Takumi Tanabe

Polymorphism in Endothelin-Related Genes Limits Exercise-Induced Decreases in Arterial Stiffness in Older Subjects

Increase in arterial stiffness is associated with aging, which is improved by regular exercise. Endothelin (ET) system has crucial roles in regulating vascular tone and in the progression of atherosclerosis. We hypothesized that molecular variations (ie, gene polymorphisms) in ET-related gene might affect exercise-induced improvement in arterial stiffness with age in human subjects. The present study provides a cross-sectional investigation of 191 healthy middle-aged and older (65±1 years) human subjects to clarify the relationship between the regular exercise-induced improvement of arterial stiffness and the gene polymorphisms of ET converting enzyme (ECE)-1, ECE-2, ET-A receptor (ET-A), and ET-B receptor (ET-B). The study subjects were divided into active and inactive groups based on the median value (186 kcal/d) of energy expenditure. Brachial-ankle arterial pulse wave velocity (baPWV) was used to evaluate arterial stiffness. All individuals were genotyped for 4 different polymorphisms of the ET system: 2013(+289)A/G in intron 17 of ECE-1, 669(+17)T/C in intron 5 of ECE-2, 958A/G in exon 6 of ET-A, and 831A/G in exon 4 of ET-B. The baseline baPWV was significantly lower in the active group without any change in blood pressure. Polymorphisms in ECE-1 influenced basal blood pressure. Polymorphisms in ECE-1 and ECE-2 had no effect on baPWV between active and inactive groups. However, polymorphisms in both ET-A and ET-B affected baPWV in the 2 groups. The present results suggest that differences in ET-A and ET-B polymorphisms may influence the response of the vascular wall to exercise whereas ECE-1 polymorphisms may affect basal blood pressure.

Involvement of Endogenous Endothelin-1 in Exercise-Induced Redistribution of Tissue Blood Flow An Endothelin Receptor Antagonist Reduces the Redistribution

Background—Endothelin-1 (ET-1) is a potent endothelium-derived vasoconstrictor peptide. Exercise results in a significant redistribution of tissue blood flow, which greatly increases blood flow in active muscles but decreases it in the splanchnic circulation. We reported that exercise causes an increase of ET-1 production in the internal organ and then hypothesized that ET-1 participates in the exercise-induced redistribution of tissue blood flow. We investigated the effects of acute endothelin-A (ETA)-receptor blockade on regional tissue blood flow during exercise in rats. Methods and Results—Regional blood flow in the kidney, spleen, stomach, intestine, and muscles was measured using the microsphere technique before and during treadmill running of 30 minutes duration at 30 m/min after pretreatment with either an ETA-receptor antagonist (TA-0201; 0.5 mg/kg) or vehicle in rats. Blood flow in the kidney, spleen, stomach, and intestine was decreased by exercise, but the magnitude of the decrease after pretreatment with TA-0201 was significantly smaller than that after pretreatment with vehicle. Furthermore, the increase in blood flow to active muscles induced by exercise was significantly smaller in rats pretreated with TA-0201 than those pretreated with vehicle. Conclusions—The present study revealed that ET-1-mediated vasoconstriction participates in the decrease of blood flow in the internal organs of rats during exercise, and therefore, that these actions of endogenous ET-1 partly contribute to the increase of blood flow in active muscles during exercise. The data suggest that endogenous ET-1 participates in the exercise-induced redistribution of tissue blood flow.

Effects of exercise training on expression of endothelin-1 mRNA in the aorta of aged rats

Aging impairs endothelial function and the vascular tone regulation, although the precise mechanism remains unclear. Endothelin-1 (ET-1) is a potent vasoconstrictor peptide produced by vascular endothelial cells. Because ET-1 has a potent vasoconstrictor effect on vessels, it may be involved in the regulation of vascular tonus. We hypothesized that aging causes a decrease in ET-1 expression in aorta, and that exercise training improves the aging-induced decrease in ET-1 expression in aorta. This study was performed to examine whether gene expression of ET-1 in the aorta of rats is altered by aging and subsequent exercise training. We studied expression of ET-1 mRNA in the aortas of sedentary young rats (Sedentary young group, 4 months old), sedentary aged rats (Sedentary aged group, 23 months old), and swim trained aged rats (Training aged group, 23 months old; swimming training for 8 weeks, 5 days/week, 90 min/day). The expression of ET-1 mRNA in the aorta was analysed by real-time quantitative PCR. Body weight and resting heart rate were significantly lower in the Training aged group compared with the Sedentary aged group. These results suggest that the Training aged rats exhibited physiological effects from exercise training. The expression of ET-1 mRNA in the aorta was markedly lower in Sedentary aged group compared with the Sedentary young group, whereas it was significantly higher in Training aged group compared with the Sedentary aged group. These results show that the expression of ET-1 mRNA in the aorta is decreased by aging, and that the expression is increased by exercise training. Therefore, the present study provides a possibility that exercise training improves endothelial function through up-regulation of the aging-induced decrease in ET-1 expression in the aorta.

Effect of Arterial Lumen Enlargement on Carotid Arterial Compliance in Normotensive Postmenopausal Women

A reduction in central arterial compliance has been identified as an independent risk factor for future cardiovascular disease. The aim of the present study was to determine the influence of age-related carotid arterial enlargement on carotid arterial compliance in postmenopausal females, using a cross-sectional study design. Carotid arterial properties were measured with applanation tonometry and ultrasound system in 113 normotensive females (aged 50–78). Brachial-ankle pulse wave velocity (baPWV) measured by a plethysmographic technique was used as an index of arterial stiffness. In comparisons among the three age groups (50–59, 60–69, and 70–78 years old), baPWV (F=11.9, p<0.001) and carotid systolic (F=4.5, p<0.05) and pulse pressures (F=9.6, p<0.0001), and lumen diameter (F=5.6, p<0.01) increased with advancing age. Carotid arterial compliance gradually decreased with age, but not significantly. A stepwise regression analysis revealed that carotid systolic pressure and lumen diameter and age were independent correlates of carotid arterial compliance. After carotid lumen diameter was taken into account (ANCOVA), the differences in carotid arterial compliance among the three age groups became significant (F=3.8, p<0.05). These results suggest that an increase in arterial lumen diameter might compensate for the age-related increase in arterial stiffness and limit the deterioration of the buffering capacity of the central artery in normotensive postmenopausal females.

Acute exercise increases systemic arterial compliance after 6-month exercise training in older women.

High physical activity or aerobic exercise training increases central arterial distensibility in older humans. However, the effect of a single bout of exercise on central arterial distensibility in older humans is unknown. Furthermore, the effect of exercise training on central arterial distensibility during exercise is unclear. We investigated whether systemic arterial compliance (SAC) changes after acute exercise in older humans, and, if so, whether this change in SAC is enhanced by aerobic exercise training. Seven untrained older women (61–69 years old) participated in a 6-month exercise intervention study. We measured SAC after acute exercise (cycling exercise at 80% of their individual ventilatory threshold for 30 min) before and after 6 months of aerobic exercise training. After exercise training, the individual ventilatory threshold was significantly increased. In addition, both the SAC at rest and that 30 min after acute exercise were significantly increased after the exercise training program. Before exercise training, there was no significant increase in SAC after acute exercise, whereas, after exercise training, the SAC was significantly increased 30 min after acute exercise. The present study suggests that, after aerobic exercise training, SAC increases after acute exercise in older humans, and that the SAC at rest and after acute exercise is enhanced by aerobic exercise training, thereby causing an effective adaptation in increase in cardiac output during exercise.

Chronic administration of an endothelin-A receptor antagonist improves exercise capacity in rats with myocardial infarction-induced congestive heart failure.

The effects of long-term administration of YM598, a selective endothelin-A antagonist, on improving the exercise tolerance of chronic heart failure model rats were examined using a treadmill exercise loading test. Rats were acclimatized to the treadmill apparatus and the coronary artery was ligated to prepare a myocardial infarction-induced congestive heart failure (CHF) model. Starting 10 days postoperatively, when the acute phase of infarction was over, YM598 was administered orally once daily for approximately 25 weeks at a dose of 1 mg/kg. At weeks 20 and 24 the treadmill test was performed. YM598 prolonged running time, which had been shortened as a result of heart failure. The weights, relative to the body weight, of the left and right ventricles and lungs of surviving rats with CHF were significantly greater than those of sham-operated rats, suggesting hypertrophy of the ventricles and congestion of the lungs. Administration of YM598 markedly reduced ventricular hypertrophy and pulmonary congestion. Examination of cardiac function revealed that, in surviving CHF rats, the peak positive first derivative of left ventricular pressure was significantly lower, and left ventricular end-diastolic pressure, right ventricular systolic pressure and central venous pressure were significantly higher in comparison to sham-operated rats. These data demonstrate that, in rats with CHF, the contractile and diastolic capacity of the left ventricle decreased and pulmonary hypertension and systemic congestion occurred. Long-term administration of YM598 improved left ventricular function of CHF rats to the level of sham-operated rats, and reduced the workload placed on the right side of the heart. Histological examination revealed that long-term treatment with YM598 prevented fibrosis of the surviving left ventricular myocardium. In conclusion, long-term administration of YM598 to rats with CHF improved exercise tolerance and inhibited remodeling of cardiac muscles, leading to marked improvement of cardiac function.

Age-related reduction of systemic arterial compliance relates to decreased aerobic capacity during sub-maximal exercise.

A decrease in systemic arterial compliance (SAC) increases left ventricular load along with the demand for excessive myocardial oxygen consumption when the age-related reduction of SAC reaches a marked level, and consequently may depress left ventricular pump function. Reduced left ventricular pump function decreases aerobic capacity, and some study groups have shown that SAC and/or central arterial distensibility is correlated with maximal aerobic capacity in humans. We thus hypothesize that, once the age-related reduction of SAC reaches a marked level, the participation of SAC in aerobic capacity will be significant even during sub-maximal exercise. Thirty young humans and 46 elderly humans participated in this study. SAC, oxygen uptake at the ventilatory threshold ([Vdot ]O2 VT), and the ratio of increase in oxygen uptake, in cardiac output, and in effective arterial elastance to increase in work rate (Δ[Vdot ]O2/ΔWR, ΔCO/ΔWR and ΔEa/ΔWR) were measured. SAC was significantly higher in young subjects compared with elderly subjects, and was significantly related to [Vdot ]O2 VT in elderly subjects. SAC also significantly correlated with Δ[Vdot ]O2/ΔWR, ΔCO/ΔWR and ΔEa/ΔWR in elderly subjects. When total subjects were divided by the value of SAC into 6 groups, the [Vdot ]O2 VT values in the 3 groups with lower SAC were significantly lower than those in the 3 groups with higher SAC, and gradually decreased with the reduction of SAC. There were no changes in [Vdot ]O2 VT among the 3 groups with higher SAC. These results suggest that the participation of SAC in aerobic capacity is significant even during sub-maximal exercise in individuals who show a pronounced age-related reduction of SAC.

Effects of aging and subsequent exercise training on gene expression of endothelin-1 in rat heart

Endothelin-1 (ET-1) is produced by endothelial cells and cardiac myocytes. ET-1 has potent positive inotropic and chronotropic effects on heart and induces myocardial cell hypertrophy. We investigated whether gene expression of ET-1 in rat hearts is altered by aging and subsequent exercise training. We also investigated whether gene expression of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP), which participate in some pathological cardiac conditions, in the rat hearts is altered by aging and subsequent exercise training. We studied mRNA expression of ET-1, ANP and BNP in hearts of sedentary young rats (Sedentary young; 4 months old), sedentary aged rats (Sedentary aged; 23 months old), and swim-trained aged rats (Trained aged; 23 months old, swimming training for 8 weeks). The left ventricle weight mass index for body weight and left ventricular end-diastolic dimension were significantly higher in the Trained aged group compared with the Sedentary aged group. These results showed that Trained aged rats developed cardiac hypertrophy with improvement of cardiac function. The mRNA expression of ET-1 in the heart was significantly higher in Sedentary aged group compared with Sedentary young group, and was significantly higher in the Trained aged group compared with the Sedentary aged group. The mRNA expression of ANP and BNP in the heart was significantly higher in Sedentary aged group compared with Sedentary young group, and was significantly higher in the Trained aged group compared with the Sedentary aged group. The present results show that mRNA expression of ET-1 in the heart is increased by aging, and that the mRNA expression is further increased by exercise-induced cardiac hypertrophy, suggesting that ET-1 in the heart may participate in these physiological cardiac adaptations.

Age-Related Reduction of Systemic Arterial Compliance Induces Excessive Myocardial Oxygen Consumption during Sub-Maximal Exercise

Reduction of systemic arterial compliance (SAC) with aging increases left ventricular afterload. The present study was designed to examine whether age-related reduction of SAC is related to excessive myocardial oxygen consumption during sub-maximal aerobic exercise. We studied elderly (60–69 years; n=25) and senior (70–82 years; n=25) subjects. We measured SAC immediately before the start of the ramp-fashion exercise (i.e., at the end of the 20 W warm-up exercise) and the double product (DP: systolic blood pressure × heart rate) during the ramp-fashion exercise (20–50 W). SAC was significantly lower in senior subjects (0.76±0.25 ml mmHg−1 m−2) compared with elderly subjects (0.95±0.22 ml mmHg−1 m−2). DP was higher in senior subjects (20 W: 14.3±3.1; 30 W: 15.9±4.2; 40 W: 17.7±4.9; 50 W: 20.6±5.6 [×103 mmHg bpm]) than in elderly subjects (12.8±3.0, 14.0±3.5, 15.1±4.0, 17.1±4.3 [×103 mmHg bpm]). In total subjects, SAC correlated significantly with DP (r=−0.64, r=−0.64, r=−0.64, r=−0.64). In senior subjects, SAC was related significantly to DP (r=−0.83, r=−0.78, r=−0.76, r=−0.74). In elderly subjects, SAC tended to correlate with DP although its relationships were not statistically significant (r=−0.34, r=−0.36, r=−0.33, r=−0.31). Correlation coefficients at each respective exercise intensity were significantly higher in senior subjects compared with elderly subjects. These results suggest that the age-related reduction of SAC is related to excessive myocardial oxygen consumption during sub-maximal aerobic exercise in older humans, but this relation does not become significant until the SAC reduction becomes pronounced.

Estrogen receptor-alpha genotype affects exercise-related reduction of arterial stiffness.

PURPOSE Arterial stiffness, an independent risk factor for cardiovascular disease, increases with advancing age. Arterial stiffness is improved by regular exercise, but individual responses to exercise training are variable. Given that estrogen and estrogen receptor-alpha (ER-alpha) can induce vasodilation and can exert an antiatherosclerotic effect in vessels, we hypothesized that gene polymorphisms of ER-alpha might influence the ability of regular exercise to improve arterial stiffness in postmenopausal women. METHODS One hundred ninety-five healthy postmenopausal women (62 +/- 6 yr, mean +/- SD) participated in our cross-sectional study. We determined the genotype of single-nucleotide polymorphisms (SNP) at -401T/C of intron 1 of the ER-alpha gene. Arterial stiffness was measured by brachial-ankle pulse wave velocity (baPWV), and daily physical activity was estimated by a uniaxial accelerometer. Subjects were divided into active and inactive groups according to the median value (200 kcal.d(-1)) of energy expenditure. RESULTS baPWV in individuals with the TT variant of -401T/C genotype were significantly higher than for individuals with the TC+CC genotype. No significant differences in mean baPWV values were found between the active group and the inactive group (P = 0.09). A significant reduction of baPWV secondary to increased daily physical activity was observed in individuals with the TC+CC genotype but not in individuals with the TT genotype (TT/active: 1470 +/- 36 cm.s(-1); TT/inactive: 1457 +/- 34 cm.s(-1); TC+CC/active: 1359 +/- 21 cm.s(-1); TC+CC/inactive: 1433 +/- 24 cm.s(-1)). CONCLUSION These results suggest that ER-alpha polymorphism affects the regular exercise-related reduction in arterial stiffness in healthy postmenopausal women.