Nobutake Shimojo

Left Ventricular Strain and Transmural Distribution of Structural Remodeling in Hypertensive Heart Disease

Left ventricular (LV) systolic wall strain is a new candidate for prognostic indicator of hypertensive heart failure. It remains unclear how underlying transmural structural remodeling corresponds to LV wall systolic deformation as hypertensive hypertrophy progresses. We fed 68 Dahl salt–sensitive rats a high-salt (hypertensive group) or low-salt diet (control group) from 6 weeks old. At 10, 14, and 18 weeks, pressure–volume relation, transmural distribution of LV fibrosis, and myocyte hypertrophy were evaluated. LV global longitudinal and circumferential strain was measured with speckle tracking echocardiography. Emax was preserved throughout the study period, whereas &tgr; and end-diastolic pressure–volume relation progressively deteriorated from 14 weeks (diastolic dysfunction stage). Lung weight increased significantly at 18 weeks (decompensated stage). Histological percentage area fibrosis and collagen type I/III, myocyte hypertrophy, and &agr;-myosin heavy chain isoform increased in the subendocardial layer at 14 weeks and progressed into the midlayer at 18 weeks. Longitudinal strain progressively deteriorated in the hypertensive group versus control group at 14 weeks (hypertensive group: −17±3%, control: −27±4%; P<0.001), and circumferential strain decreased at 18 weeks (hypertensive group: −17±2%, control: −27±3%; P=0.002). After adjustment for systolic wall stress, subendocardial percentage area fibrosis was selected as the independent determinant of longitudinal strain. This study showed that LV wall strain alternations were accompanied by fibrosis and myocyte hypertrophy from subendocardium to epicardium, and longitudinal strain related significantly to subendocardial layer fibrosis. Longitudinal strain could be a surrogate of subendocardial fibrotic changes and may be useful for risk stratification of hypertensive heart failure.

Additive beneficial effects of lactotripeptides and aerobic exercise on arterial compliance in postmenopausal women

Central arterial compliance plays an important role in the functional abilities of the vasculature. Two active tripeptides, valine-proline-proline and isoleucine-proline-proline, were isolated from sour milk and were referred to as lactotripeptides (LTP). Because LTP appears to act as an angiotensin-converting enzyme inhibitor, it is plausible to hypothesize that LTP improves arterial compliance. We determined the effects of LTP ingestion alone or in combination with regular aerobic exercise on arterial compliance. A total of 55 postmenopausal women (50-65 yr old) were randomly divided into four groups: placebo, LTP, exercise and placebo (Ex + placebo), or exercise and LTP (Ex + LTP). LTP or placebo was administered orally for 8 wk. The exercise groups completed an 8-wk moderate aerobic exercise intervention. There were no differences in baseline arterial compliance and most other key dependent variables among the groups. Carotid arterial compliance increased significantly in the LTP (0.93 + or - 0.07 vs. 0.99 + or - 0.08 mm(2)/mmHg x 10(-1)), Ex + placebo (0.92 + or - 0.04 vs. 1.00 + or - 0.05 mm(2)/mmHg x 10(-1)), and Ex + LTP groups (0.86 + or - 0.06 vs. 1.00 + or - 0.06 mm(2)/mmHg x 10(-1)), whereas no such changes were observed in the placebo control group (0.86 + or - 0.06 vs. 0.85 + or - 0.07 mm(2)/mmHg x 10(-1)). The magnitude of increases in carotid arterial compliance was significantly greater in the Ex + LTP group (19 + or - 4%) than in other groups. The improvements in arterial compliance with LTP were associated with the corresponding reductions in arterial blood pressure and plasma angiotensin II concentrations. We concluded that LTP ingestion improves carotid arterial compliance and that the combination of LTP ingestion and regular exercise is additive and synergistic in improving arterial compliance in postmenopausal women.

Involvement of endothelin-1 in habitual exercise-induced increase in arterial compliance.

Aim:  Habitual aerobic exercise results in a significant increase in central arterial compliance. Endothelin‐1 (ET‐1) is a potent endothelium‐derived vasoconstrictor peptide and could play a role in mediating the habitual aerobic exercise‐induced increase in central arterial compliance. The aim of the present study was to examine whether ET‐1 is involved in the mechanisms underlying the increase in central arterial compliance with aerobic exercise training.

Additive beneficial effects of lactotripeptides intake with regular exercise on endothelium-dependent dilatation in postmenopausal women.

BACKGROUND Peripheral conduit artery endothelium-dependent dilatation decreases with aging in humans. Lactotripeptides (LTPs) and regular exercise can improve endothelium-dependent dilatation, but combining these lifestyle modifications may be more effective than either treatment alone. We conducted a randomized, place-controlled trial with four different intervention arms. METHODS A total of 43 postmenopausal women (50-65 years old) were randomly divided into placebo, LTP, exercise and placebo (Ex+placebo), or exercise and LTP (Ex+LTP) groups. LTP or placebo was administered orally for 8 weeks. The exercise groups completed an 8-week moderate aerobic exercise (walking or cycling) intervention. RESULTS There were no statistically significant differences in baseline flow-mediated dilatation (FMD) and most other key dependent variables among the groups. FMD significantly increased in the LTP, Ex+placebo, and Ex+LTP groups whereas no such changes were observed in the placebo control group. The magnitude of increases in FMD was significantly greater in the Ex+LTP group than other intervention groups. CONCLUSION We concluded that LTP ingestion combined with regular aerobic exercise improves endothelium-dependent dilatation to a greater extent than monotherapy with either intervention alone in postmenopausal women.

Effect of systemic nitric oxide synthase inhibition on arterial stiffness in humans.

Stiffening of large elastic arteries impairs the buffering function of the arterial system and contributes to cardiovascular disease. The aim of this study was to determine whether endothelium-derived nitric oxide (NO) modulates the stiffness of large elastic arteries in humans. Seven apparently healthy adults (60±3 years, 2 males and 5 females) underwent systemic α-adrenergic blockade (phentolamine) and systemic NO synthase inhibition using NG-monomethyl-L-arginine (L-NMMA) in sequence. Phentolamine was given first to isolate contribution of NO to arterial stiffness by preventing reflex changes in sympathetic tone that result from systemic NO synthase inhibition, and also to compare arterial stiffness at a similar mean arterial pressure. Mean arterial blood pressure decreased (p<0.05) after phentolamine infusion but returned to baseline levels after L-NMMA infusion. The carotid β-stiffness index (via simultaneous ultrasound and applanation tonometry on the common carotid artery) did not change after the restraint of systemic α-adrenergic nerve activity (9.8±1.2 vs. 9.1±1.1 U) but increased (p<0.05) after NO synthase inhibition (12.6±2.0 U). These results suggest that NO appears to modulate central arterial stiffness in humans.

Effects of a Low-Volume Aerobic-Type Interval Exercise on V˙O2max and Cardiac Mass

PURPOSE The aim of this study was to compare the effects of time-efficient, low-volume interval exercises on cardiorespiratory capacity and left ventricular (LV) mass with traditional continuous exercise in sedentary adults. METHODS Forty-two healthy but sedentary male subjects (age 26.5 ± 6.2 yr) participated in an 8-wk, five times per week, supervised exercise intervention. They were randomly assigned to one of three exercise protocols: sprint interval training (SIT, 5 min, 100 kcal), high-intensity interval aerobic training (HIAT, 13 min, 180 kcal), and continuous aerobic training (CAT, 40 min, 360 kcal). Cardiorespiratory capacity (V˙O2max) and LV mass (3T-MRI) were measured preintervention and postintervention. RESULTS We observed significant (P < 0.01) increases in V˙O2max in all three groups, and the effect of the HIAT was the greatest of the three (SIT, 16.7% ± 11.6%; HIAT, 22.5% ± 12.2%; CAT, 10.0% ± 8.9%; P = 0.01). There were significant changes in LV mass, stroke volume (SV), and resting HR in both the SIT (LV mass, 6.5% ± 8.3%; SV, 5.3% ± 8.3%; HR, -7.3% ± 11.1%; all P < 0.05) and HIAT (LV mass, 8.0% ± 8.3%; SV, 12.1% ± 9.8%; HR, -12.7% ± 12.2%; all P < 0.01) but not in the CAT (LV mass, 2.5% ± 10.1%; SV, 3.6% ± 6.6%; HR, -2.2% ± 13.3%; all P > 0.05). CONCLUSIONS Our study revealed that V˙O2max improvement with the HIAT was greater than with the CAT despite the HIAT being performed with a far lower volume and in far less time than the CAT. This suggests that the HIAT has potential as a time-efficient training mode to improve V˙O2max in sedentary adults.

Time-dependent expression of renal vaso-regulatory molecules in LPS-induced endotoxemia in rat

To elucidate roles of microvascular factors in the pathogenesis of renal complications during endotoxemia, that is characterized by renal vasoconstriction and systemic hypotension/generalized non-renal vasodilation, we profile the expression pattern and time-course of three key vaso-regulators, namely endothelin (ET)-1, nitric oxide (NO), and angiotensin II (Ang II). We hypothesize that disruption of the overall balance between vasodilatation and vasoconstriction in the kidney, during the early phase of sepsis, contribute to its (kidney) predisposition to acute renal failure. Adult male Wistar rats were rendered endotoxemic at different time points (1, 3, 6 and 10 h) by a single i.p. injection of lipopolysaccharide (LPS) (15 mg/kg) dissolved in saline. Control group was injected vehicle only (saline). Both systolic and diastolic blood pressures significantly decreased at different time points after LPS administration. Surprisingly, renal histopathological evaluation showed no remarkable changes in LPS-induced endotoxemia. However, overall, levels of the vaso-regulators and, where applicable, their respective receptors were upregulated: (1) plasma ET-1 increased 25-fold and peaked, as renal ET-1 mRNA, at 3 h; renal ET-1 protein and its receptors, ET type A (ET(A)) receptor (vasoconstrictive) and ET type B (ET(B)) receptor (vasodilatatory) increased in a time-dependent fashion, (2) Ang II increased by 53% compared to control, peaking at 6 h. However, while levels of Ang II type 1 (AT1) receptor increased over time after LPS injection, those of Ang II type 2 (AT2) receptor were downregulated, (3) data of NO system (NO-NOS), the key vasodilator, were the most intriguing. Whereas levels of renal NO increased time-dependently following LPS administration, with a 2240-fold increase in renal iNOS expression, levels of eNOS, were almost unchanged. In conclusion, the present study overall reveals intriguing and complex dynamics between levels of vasoconstrictors and vasodilators during the early phase of LPS-induced endotoxemia. These shifts in molecular expressions are likely triggered by compensatory mechanisms aimed at counteracting the undesirable and dominant effects of one group of vaso-regulatory moiety over the other.

Reduction in α-adrenergic receptor-mediated vascular tone contributes to improved arterial compliance with endurance training

BACKGROUND Regular aerobic exercise improves large artery compliance in middle-aged and older humans. However, the underlying mechanisms are unknown. We tested the hypothesis that the improved central arterial compliance with endurance training is mediated by decreased alpha-adrenergic tone and/or increased endothelial function. METHODS Seven sedentary healthy adults (60+/-3 years) underwent systemic alpha-adrenergic blockade (phentolamine) and nitric oxide synthase (NOS) inhibition using N(G)-monomethyl-L-arginine in sequence before and after a 3-month moderate endurance training (walk/jog, 4-5 days/week). Phentolamine was given first to isolate the contribution of nitric oxide to arterial compliance by minimizing reflex suppression of sympathetic tone resulting from systemic NOS inhibition as well as to assess the alpha-adrenergic receptor-mediated modulation of arterial compliance. RESULTS Baseline arterial compliance (via simultaneous ultrasound and applanation tonometry on the carotid artery) increased 34+/-12% after exercise training (P<0.01). When alpha-adrenergic blockade was performed, arterial compliance increased 37+/-6% (P<0.01) before the exercise training but did not change significantly after the training. Decreases in arterial compliance from the alpha-adrenergic blockade to the subsequent additional NOS blockade were not different before and after exercise training. CONCLUSION Our results suggest that the reduction in alpha-adrenergic receptor-mediated vascular tone contributes to the improved central arterial compliance with endurance training.

Physician–Pharmacist Cooperation Program for Blood Pressure Control in Patients With Hypertension: A Randomized-Controlled Trial

BACKGROUND The aim of the trial was to evaluate the effectiveness of a program of cooperation between physician and pharmacist to reduce cardiovascular risk factors in patients with mild to moderate hypertension by promoting better blood pressure (BP) control, appropriate changes in antihypertensive medications, and beneficial changes in lifestyle. METHODS The 132 subjects in this randomized, controlled trial were in the age range of 40-79 years. The inclusion criteria were: systolic BP (SBP) ranging from 140-179 mm Hg and/or diastolic BP (DBP) ranging from 90-99 mm Hg and treatment-naive (untreated for hypertension); or on a regimen of medication for hypertension. Of these 132 subjects, 124 (94%) were already receiving treatment with antihypertensive medications. Equal numbers of subjects were randomly assigned to one of two groups: a physician-pharmacist intervention group (n = 66) and a control group (n = 66). RESULTS The 6-month follow-up rate was 97% in both groups. At 6 months, the mean decrease in SBP/DBP, as measured at home in the morning, was 2.9/3.3 mm Hg in the intervention group relative to baseline (P = 0.02 and P < 0.0001 for SBP and DBP, respectively). The mean decrease in home morning SBP in the intervention group was not significantly greater than in the control group. However, the DBP decline was significantly greater in the intervention than control groups, which showed a mean decrease of 2.8 mm Hg (confidence interval: -5.5 to -0.1; P = 0.04). The percentage of patients in whom control of home morning BP was achieved was 53% in the intervention group and 47% in the control group (P = 0.40). A higher percentage of patients in the intervention group, relative to the control group, were able to reduce the use of antihypertensive medications (31 vs. 8%, P < 0.0001), and fewer patients in this group required additional medications or increases in dosage relative to the controls (11 vs. 28%, P = 0.03). Patients of the intervention group were more likely to show reduction in body mass index and sodium intake and to stop smoking, as compared with the control group. CONCLUSIONS A program of cooperation between physician and pharmacist was successful in reducing cardiovascular risk factors in patients with mild to moderate hypertension by promoting better blood pressure (BP) control, appropriate changes in antihypertensive medications, and beneficial changes in lifestyle.

Effect of Endothelin Dual Receptor Antagonist on VEGF Levels in Streptozotocin-Induced Diabetic Rat Retina

Diabetic retinopathy (DR), one of the most serious causes of blindness, is often associated with the upregulation of vascular endothelial growth factor (VEGF) in retina. Recently, leukocyte adhesion (leukostasis) is blamed for the occlusion of retinal capillary vascularity, which ultimately contributes to the progression of diabetic retinopathy. In addition, intercellular adhesion molecule-1 (ICAM-1), a representative factor for leukostasis, is increased in the diabetic retina. Endothelin (ET)-1, a potent vasoconstrictor peptide, is deeply linked to the pathogenesis of diabetic retinopathy. Different therapeutic interventions concerning VEGF have already been proposed to prevent diabetic retinopathy. However, no study yet has reported whether ET-1 dual receptor antagonist could alter the upregulated VEGF and ICAM-1 levels in the diabetic retina. The present study investigated the effect of ETA/B dual receptor antagonist (SB209670; 1 mg/rat/day) on the expression of VEGF and ICAM-1 in the diabetic rat retina. Diabetes was induced by intraperitoneal injection of streptozotocin (STZ; 65 mg/kg) in Sprague-Dawley rats, whereas control rats (non-DM control) received only citrate buffer. After 1 week, the STZ-administered rats were randomly divided into two groups: one group (DM+SB209670) received ETA/B dual receptor antagonist for 2 weeks, and a vehicle group (DM+vehicle) was treated only with saline. After the treatment period, the retinas were removed from the eyeballs. In DM+vehicle group, the VEGF expression of the retinas was significantly increased (32.8 pg/mg) in comparison to that in the non-DM control group (26.2 pg/mg); this upregulation of VEGF was reversed in the DM+SB209670 group (28.6 pg/mg). The expression of retinal ICAM-1 was increased in the DM+vehicle group (152.2 pg/mg) compared with the non-DM control group (121.6 pg/mg). However, SB209670 treatment did not alter the expression of retinal ICAM-1 level (154.8 pg/ml) in DM rats. Thus we conclude that an ETA/B dual receptor antagonist could reverse the expression level of VEGF in the diabetic retina while failing to normalize the upregulated ICAM-1 expression.