Progressive resistance training without volume increases does not alter arterial stiffness and aortic wave reflection

Endurance exercise is efficacious in reducing arterial stiffness. However, the effect of resistance training (RT) on arterial stiffening is controversial. High-intensity, high-volume RT has been shown to increase arterial stiffness in young adults. We tested the hypothesis that an RT protocol consisting of progressively higher intensity without concurrent increases in training volume would not elicit increases in either central or peripheral arterial stiffness or alter aortic pressure wave reflection in young men and women. The RT group (n = 24; 21 +/- 1 years) performed two sets of 8-12 repetitions to volitional fatigue on seven exercise machines on 3 days/week for 12 weeks, whereas the control group (n = 18; 22 +/- 1 years) did not perform RT. Central and peripheral arterial pulse wave velocity (PWV), aortic pressure wave reflection (augmentation index; AIx), brachial flow-mediated dilation (FMD), and plasma levels of nitrate/nitrite (NOx) and norepinephrine (NE) were measured before and after RT. RT increased the one-repetition maximum for the chest press and the leg extension (P < 0.001). RT also increased lean body mass (P < 0.01) and reduced body fat (%; P < 0.01). However, RT did not affect carotid-radial, carotid-femoral, and femoral-distal PWV (8.4 +/- 0.2 vs. 8.0 +/- 0.2 m/sec; 6.5 +/- 0.1 vs. 6.3 +/- 0.2 m/sec; 9.5 +/- 0.3 vs. 9.5 +/- 0.3 m/sec, respectively) or AIx (2.5% +/- 2.3% vs. 4.8% +/- 1.8 %, respectively). Additionally, no changes were observed in brachial FMD, NOx, NE, or blood pressures. These results suggest that an RT protocol consisting of progressively higher intensity without concurrent increases in training volume does not increase central or peripheral arterial stiffness or alter aortic pressure wave characteristics in young subjects.     

Increased aortic stiffness assessed by pulse wave velocity in apolipoprotein E-deficient mice

Atherosclerosis develops and progresses spontaneously in apolipoprotein E-knockout (apoE-KO) mice. A direct consequence of atherosclerosis is an increase in vascular stiffness. Pulse wave velocity (PWV) has been used to assess the stiffness of large vessels and was found to be increased in patients with atherosclerosis. In the present study, aortic stiffness was assessed by PWV in 4- and 13-mo-old apoE-KO mice and age-matched controls (C57BL/6J). In 13-mo-old apoE-KO mice with extensive atherosclerotic lesions in the aorta (61 +/- 4%), PWV increased significantly (3.8 +/- 0.2 m/s) compared with controls (2.9 +/- 0.2 m/s). Endothelial nitric oxide (EDNO)-mediated vasorelaxation in response to ACh was markedly diminished in the aortic rings isolated from 13-mo-old apoE-KO mice compared with age-matched controls. In contrast, in 4-mo-old apoE-KO mice with only moderate atherosclerotic lesions in the aorta (23 +/- 5%), there were no significant changes in PWV and EDNO-mediated relaxation compared with controls. Blood pressure was not different among the four groups of mice. There were no significant differences in endothelium-independent vascular responses to sodium nitroprusside among different groups investigated. Histological evaluation revealed focal fragmentation of the elastic laminae in the aortic walls of 13-mo-old apoE-KO mice. These results demonstrate for the first time that aortic stiffness determined by PWV increases in 13-mo-old apoE-KO mice. Endothelial dysfunction and elastic destruction in vascular wall caused by atherosclerosis may have contributed.     

Nitrite supplementation reverses vascular endothelial dysfunction and large elastic artery stiffness with aging

We tested the hypothesis that short-term nitrite therapy reverses vascular endothelial dysfunction and large elastic artery stiffening with aging, and reduces arterial oxidative stress and inflammation. Nitrite concentrations were lower (P < 0.05) in arteries, heart, and plasma of old (26-28 month) male C57BL6 control mice, and 3 weeks of sodium nitrite (50 mg L(-1) in drinking water) restored nitrite levels to or above young (4-6 month) controls. Isolated carotid arteries of old control mice had lower acetylcholine (ACh)-induced endothelium-dependent dilation (EDD) (71.7 ± 6.1% vs. 93.0 ± 2.0%) mediated by reduced nitric oxide (NO) bioavailability (P < 0.05 vs. young), and sodium nitrite restored EDD (95.5 ± 1.6%) by increasing NO bioavailability. 4-Hydroxy-2,2,6,6-tetramethylpiperidine 1-oxyl (TEMPOL), a superoxide dismutase (SOD) mimetic, apocynin, a nicotinamide adenine dinucleotide phosphate-oxidase (NADPH) inhibitor, and sepiapterin (exogenous tetrahydrobiopterin) each restored EDD to ACh in old control, but had no effect in old nitrite-supplemented mice. Old control mice had increased aortic pulse wave velocity (478 ± 16 vs. 332 ± 12 AU, P < 0.05 vs. young), which nitrite supplementation lowered (384 ± 27 AU). Nitrotyrosine, superoxide production, and expression of NADPH oxidase were ～100-300% greater and SOD activity was ～50% lower in old control mice (all P < 0.05 vs. young), but were ameliorated by sodium nitrite treatment. Inflammatory cytokines were markedly increased in old control mice (P < 0.05), but reduced to levels of young controls with nitrite supplementation. Short-term nitrite therapy reverses age-associated vascular endothelial dysfunction, large elastic artery stiffness, oxidative stress, and inflammation. Sodium nitrite may be a novel therapy for treating arterial aging in humans.     

Angiotensin II injures the arterial wall causing increased aortic stiffening in apolipoprotein E-deficient mice

Cardiovascular diseases, such as atherosclerosis and hypertension, are associated with arterial stiffening. Previous studies showed that ANG II exacerbated atherosclerosis and induced hypertension and aneurysm formation in apolipoprotein E-deficient (apoE-KO) mice. The aim of the present study was to examine the effects of chronic treatment of ANG II on the arterial elastic properties in apoE-KO mice. We hypothesized that ANG II will injure the arterial wall resulting in increased arterial stiffening. Male apoE-KO mice were infused with either ANG II (1.44 mg. kg(-1). day(-1)) or vehicle (PBS) for 30 days. ANG II treatment accelerated atherosclerosis in the carotid artery by sixfold (P < 0.001) and increased blood pressure by 30% (P < 0.05). Additionally, our data demonstrated that ANG II increased arterial stiffening using both in vivo and in vitro methods. ANG II significantly increased pulse wave velocity by 36% (P < 0.01) and decreased arterial elasticity as demonstrated by a more than 900% increase in maximal stiffening (high strain Young's modulus) compared with vehicle (P < 0.05). These functional changes were correlated with morphological and biochemical changes as demonstrated by an increase in collagen content (60%), a decrease in elastin content (74%), and breaks in the internal elastic lamina in the aortic wall. In addition, endothelium-independent vasorelaxation to sodium nitroprusside was impaired in the aortic rings of ANG II-treated mice compared with vehicle. Thus, the present data indicate that ANG II injures the artery wall in multiple ways and arterial stiffening may be a common outcome of ANG II-induced arterial damage.     

Electromechanical and structural alterations in the aging rabbit heart and aorta

Aging increases the risk for arrhythmias and sudden cardiac death (SCD). We aimed at elucidating aging-related electrical, functional, and structural changes in the heart and vasculature that account for this heightened arrhythmogenic risk. Young (5-9 mo) and old (3.5-6 yr) female New Zealand White (NZW) rabbits were subjected to in vivo hemodynamic, electrophysiological, and echocardiographic studies as well as ex vivo optical mapping, high-field magnetic resonance imaging (MRI), and histochemical experiments. Aging increased aortic stiffness (baseline pulse wave velocity: young, 3.54 ± 0.36 vs. old, 4.35 ± 0.28 m/s, P < 0.002) and diastolic (end diastolic pressure-volume relations: 3.28 ± 0.5 vs. 4.95 ± 1.5 mmHg/ml, P < 0.05) and systolic (end systolic pressure-volume relations: 20.56 ± 4.2 vs. 33.14 ± 8.4 mmHg/ml, P < 0.01) myocardial elastances in old rabbits. Electrophysiological and optical mapping studies revealed age-related slowing of ventricular and His-Purkinje conduction (His-to-ventricle interval: 23 ± 2.5 vs. 31.9 ± 2.9 ms, P < 0.0001), altered conduction anisotropy, and a greater inducibility of ventricular fibrillation (VF, 3/12 vs. 7/9, P < 0.05) in old rabbits. Histochemical studies confirmed an aging-related increased fibrosis in the ventricles. MRI showed a deterioration of the free-running Purkinje fiber network in ventricular and septal walls in old hearts as well as aging-related alterations of the myofibrillar orientation and myocardial sheet structure that may account for this slowed conduction velocity. Aging leads to parallel stiffening of the aorta and the heart, including an increase in systolic stiffness and contractility and diastolic stiffness. Increasingly, anisotropic conduction velocity due to fibrosis and altered myofibrillar orientation and myocardial sheet structure may contribute to the pathogenesis of VF in old hearts. The aging rabbit model represents a useful tool for elucidating age-related changes that predispose the aging heart to arrhythmias and SCD.     

Wave reflection augments central systolic and pulse pressures during facial cooling

Cardiovascular events are more common in the winter months, possibly because of hemodynamic alterations in response to cold exposure. The purpose of this study was to determine the effect of acute facial cooling on central aortic pressure, arterial stiffness, and wave reflection. Twelve healthy subjects (age 23 +/- 3 yr; 6 men, 6 women) underwent supine measurements of carotid-femoral pulse wave velocity (PWV), brachial artery blood pressure, and central aortic pressure (via the synthesis of a central aortic pressure waveform by radial artery applanation tonometry and generalized transfer function) during a control trial (supine rest) and a facial cooling trial (0 degrees C gel pack). Aortic augmentation index (AI), an index of wave reflection, was calculated from the aortic pressure waveform. Measurements were made at baseline, 2 min, and 7 min during each trial. Facial cooling increased (P < 0.05) peripheral and central diastolic and systolic pressures. Central systolic pressure increased more than peripheral systolic pressure (22 +/- 3 vs. 15 +/- 2 mmHg; P < 0.05), resulting in decreased pulse pressure amplification ratio. Facial cooling resulted in a robust increase in AI and a modest increase in PWV (AI: -1.4 +/- 3.8 vs. 21.2 +/- 3.0 and 19.9 +/- 3.6%; PWV: 5.6 +/- 0.2 vs. 6.5 +/- 0.3 and 6.2 +/- 0.2 m/s; P < 0.05). Change in mean arterial pressure but not PWV predicted the change in AI, suggesting that facial cooling may increase AI independent of aortic PWV. Facial cooling and the resulting peripheral vasoconstriction are associated with an increase in wave reflection and augmentation of central systolic pressure, potentially explaining ischemia and cardiovascular events in the cold.     

Ventricular-arterial coupling in a rat model of reduced arterial compliance provoked by hypervitaminosis D and nicotine

The vitamin D(3) and nicotine (VDN) model is one of isolated systolic hypertension (ISH) in which arterial calcification raises arterial stiffness and vascular impedance. The effects of VDN treatment on arterial and cardiac hemodynamics have been investigated; however, a complete analysis of ventricular-arterial interaction is lacking. Wistar rats were treated with VDN (VDN group, n = 9), and a control group (n = 10) was included without the VDN. At week 8, invasive indexes of cardiac function were obtained using a conductance catheter. Simultaneously, aortic pressure and flow were measured to derive vascular impedance and characterize ventricular-vascular interaction. VDN caused significant increases in systolic (138 +/- 6 vs. 116 +/- 13 mmHg, P < 0.01) and pulse (42 +/- 10 vs. 26 +/- 4 mmHg, P < 0.01) pressures with respect to control. Total arterial compliance decreased (0.12 +/- 0.08 vs. 0.21 +/- 0.04 ml/mmHg in control, P < 0.05), and pulse wave velocity increased significantly (8.8 +/- 2.5 vs. 5.1 +/- 2.0 m/s in control, P < 0.05). The arterial elastance and end-systolic elastance rose significantly in the VDN group (P < 0.05). Wave reflection was augmented in the VDN group, as reflected by the increase in the wave reflection coefficient (0.63 +/- 0.06 vs. 0.52 +/- 0.05 in control, P < 0.05) and the amplitude of the reflected pressure wave (13.3 +/- 3.1 vs. 8.4 +/- 1.0 mmHg in control, P < 0.05). We studied ventricular-arterial coupling in a VDN-induced rat model of reduced arterial compliance. The VDN treatment led to development of ISH and provoked alterations in cardiac function, arterial impedance, arterial function, and ventricular-arterial interaction, which in many aspects are similar to effects of an aged and stiffened arterial tree.     

Acute effects of 17beta-estradiol on ventricular and vascular hemodynamics in postmenopausal women

Because premenopausal women have lower cardiovascular morbidity than postmenopausal women, it has been proposed that estrogen may have a protective role. Estrogen is involved in smooth muscle relaxation both through its specific receptor as well as through calcium channel blockade. This study examined the acute effect of estradiol on invasive cardiovascular hemodynamics in 18 postmenopausal women (age 62.6 +/- 7.6 years, means +/- SD). The effect of estradiol on left ventricular chamber performance was studied in 9 women using simultaneous left ventricular pressure-volume recordings. In a further group of 9 women, the acute effect of estradiol on arterial function was assessed using input impedance (derived from simultaneous aortic pressure and flow recordings), pressure waveform analysis, and pulse wave velocity. After 2 mg micronized 17beta-estradiol was administered, serum estradiol levels increased from 50.9 +/- 21.9 to 3,190 +/- 2,216 pmol/l, P < 0.0001. There was no effect of estradiol on either left ventricular inotropic or lusitropic function. There was no acute effect of estradiol on arterial impedance, reflection coefficient, augmentation index, or pulse wave velocity. There was a trend to decreased heart rate and cardiac output in both groups of 9 women. Because heart rate and cardiac output were common to both hemodynamic data sets, results for these parameters were pooled. Across all 18 women, there was a small but significant decrease in heart rate (69.2 +/- 10.4 vs. 67.2 +/- 9.9 beats/min, P = 0.02), as well as a significant decrease in cardiac output (4.82 +/- 1.77 vs. 4.17 +/- 1.56 l/min, P = 0.002). Despite achieving supraphysiological serum levels, this study found no significant effect of acute 17beta-estradiol on ventricular or large artery function.     

Conductance catheter-based assessment of arterial input impedance, arterial function, and ventricular-vascular interaction in mice

Global assessment of both cardiac and arterial function is important for a meaningful interpretation of pathophysiological changes in animal models of cardiovascular disease. We simultaneously acquired left ventricular (LV) and aortic pressure and LV volume (V(LV)) in 17 open-chest anesthetized mice (26.7 +/- 3.2g) during steady-state (BL) and caval vein occlusion (VCO) using a 1.4-Fr dual-pressure conductance catheter and in a subgroup of eight animals during aortic occlusion (AOO). Aortic flow was obtained from numerical differentiation of V(LV). AOO increased input impedance (Z(in)) for the first two harmonics, increased characteristic impedance (0.025 +/- 0.007 to 0.040 +/- 0.011 mmHg x microl(-1) x s, P < 0.05), and shifted the minimum in Z(in) from the third to the sixth harmonic. For all conditions, the Z(in) could be well represented by a four-element windkessel model. The augmentation index increased from 116.7 +/- 7.8% to 145.9 +/- 19.5% (P < 0.01) as well as estimated pulse-wave velocity (3.50 +/- 0.94 to 5.95 +/- 1.62 m/s, P < 0.05) and arterial elastance (E(a), 4.46 +/- 1.62 to 6.02 +/- 1.43 mmHg/microl, P < 0.01). AOO altered the maximal slope (E(max), 3.23 +/- 1.02 to 5.53 +/- 1.53 mmHg/microl, P < 0.05) and intercept (-19.9 +/- 8.6 to 1.62 +/- 13.51 microl, P < 0.01) of the end-systolic pressure-volume relation but not E(a)/E(max) (1.44 +/- 0.43 to 1.21 +/- 0.37, not significant). We conclude that simultaneous acquisition of Z(in) and arterial function parameters in the mouse, based solely on conductance catheter measurements, is feasible. We obtained an anticipated response of Z(in) and arterial function parameters following VCO and AOO, demonstrating the sensitivity of the measuring technique to induced physiological alterations in murine hemodynamics.     

Ascorbic acid does not affect large elastic artery compliance or central blood pressure in young and older men

Large elastic artery compliance is reduced and arterial blood pressure (BP) is increased in the central (cardiothoracic) circulation with aging. Reactive oxygen species may tonically modulate central arterial compliance and BP in humans, and oxidative stress may contribute to adverse changes with aging. If so, antioxidant administration may have beneficial effects. Young (Y; 26 +/- 1 yr, mean +/- SE) and older (O; 63 +/- 2 yr, mean +/- SE) healthy men were studied at baseline and during acute (intravenous infusion; Y: n = 13, O: n = 12) and chronic (500 mg/day for 30 days; Y: n = 10, O: n = 10) administration of ascorbic acid (vitamin C). At baseline, peripheral (brachial artery) BP did not differ in the two groups, but carotid artery compliance was 43% lower (1.2 +/- 0.1 vs. 2.1 +/- 0.1 mm(2)/mmHg x 10(-1), P < 0.01) and central (carotid) BP (systolic: 116 +/- 5 vs. 101 +/- 3 mmHg, P < 0.05, and pulse pressure: 43 +/- 4 vs. 36 +/- 3 mmHg, P = 0.16), carotid augmentation index (AIx; 27.8 +/- 7.8 vs. -20.0 +/- 6.6%, P < 0.001), and aortic pulse wave velocity (PWV; 950 +/- 88 vs. 640 +/- 38 cm/s, P < 0.01) were higher in the older men. Plasma ascorbic acid concentrations did not differ at baseline (Y: 71 +/- 5 vs. O: 61 +/- 7 micromol/l, P = 0.23), increased (P < 0.001) to supraphysiological levels during infusion (Y: 1240 +/- 57 and O: 1,056 +/- 83 micromol/l), and were slightly elevated (P < 0.001 vs. baseline) with supplementation (Y: 96 +/- 5 micromol/l vs. O: 85 +/- 6). Neither ascorbic acid infusion nor supplementation affected peripheral BP, heart rate, carotid artery compliance, central BP, carotid AIx, or aortic PWV (all P > 0.26). These results indicate that the adverse changes in large elastic artery compliance and central BP with aging in healthy men are not 1). mediated by ascorbic acid-sensitive oxidative stress (infusion experiments) and 2). affected by short-term, moderate daily ascorbic acid (vitamin C) supplementation.     

Aortic reflection coefficients and their association with global indexes of wave reflection in healthy controls and patients with Marfan's syndrome

Early return of reflected pressure waves increases the load on central arteries and may increase the risk of aortic rupture in patients with Marfan's syndrome (MFS). To assess whether wave reflection is elevated in MFS, we used ultrasound and MRI to measure central pressure and flow waveforms in 26 patients (13-54 yr of age) and 26 age- and gender-matched controls. Aortic systolic and diastolic cross-sectional areas were measured at the ascending and descending aorta (AA and DA), diaphragm (DIA), and lower abdominal aorta (AB). From these measurements, local characteristic impedance (Z(0-xx)) and local reflection coefficients (Gamma(xx-yy)) were calculated. Calculated global wave reflection indexes were the augmentation index (AIx) and the ratio of backward to forward pressure wave (P(b)/P(f)). The aorta was wider in MFS patients at AA (P < 0.01) and DA (P < 0.01). Aortic pulse wave velocity was 42 cm/s higher in MFS patients (P < 0.05). Z(0-xx) was not different between groups, except at DA, where it was lower in MFS patients. In controls, Gamma(AA-DA) was 0.31 +/- 0.08, Gamma(DA-DIA) was 0.00 +/- 0.11, and Gamma(DIA-AB) was 0.31 +/- 0.16. Mean values of Gamma(xx-yy) were not different between MFS patients and controls. In controls, aging diminished Gamma(AA-DA) but increased Gamma(DIA-AB). Clear age-related patterns were absent in MFS patients. AIx or P(b)/P(f) was not higher in MFS patients than in controls. There were indications for enhanced wave reflection in young MFS patients. Our data demonstrated that the major determinants of AIx were pulse wave velocity and the effective length of the arterial system and, to a lesser degree, HR and P(b)/P(f).     

Impaired shear stress-induced nitric oxide production through decreased NOS phosphorylation contributes to age-related vascular stiffness.

Endothelial dysfunction and increased arterial stiffness contribute to multiple vascular diseases and are hallmarks of cardiovascular aging. To investigate the effects of aging on shear stress-induced endothelial nitric oxide (NO) signaling and aortic stiffness, we studied young (3-4 mo) and old (22-24 mo) rats in vivo and in vitro. Old rat aorta demonstrated impaired vasorelaxation to acetylcholine and sphingosine 1-phosphate, while responses to sodium nitroprusside were similar to those in young aorta. In a customized flow chamber, aortic sections preincubated with the NO-sensitive dye, 4-amino-5-methylamino-2',7'-difluorofluorescein diacetate, were subjected to steady-state flow with shear stress increase from 0.4 to 6.4 dyn/cm(2). In young aorta, this shear step amplified 4-amino-5-methylamino-2',7'-difluorofluorescein fluorescence rate by 70.6 +/- 13.9%, while the old aorta response was significantly attenuated (23.6 +/- 11.3%, P < 0.05). Endothelial NO synthase (eNOS) inhibition, by N(G)-monomethyl-l-arginine, abolished any fluorescence rate increase. Furthermore, impaired NO production was associated with a significant reduction of the phosphorylated-Akt-to-total-Akt ratio in aged aorta (P < 0.05). Correspondingly, the phosphorylated-to-total-eNOS ratio in aged aortic endothelium was markedly lower than in young endothelium (P < 0.001). Lastly, pulse wave velocity, an in vivo measure of vascular stiffness, in old rats (5.99 +/- 0.191 m/s) and in N(omega)-nitro-l-arginine methyl ester-treated rats (4.96 +/- 0.118 m/s) was significantly greater than that in young rats (3.64 +/- 0.068 m/s, P < 0.001). Similarly, eNOS-knockout mice demonstrated higher pulse wave velocity than wild-type mice (P < 0.001). Thus impaired Akt-dependent NO synthase activation is a potential mechanism for decreased NO bioavailability and endothelial dysfunction, which likely contributes to age-associated vascular stiffness.     

Noninvasive ultrasonic measurement of arterial wall motion in mice

Despite the extensive use of genetically altered mice to study cardiovascular physiology and pathology, it remains difficult to quantify arterial function noninvasively in vivo. We have developed a noninvasive Doppler method for quantifying vessel wall motion in anesthetized mice. A 20-MHz probe was held by an alligator clip and positioned over the carotid arteries of 16 mice, including six 3- to 5-mo-old wild-type (WT), four 30-mo-old senescent (old), two apolipoprotein E null (ApoE), and four alpha-smooth muscle actin null (alpha-SMA) mice. Doppler signals were obtained simultaneously from both vessel walls and from blood flow. The calculated displacement signals from the near and far walls were subtracted to generate a diameter signal from which the excursion and an augmentation index were calculated. The excursion ranged between 13 microm (in ApoE) and 95 microm (in alpha-SMA). The augmentation index was lowest in the WT mice (0.06) and highest in the old mice (0.29). We conclude that Doppler signal processing may be used to measure vessel wall motion in mice with high spatial and temporal resolution and that diameter signals can replace pressure signals for calculating the augmentation index. This noninvasive method is able to identify and confirm characteristic changes in arterial properties previously associated with age, atherosclerosis, and the absence of vascular tone.     

Superoxide-lowering therapy with TEMPOL reverses arterial dysfunction with aging in mice

To test the hypothesis that the antioxidant enzyme superoxide dismutase (SOD) mimetic TEMPOL improves arterial aging, young (Y, 4-6 months) and old (O, 26-28 months) male C57BL6 mice received regular or TEMPOL-supplemented (1mM) drinking water for 3 weeks (n = 8 per group). Aortic superoxide was 65% greater in O (P < 0.05 vs. Y), which was normalized by TEMPOL. O had large elastic artery stiffening, as indicated by greater aortic pulse wave velocity (aPWV, 508 ± 22 vs. 418 ± 22 AU), which was associated with increased adventitial collagen I expression (P < 0.05 vs. Y). TEMPOL reversed the age-associated increases in aPWV (434 ± 21 AU) and collagen in vivo, and SOD reversed the increases in collagen I in adventitial fibroblasts from older rats in vitro. Isolated carotid arteries of O had impaired endothelial function as indicated by reduced acetylcholine-stimulated endothelium-dependent dilation (EDD) (75.6 ± 3.2 vs. 94.5 ± 2.0%) mediated by reduced nitric oxide (NO) bioavailability (L-NAME) associated with decreased endothelial NO synthase (eNOS) expression (P < 0.05 vs. Y). TEMPOL restored EDD (94.5 ± 1.4%), NO bioavailability and eNOS in O. Nitrotyrosine and expression of NADPH oxidase were ~100-200% greater, and MnSOD was ~75% lower in O (P < 0.05 vs. Y). TEMPOL normalized nitrotyrosine and NADPH oxidase in O, without affecting MnSOD. Aortic pro-inflammatory cytokines were greater in O (P < 0.05 vs. Y) and normalized by TEMPOL. Short-term treatment of excessive superoxide with TEMPOL ameliorates large elastic artery stiffening and endothelial dysfunction with aging, and this is associated with normalization of arterial collagen I, eNOS, oxidative stress, and inflammation.     

Aminoguanidine prevents fructose-induced arterial stiffening in Wistar rats: aortic impedance analysis

Fructose has been reported as a potent agent in forming advanced glycation end products (AGEs) and, thus, may play a significant role in the pathogenesis of diabetic complications. Herein, we determined the effects of aminoguanidine (AG), an inhibitor of AGEs, on the mechanical properties of the arterial system in fructose-fed (FF) rats, using aortic impedance analysis. Rats at 2 months were given 10% fructose in drinking water for 2 weeks and compared with untreated age-matched controls. Meanwhile, FF rats were treated for 2 weeks with AG (daily peritoneal injections of 50 mg kg(-1)) and compared with the untreated FF group. Neither fructose nor AG affects body weight, blood glucose level, and basal heart rate. In comparison with controls, FF rats showed a decrease in cardiac output in the absence of any significant changes in mean aortic pressure, having increased total peripheral resistance (R(p)), at 51.1 +/- 2.9 versus 66.2 +/- 1.9 mm Hg sec ml(-1) (P < 0.05). Fructose also contributed to an increase in aortic characteristic impedance (Z(c)), from 1.528 +/- 0.094 to 1.933 +/- 0.084 mm Hg sec ml (-1) (P < 0.05) and a decrease in wave transit time (tau), from 22.6 +/- 0.6 to 19.2 +/- 0.7 msec (P < 0.05). The elevated Z(c) and the reduced tau suggest that fructose may cause a detriment to the aortic distensibility in animals. After exposure to AG, FF rats exhibited a significant improvement in physical properties of the resistance vessels, as evidenced by the reduction of 21.3% in R(p). Meanwhile, AG retarded the fructose-induced decline in aortic distensibility, as reflected in the decrease of 16.0% in Z(c) (P < 0.05) and the increase of 18.1% in tau (P < 0.05). By contrast, AG exerted no effects on the mechanical properties of Windkessel vessels, as well as resistance vessels, in normal diet controls. We conclude that AG may prevent the fructose-derived changes in arterial stiffening, possibly through inhibition of the fructose-derived advanced glycation end product formation in Wistar rats.     

Biological aortic age derived from the arterial pressure waveform

Indexes for arterial stiffness are, by their nature, influenced by the ambient blood pressure due to the curvilinear nature of arterial compliance. We developed a new concept of the "Modelflow aortic age," which is, theoretically, not influenced by the ambient blood pressure and provides an easily understood context (biological vs. chronological age) for measures of arterial stiffness. The purpose of the present study was to validate this pressure-independent index for aortic stiffness in humans. Twelve sedentary elderly (65-77 yr), 11 Masters athletes (65-73 yr), and 12 sedentary young individuals (20-42 yr) were studied. Modelflow aortic ages were comparable with chronological ages in both sedentary groups, indicating that healthy sedentary individuals have age-appropriate aortas. In contrast, Masters athletes showed younger Modelflow aortic ages than their chronological ages. The coefficient of variation of sedentary subjects was three times smaller with the Modelflow aortic age (21%) than with other indexes, such as static systemic arterial stiffness (61%), central pulse wave velocity (61%), or carotid β-stiffness index (58%). The typical error was very small and two times smaller in the Modelflow aortic age (<7%) than in static systemic arterial stiffness (>13%) during cardiac unloading by lower body negative pressure. The Modelflow aortic age can more precisely and reliably estimate aortic stiffening with aging and modifiers, such as life-long exercise training compared with the pressure-dependent index of static systemic arterial stiffness, and provides a physiologically relevant and clinically compelling context for such measurements.     

Cyclooxygenase inhibition augments central blood pressure and aortic wave reflection in aging humans

The augmentation index and central blood pressure increase with normal aging. Recently, cyclooxygenase (COX) inhibitors, commonly used for the treatment of pain, have been associated with transient increases in the risk of cardiovascular events. We examined the effects of the COX inhibitor indomethacin (Indo) on central arterial hemodynamics and wave reflection characteristics in young and old healthy adults. High-fidelity radial arterial pressure waveforms were measured noninvasively by applanation tonometry before (control) and after Indo treatment in young (25 ± 5 yr, 7 men and 6 women) and old (64 ± 6 yr, 5 men and 6 women) subjects. Aortic systolic (control: 115 ± 3 mmHg vs. Indo: 125 ± 5 mmHg, P < 0.05) and diastolic (control: 74 ± 2 mmHg vs. Indo: 79 ± 3 mmHg, P < 0.05) pressures were elevated after Indo treatment in older subjects, whereas only diastolic pressure was elevated in young subjects (control: 71 ± 2 mmHg vs. Indo: 76 ± 1 mmHg, P < 0.05). Mean arterial pressure increased in both young and old adults after Indo treatment (P < 0.05). The aortic augmentation index and augmented pressure were elevated after Indo treatment in older subjects (control: 30 ± 5% vs. Indo 36 ± 6% and control 12 ± 1 mmHg vs. Indo: 18 ± 2 mmHg, respectively, P < 0.05), whereas pulse pressure amplification decreased (change: 8 ± 3%, P < 0.05). In addition, older subjects had a 61 ± 11% increase in wasted left ventricular energy after Indo treatment (P < 0.05). In contrast, young subjects showed no significant changes in any of the variables of interest. Taken together, these results demonstrate that COX inhibition with Indo unfavorably increases central wave reflection and augments aortic pressure in old but not young subjects. Our results suggest that aging individuals have a limited ability to compensate for the acute hemodynamic changes caused by systemic COX inhibition.     

Hemodynamic changes in apolipoprotein E-knockout mice

Apolipoprotein E-knockout (ApoE-KO) mice develop advanced atherosclerotic lesions by 1 yr of age and have been well characterized pathologically and morphologically, but little is known regarding their cardiovascular physiology and hemodynamics. We used noninvasive Doppler ultrasound to measure aortic and mitral blood velocity and aortic pulse-wave velocity in 13-mo-old ApoE-KO and wild-type (WT) mice anesthetized with isoflurane. In other mice from the same colony, we measured systolic blood pressure, body weight, heart weight, cholesterol, and hematocrit. Heart rate and blood pressure were comparable (P = not significant) between ApoE-KO and WT mice, but significant decreases (P < 0.001) were found in body weight (-22%) and hematocrit (-11%), and significant increases were found in heart weight (+23%), aortic velocity (+60%), mitral velocity (+81%) (all P < 0.001), and pulse-wave velocity (+13%, P < 0.05). We also found inflections in the aortic arch velocity signal consistent with enhanced peripheral wave reflection. Thus ApoE-KO mice have phenotypic alterations in indexes of peripheral vascular resistance and compliance and significantly elevated cardiac outflow velocities and heart weight-to-body weight ratios.     

Acute effects of cold exposure on central aortic wave reflection.

The purpose of this study was to determine the effects of acute cold exposure on the timing and amplitude of central aortic wave reflection and central pressure. We hypothesized that cold exposure would result in an early return of reflected pressure waves from the periphery and an increase in central aortic systolic pressure as a result of cold-induced vasoconstriction. Twelve apparently healthy men (age 27.8 +/- 2.0 yr) were studied at random, in either temperate (24 degrees C) or cold (4 degrees C) conditions. Measurements of brachial artery blood pressure and the synthesis of a central aortic pressure waveform (by noninvasive radial artery applanation tonometry and use of a generalized transfer) were conducted at baseline and after 30 min in each condition. Central aortic augmentation index (AI), an index of wave reflection, was calculated from the aortic pressure waveform. Cold induced an increase (P < 0.05) in AI from 3.4 +/- 1.9 to 19.4 +/- 1.8%. Cold increased (P < 0.05) both brachial and central systolic pressure; however, the magnitude of change in central systolic pressure was greater (P < 0.05) than brachial (13 vs. 2.5%). These results demonstrate that cold exposure and the resulting peripheral vasoconstriction increase wave reflection and central systolic pressure. Additionally, alterations in central pressure during cold exposure were not evident from measures of brachial blood pressure.     

Effects of diabetes and gender on mechanical properties of the arterial system in rats: aortic impedance analysis

We determined the effects of diabetes and gender on the physical properties of the vasculature in streptozotocin (STZ)-treated rats based on the aortic input impedance analysis. Rats given STZ 65 mg/kg i.v. were compared with untreated age-matched controls. Pulsatile aortic pressure and flow signals were measured and were then subjected to Fourier transformation for the analysis of aortic input impedance. Wave transit time was determined using the impulse response function of the filtered aortic input impedance spectra. Male but not female diabetic rats exhibited an increase in cardiac output in the absence of any significant changes in arterial blood pressure, resulting in a decline in total peripheral resistance. However, in each gender group, diabetes contributed to an increase in wave reflection factor, from 0.47 +/- 0.04 to 0.84 +/- 0.03 in males and from 0.46 +/- 0.03 to 0.81 +/- 0.03 in females. Diabetic rats had reduced wave transit time, at 18.82 +/- 0.60 vs 21.34 +/- 0.51 msec in males and at 19.63 +/- 0.37 vs 22.74 +/- 0.57 msec in females. Changes in wave transit time and reflection factor indicate that diabetes can modify the timing and magnitude of the wave reflection in the rat arterial system. Meanwhile, diabetes produced a fall in aortic characteristic impedance from 0.023 +/- 0.002 to 0.009 +/- 0.001 mmHg/min/kg/ml in males and from 0.028 +/- 0.002 to 0.014 +/- 0.001 mmHg/min/kg/ml in females. With unaltered aortic pressure, both the diminished aortic characteristic impedance and wave transit time suggest that the muscle inactivation in diabetes may occur in aortas and large arteries and may cause a detriment to the aortic distensibility in rats with either sex. We conclude that only rats with male gender diabetes produce a detriment to the physical properties of the resistance arterioles. In spite of male or female gender, diabetes decreases the aortic distensibility and impairs the wave reflection phenomenon in the rat arterial system.