothelium-dependent vasodilator, and isosorbide dinitrate (ISDN), an endothelium-independent vasodilator, infusion in 20 patients with non-dipper hypertension and 20 age- and gender-matched patients with dipper hypertension. The FBF was measured using a mercury-filled Silastic strain-gauge plethysmograph. RESULTS The 24-h systolic BP, as well as nocturnal systolic and diastolic BPs were higher in non-dipper patients than in dipper patients. The 24-h urinary excretion of nitrite/nitrate and cyclic guanosine monophosphate was lower in non-dippers than in dippers. The response of FBF to ACh was smaller in non-dippers than in dippers (25.1 +/- 3.1 vs. 20.2 +/- 3.0 ml/min/100 ml tissue, p < 0.05). The FBF response to ISDN was similar in dippers and non-dippers. The FBF response to ACh was similar in the two groups following intra-arterial infusion of the nitric oxide (NO) synthase inhibitor N(G)-monomethyl-L-arginine. CONCLUSIONS These findings suggest that endothelium-dependent vasodilation is blunted through a decrease in NO release in non-dippers compared with patients who have dipper hypertension.

Effect of obesity on endothelium-dependent, nitric oxide-mediated vasodilation in normotensive individuals and patients with essential hypertension

The purpose of this study was to determine the interdependent and independent effects of hypertension and obesity on endothelial function in humans. We evaluated the forearm blood flow (FBF) response to acetylcholine, an endothelium-dependent vasodilator, and isosorbide dinitrate (ISDN), an endothelium-independent vasodilator, in 16 lean and 12 obese normotensive individuals and the 18 lean and 15 obese hypertensive patients with no history of smoking, hypercholesterolemia, diabetes mellitus, or renal dysfunction. The FBF was measured using a mercury-filled Silastic strain-gauge plethysmograph. The systolic and diastolic blood pressures (BP) and forearm vascular resistance were significantly greater in hypertensive patients than in the normotensive individuals. Insulin resistance, determined by a homeostatic model assessment (HOMA), was significantly greater in the obese group than in the lean group (3.59 +/- 1.68 v 1.91 +/- 1.12, P < .01). There was no significant difference in the HOMA index between normotensive and hypertensive subjects regardless of weight. The response of FBF to acetylcholine was greatest in lean normotensive individuals and least in obese hypertensive patients (40.5 +/- 8.5 and 10.4 +/- 2.8 mL/min/100 mL of tissue, P < .001 v other groups). The FBF response was similar in obese normotensive individuals and lean hypertensive patients (24.1 +/- 7.9 and 19.3 +/- 3.2 mL/min/100 mL of tissue). The vasodilatory effect of ISDN was similar in all four groups. Multiple regression analysis revealed that the maximal FBF response to acetylcholine correlated independently with age (P = .043), obesity (P = .012), HOMA index (P = .002), and mean BP (P < .001). These findings suggest that obesity and hypertension are independently involved in abnormal endothelium-dependent vasodilation by attenuated nitric oxide production.

A low-calorie diet improves endothelium-dependent vasodilation in obese patients with essential hypertension*

BACKGROUND Both obesity and hypertension are associated with endothelial dysfunction. The purpose of this study was to investigate the effects of a low-calorie diet on endothelial function in obese patients with essential hypertension. METHODS We measured forearm blood flow (FBF) during intra-arterial infusion of acetylcholine (ACh; 7.5, 15, 30 microg/min), an index of endothelium-dependent vasodilation, and isosorbide dinitrate (ISDN; 0.75, 1.5, 3.0 microg/min), an index of endothelium-independent vasodilation, in obese patients with essential hypertension before and after 2 weeks on a low-calorie diet (800 kcal/d). The study included 11 obese hypertensive Japanese patients (mean body mass index, 30.8 +/- 3.6 kg/m2). Fifteen healthy Japanese normotensive individuals were recruited as a control group. RESULTS In obese patients with hypertension, the response of FBF to ACh was attenuated compared to healthy individuals (P < .001). Caloric restriction reduced body weight from 77.5 +/- 15.0 to 73.2 +/- 13.5 kg (P < .01), the mean blood pressure from 118.4 +/- 8.7 to 105.7 +/- 8.5 mm Hg (P < .01), fasting plasma insulin from 85.8 +/- 22.8 to 64.8 +/- 27.0 pmol/L (P < .05), serum total cholesterol from 5.30 +/- 0.76 to 4.67 +/- 0.58 mmol/L (P < .05), and low density lipoprotein cholesterol from 3.80 +/- 0.48 to 3.29 +/- 0.44 mmol/L (P < .05). Basal FBF was similar before and after weight reduction. Caloric restriction enhanced the response of FBF to ACh (P < .05), but did not alter the response to ISDN. The intra-arterial infusion of NG-monomethyl-L-arginine (8 micromol/min), a nitric oxide synthase inhibitor, decreased the enhanced ACh-induced blood flow response induced by caloric restriction. CONCLUSIONS The present findings suggest that the caloric restriction improves endothelial-dependent vasodilation through an increased release of nitric oxide in obese hypertensive patients.

Effects of l-Arginine Infusion on Renal Hemodynamics in Patients With Mild Essential Hypertension

Previous studies have shown that endothelium-derived relaxing factor/nitric oxide plays an important role in the regulation of systemic and renal hemodynamics. The purpose of the present study was to determine whether endothelium-dependent renovascular relaxation was impaired in patients with mild essential hypertension who had normal renal plasma flow and glomerular filtration rate. We evaluated the effects of intravenous administration of L-arginine on blood pressure and renal hemodynamics in 13 patients with mild essential hypertension and 15 normotensive control subjects. L-Arginine infusion (500 mg/kg over 30 minutes) reduced mean blood pressure (from 82.5 +/- 2.5 to 76.3 +/- 2.6 mm Hg in hypertensive patients and from 106.1 +/- 3.0 to 97.5 +/- 2.9 mm Hg in control subjects; P < .001) and renovascular resistance (from 0.084 +/- 0.009 to 0.067 +/- 0.009 mm Hg.mL-1.min-1.[1.48 m2]-1 and from 0.105 +/- 0.010 to 0.093 +/- 0.011 mm Hg.mL-1.min-1.[1.48 m2]-1, respectively; P < .001). L-Arginine infusion increased renal plasma flow (from 602 +/- 36 to 698 +/- 40 mL.min-1.[1.48 m2]-1, P < .05) in normotensive subjects but not in hypertensive subjects, and glomerular filtration rate was unaffected in both groups. Although the L-arginine-induced reduction in mean blood pressure was similar in both groups, the decline in renovascular resistance was smaller in hypertensive subjects. The response of renal plasma flow was also smaller in hypertensive subjects. These findings suggest that dysfunction of the L-arginine-nitric oxide pathway exists in the renal circulation even in mild essential hypertension with normal renal plasma flow and glomerular filtration rate.(ABSTRACT TRUNCATED AT 250 WORDS)