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1Institute for Human Science and Biomedical Engineering, National Institute of Advanced Industrial Science and Technology, 1-1-1 Higashi, Tsukuba, Ibaraki 305-8566; and 2Center for Tsukuba Advanced Research Alliance and 3Institute of Health and Sport Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8574, Japan
Submitted 28 January 2004 ; accepted in final form 21 July 2004
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ABSTRACT |
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22–28 yr) performed a 5-min single-leg cycling exercise (30 W) in the supine position under an intravenous infusion of NG-monomethyl-L-arginine (L-NMMA; 3 mg/kg during the initial 5 min and subsequent continuous infusion of 50 µg·kg–1·min–1 in saline) or vehicle (saline) in random order on separate days. The pulse wave velocity (PWV) from the femoral to posterior tibial artery was measured on both legs before and after the infusion at rest and 2 min after exercise. Under the control condition, exercised leg PWV significantly decreased after exercise (P < 0.05), whereas nonexercised leg PWV did not show a significant change throughout the experiment. Under L-NMMA administration, exercised leg PWV was increased significantly by the infusion (P < 0.05) but decreased significantly after the exercise (P < 0.05). Nonexercised leg PWV increased with L-NMMA administration and maintained a significantly higher level during the administration compared with baseline (before the infusion, all P < 0.05). The NO synthase blockade x time interaction on exercised leg PWV was not significant (P = 0.706). These results suggest that increased production of NO is not a major factor in the decrease of regional arterial stiffness with low-intensity, short-duration aerobic exercise.
femoral artery; single-leg exercise; pulse wave velocity
23% below baseline 10 min after the exercise and then gradually increased to a near steady level of 10% below baseline by 60 min of recovery. Arterial stiffness is determined by both the properties of the arterial wall matrix and the vascular smooth muscle tone. An acute change in arterial stiffness is probably mediated by an alteration of vascular muscle tone with exercise. Systemic (e.g., sympathetic nervous activity, circulating hormones) and regional (e.g., endothelium-derived vasoactive substances, exercised muscle-derived metabolites) factors can alter the smooth muscle tone (11, 16), but conclusive evidence about whether these are major factors affecting arterial stiffness in this case has not been reported. We previously demonstrated (29) that low-intensity, short-duration single-leg exercise (20–30 W, 5 min) in healthy subjects induced a significant decrease in the PWV of the exercised leg but not that of the nonexercised leg. These results suggest that the decrease of peripheral arterial stiffness with exercise may be induced mainly by exercise-related regional factors.
It is well known that an increase in blood flow stimulates vascular endothelial cells and advances the production of various vasodilatory substances, e.g., NO (2, 9, 12, 23, 24), prostacyclin (1, 8), and endothelium-derived hyperpolarizing factor (EDHF) (15). In particular, NO is a potent endothelium-dependent vasodilator that, moreover, reduces the vasoconstrictor response to 
-adrenergic receptor stimulation (21). Recent studies demonstrated that NO modulates conduit arterial stiffness (or distensibility) in animals (5, 30) and humans (10). NO is increased with increased cyclic wall stress associated with increased pulsatile blood flow, e.g., during acute exercise (9).
We hypothesized that the exercise-induced decrease in peripheral arterial stiffness is caused by the increased production of NO in vascular endothelium with exercise, and we tested this hypothesis by examining the effects of systemic NO synthase (NOS) inhibition on changes of PWV in both leg arteries with low-intensity, single-leg aerobic exercise.
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METHODS |
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22–28) yr of age, 171.4 ± 1.6 (165–178) cm in height, 68.0 ± 2.3 (62.1–81.3) kg in body weight, and with body mass index (BMI) of 23.1 ± 0.5 (21.1–26.0), participated in this study. Written informed consent was obtained from all subjects, and the study was approved by the institutional review board of the University of Tsukuba. Because risk factors such as hypercholesterolemia and insulin resistance have been shown to correlate with abnormal blood pressure responses to exercise (4) and they also adversely affect endothelial function, we selected apparently healthy men [i.e., normotensive (<140/90 mmHg), nonobese (BMI < 30), and free of overt chronic diseases as assessed by medical history]. None of the subjects was taking medications or smoking. The subjects were either sedentary or recreationally active. Peak oxygen uptake determined with an incremental maximal exercise test was 41.6 ± 1.0 (38.0–47.4) ml·kg–1·min–1. Experimental protocol and measurements. Each subject underwent two experiments with a counterbalanced design in a blind manner on separate days, i.e., systemic NOS inhibition and control conditions. All experiments were done after an overnight fast. The subjects abstained from alcohol, caffeine, and intense exercise for at least 24 h before the experiments. All experiments were carried out in a temperature-controlled room (25°C).
All subjects rested for at least 30 min in the supine position to establish a stable baseline. Each subject received an initial bolus intravenous (left brachial vein) infusion of NG-monomethyl-L-arginine (L-NMMA; 3 mg/kg) or vehicle (saline) over 5 min and a subsequent continuous infusion of L-NMMA (50 µg·kg–1·min–1) or vehicle during the experiments. The procedure and dose of L-NMMA infusion accorded with the method of Mayer et al. (13).
Heart rate and blood pressure were continuously monitored at the finger during the experiments with a Portapres 2.0 (TNO-Biomedical Instrumentation, Amsterdam, The Netherlands). Before and >5 min after the start of the constant infusion, when the heart rate and blood pressure were in the steady state, PWV in both legs was measured with an automatic PWV measurement system (form-PWV/ABI, Colin, Komaki, Japan). After these measurements, each subject performed 5 min of single-leg (left) cycling at 30-W workload on a cycle ergometer (232C-EX, Combi, Tokyo, Japan). The measurements of PWV were repeated at 2 min after the cessation of the exercise. The automatic PWV measurement system consists of an applanation tonometry probe, cuffs connected to a plethysmographic sensor, and an automatic waveform analyzer. The applanation tonometry probe was placed at the right inguinal region to record pressure waveforms of the right common femoral artery. Cuffs were wrapped over both ankles to record pressure waveforms of the posterior tibial arteries. These pressure waveforms were simultaneously recorded at 1,200 Hz (common femoral artery) or 240 Hz (posterior tibial arteries). The delay times between the sharp systolic upstroke starts of the right femoral and both posterior tibial arterial pulse waves were determined by the automatic waveform analyzer (Fig. 1). We assumed that the sharp systolic upstroke starts of the right and left femoral arteries occurred at the same time and obtained the delay times of both legs for the same cardiac cycles. The sharp systolic upstroke start was determined based on the phase velocity theory. As mean phase velocity >2.5 Hz is constant and coincides with the wave-front velocity (14), the high-frequency components of the arterial wave could be used as a marker of phase shift. The high-frequency components of the arterial wave are derived mainly from the sharp systolic upstroke start and are 30 Hz. Accordingly, to extract the high-frequency components a band-pass filter with a lower cut-off frequency of 5 Hz and a higher cut-off frequency at 30 Hz was used in this system (17). Additionally, the R wave from the simultaneously recorded electrocardiogram was used as a reference to identify the sharp systolic upstroke starts. The distance between the point of placement of the applanation tonometry sensor on the femoral artery and the top of the medial malleolus was measured manually in duplicate with a tape measure, and the mean value was calculated. The PWV was determined from the distance between the two recording sites of the arterial pressure pulse wave and the delay time of wave travel. The day-to-day coefficient of variation for leg PWV in our laboratory was 2.3 ± 0.6%. Heart rate and blood pressure during corresponding periods of PWV measurements (1 min) were calculated from the beat-to-beat Portapres data.
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RESULTS |
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DISCUSSION |
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We induced systemic NOS inhibition by intravenous L-NMMA infusion. The dose and method of L-NMMA infusion in this study were similar to those in the previous studies by Stamler et al. (27) and Mayer et al. (13). Mayer et al. (13) reported that bolus infusion of 3 mg/kg L-NMMA resulted in a maximal plasma concentration of 13 µg/ml with an 1-h elimination half-time and caused a small hypertensive response, decreased cardiac output, and increased systemic vascular resistance. Mayer et al. (13) also reported that continuous infusion of 50 µg·kg–1·min–1 L-NMMA after the bolus infusion reduced exhaled NO by 69% without significant alterations of blood pressure and heart rate. Stamler et al. (27) reported a 65% reduction of serum NO level by an intravenous bolus infusion of 3 mg/kg L-NMMA, with a significant decrease of heart rate and significant increases of systolic, diastolic, and mean blood pressures. Although the production of NO was not evaluated in the present study, the changes of heart rate and blood pressures caused by infusion of L-NMMA were similar to those in the study of Stamler et al. (27). Additionally, the significant elevation of mean blood pressure lasted beyond the exercise. Several previous studies indicated that the basal production of endothelium-derived NO affects basal arterial stiffness via the regulation of smooth muscle tone of the arterial wall and/or via increase in systemic arterial pressure. The aortic PWV (aortic arch-abdominal artery) in rats was increased independent of concomitant increase in blood pressure when an NOS inhibitor, N
-nitro-L-arginine methyl ester, was infused into the jugular vein (5). In a human study, however, the aortic PWV (carotid artery-femoral artery) was suggested to be increased mainly via the increase in mean arterial pressure when basal NO release was systemically inhibited by L-NMMA (28). PWV measured in the common iliac artery of sheep was increased by intra-arterial (iliac artery) L-NMMA infusion (30). In humans, compliance of the brachial artery was decreased and PWV was increased by intra-arterial (brachial artery) infusion of L-NMMA (10). Together, changes in peripheral arterial stiffness could be produced by a NOS inhibitor because of the depression of NO production per se. In the present study, L-NMMA administration induced significant increase in PWV of both exercised and nonexercised legs. PWV after exercise was also higher than that before L-NMMA administration in the nonexercised leg. Thus it seems likely that the systemic L-NMMA administration in the present study could reduce at least the basal production of NO in systemic vascular endothelial cells.
Kingwell et al. (11) showed that the PWV of the femoral arteries in young men significantly decreased 30 min after moderate-intensity exercise (30 min, 65% of maximal oxygen uptake). They pointed out that shear stress-induced release of NO was one of the mechanisms associated with the decreased arterial stiffness. In the present study, we hypothesized that the exercise-induced decrease in peripheral arterial stiffness is caused by the increased production of NO in vascular endothelium with exercise and, accordingly, that L-NMMA administration would interfere with the exercise-induced decrease of PWV. It was suggested that the production of NO might be increased in nonexercised limbs during exercise at moderate to high intensity (e.g., 60–160 W) but not at lower intensity (e.g., 40 W) (7). Under the condition without L-NMMA administration, PWV was decreased with low-intensity, short-duration exercise in the exercised leg but not in the nonexercised leg. These results were identical with those of our previous study (29). The decrease of arterial stiffness in the exercised leg might have been induced mainly by exercise-related regional factors. The administration of L-NMMA, however, had no effect on the exercise-induced change of PWV. It cannot be ruled out that the L-NMMA administration in the present study could not perfectly inhibit the increased production of NO from the exercising muscle bed. It might have been interesting to infuse L-arginine in the current series of experiments to ascertain whether NO had any effect on exercise-induced changes in arterial stiffness (3). Alternatively, the decrease of arterial stiffness in the exercised leg might have been induced by some regional factors other than NO, because multiple redundant mechanisms may substitute to regulate vascular tone under the condition when NOS is inhibited.
NOS inhibition does not affect hemodynamics during exercise (3, 22) but reduces postexercise hyperemic flow (6, 22, 26). The reduced hyperemic flow is presumable because of the impaired vasodilation and consequent inhibition of the decrease in vascular resistance due to the reduction in NO production. The inhibition of the decrease in vascular resistance would have resulted in increased peripheral conduit arterial stiffness via increased arterial pressure. Although we did not estimate blood flow and, consequently, vascular resistance, systemic arterial pressure was increased with administration of L-NMMA. Nevertheless, under NOS inhibition, PWV in the exercised leg decreased regardless of the increased arterial pressure. In peripheral muscular arteries, stiffness is influenced by arterial pressure and/or by the tone of arterial smooth muscle. Thus it is considered that the decrease in the exercised leg PWV is explained by the effect of decreased vascular smooth muscular tone, which might surmount the effect of increased arterial pressure. Additionally, it has been indicated that an arterial pressure is not an independent determinant of PWV in young healthy men and that PWV does not correlate with systemic vascular resistance (19).
Prostacyclin is a potential factor that may induce the postexercise decrease in arterial stiffness. The production of prostacyclin is enhanced by an increase of shear stress in the regional vessels, and prostacyclin attenuates neurogenic and myogenic vasoconstriction (8). Furthermore, a recent study reported that flow-induced prostacyclin production might be enhanced by the inhibition of NOS (20). EDHF causes the relaxation of vascular smooth muscle cells (15). Interstitial metabolites (e.g., lactate, adenosine, phosphate, H+) that are released by exercising muscle also attenuate the arterial smooth muscle tone in the proximal arteries by an upstream transmission of vasodilatory stimuli (25). Our data, however, cannot specify which factor induced the postexercise decrease of arterial stiffness in the exercised leg.
In summary, PWV of the exercised leg was decreased by low-intensity single-leg cycling exercise, but that of the nonexercised leg was not, under both the systemic inhibition of NOS by intravenous administration of L-NMMA and the control condition. Thus, at least under the conditions of the present protocol, systemic NOS inhibition appears to have no effect on the decrease in middle-sized muscular arterial stiffness with exercise.
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FOOTNOTES |
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The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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