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INTEGRATIVE |
1 Department of Kinesiology
2 Graduate Physiology Program, Noll Laboratory, Pennsylvania State University, University Park, PA 16802, USA
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Abstract |
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-hydroxy-nor-L-arginine), L-arg supplemented (L-Arg; 10.0 mM
L-arginine) and combined arginase-inhibited +
L-Arg sites. After 20 min thermoneutral baseline, cutaneous vasodilatation was induced by passive whole-body heating to increase oral temperature (Tor) by 1.0°C. Red blood cell flux was measured by laser-Doppler flowmetry over each microdialysis site. Cutaneous vascular conductance was calculated (CVC = flux/mean arterial pressure) and normalized to maximal CVC (CVCmax, 28.0 mM sodium nitroprusside + local heating to 43°C). Cutaneous vasodilatation during heating was attenuated in O (Y, 42 ± 1, versus O, 30 ± 1%CVCmax, P < 0.001) at control sites. NOS inhibition decreased vasodilatation in both age groups compared to C (Y, 22 ± 2; O, 18 ± 2%CVCmax; P < 0.001). Arginase inhibition, L-Arg supplementation, and arginase inhibition +
L-Arg supplementation augmented vasodilatation in O (arginase-inhibited, 46 ± 4; L-Arg, 44 ± 4; arginase-inhibited +
L-arg, 46 ± 5%CVCmax; P < 0.001 versus C) but not in Y (arginase-inhibited, 46 ± 4; L-Arg, 38 ± 4; arginase-inhibited +
L-Arg, 44 ± 4%CVCmax; P > 0.05 versus C). Increasing L-Arg for NO synthesis by either arginase inhibition or direct L-Arg supplementation restores the age-related deficit in reflex cutaneous vasodilatation.
(Received 6 March 2006;
accepted after revision 28 April 2006;
first published online 4 May 2006)
Corresponding author L. A. Holowatz: 123 Noll Laboratory, University Park, PA 16802, USA. Email: lma191{at}psu.edu
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Introduction |
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Aged humans exhibit attenuated cutaneous vasodilatory responses during hyperthermia (Kenney et al. 1997), resulting from a diminished neurogenic cotransmitter contribution and an increased reliance on impaired NO-dependent vasodilatation (Holowatz et al. 2003). Attenuated NO-dependent vasodilatation is associated with decreased NO bioavailability. In aged skin, decreased NO bioavailability is probably multifaceted, involving several potential signalling pathways, including dysregulated utilization of the NO substrate L-arginine (L-Arg).
One potential mechanism that has been implicated in reduced L-Arg availability for NOS is augmented vascular arginase activity (Hecker et al. 1995; Berkowitz et al. 2003). Arginase is constitutively expressed in two isoforms (I and II), which catalyse the conversion of L-Arg to L-ornithine and urea during the final step of the urea cycle. Arginase I is most likely the predominant isoform in the vasculature and is capable of reciprocally regulating endothelial NOS by competing for the common substrate L-Arg (Berkowitz et al. 2003; White et al. 2006) (Fig. 1).
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Therefore, the purpose of this study was to determine the role of arginase in reflex cutaneous vasodilatation in aged humans. We hypothesized that arginase inhibition alone and with concurrent L-Arg supplementation would augment cutaneous vasodilatation during passive whole-body heat stress by increasing L-Arg availability for NO synthesis.
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Methods |
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Experimental protocols were approved by the Institutional Review Board at The Pennsylvania State University, and conformed to the guidelines set forth by the Declaration of Helsinki. Verbal and written consent was voluntarily obtained from all subjects prior to participation. Studies were performed on 10 young (18–27 years) and 9 older (65–72 years) men and women. Each subject underwent a complete medical screening, including blood chemistry, lipid profile evaluation (Quest Diagnostics, Nichol Institute, Chantilly, VA, USA), physical examination, and an assessment of maximal oxygen uptake 
(SensorMedics Corporation, Yorba Linda, CA, USA). All subjects were screened for the presence of cardiovascular, dermatological and neurological disease. Subjects were normally active, normotensive, nondiabetic, healthy nonsmokers who were currently not taking medications, including aspirin therapy, hormone replacement therapy or oral contraceptives. All young female subjects were studied on days 2–7 of the early follicular phase of their menstrual cycle.
Instrumentation and measurements
All protocols were performed in a thermoneutral laboratory, with the subject in the supine position and with the experimental arm at heart level. Upon arrival at the laboratory between 07.00 and 09.00 h, subjects were instrumented with five intradermal microdialysis fibres (MD 2000; Bioanalytical Systems, IN, USA) (10 mm, 20 kDa cutoff membrane) in the skin on the right ventral forearm. Microdialysis sites were at least 4.0 cm apart to insure no cross-reactivity of pharmacological agents being delivered to the skin. Microdialysis fibres were placed at each site by first inserting a 25 gauge needle through unanaesthetized skin using sterile technique. The entry and exit points were 
2.5 cm apart. The microdialysis fibre was then threaded through the needle, and the needle was withdrawn, leaving the fibre in place. The microdialysis fibres were taped in place and perfused with lactated Ringer solution during the insertion trauma resolution period at a rate of 2.0 µl min–1 (Bee Hive controller and Baby Bee microinfusion pumps; Bioanalytical Systems) for 60–90 min.
To obtain an index of skin blood flow, cutaneous red blood cell (RBC) flux was measured with an integrated laser-Doppler flowmeter probe placed in a local heater (MoorLAB, Temperature Monitor SH02; Moor Instruments, Devon, UK) on the skin directly above each microdialysis membrane. All laser-Doppler probes were calibrated using Brownian standard solution. Cutaneous vascular conductance (CVC) was calculated as RBC flux divided by mean arterial pressure.
To control whole-body temperature, subjects wore a water-perfused suit that covered the entire body except head, hands and experimental arm, and a water-impermeable rain suit to minimize evaporative heat loss. The subject's electrocardiogram was monitored throughout the protocol, and blood pressure was measured via brachial auscultation every 5 min. Oral temperature (Tor) was continuously monitored during baseline and throughout whole-body heating with a thermister placed in the sublingual sulcas as an index of body core temperature. The subjects were instructed to keep the thermister in the same location in the sublingual sulcus and not to open their mouths or speak during the protocol. Mean skin temperature was calculated as the unweighted average of six copper–constantan thermocouples placed on the chest, middle back, abdomen, upper arm, thigh and calf. During the insertion trauma resolution and baseline periods, thermoneutral water (34°C) was perfused through the suit to clamp whole-body temperature. During whole-body heating, 50°C water was perfused through the suit to raise the Tor of the subject by 1.0°C above baseline body temperature.
Experimental protocol
A schematic representation of the protocol is illustrated in Fig. 2. RBC flux over each microdialysis site was monitored during the insertion trauma resolution period. Following this period, microdialysis sites were randomly assigned to receive the following: (1) 10.0 mM
NG-nitro-L-arginine methylester (L-NAME) to inhibit NO production by NOS, (2) a combination of 5.0 mM (S)-(2-boronoethyl)-L-cysteine-HCl (BEC) and 5.0 mM
N-hydroxy-nor-L-arginine (nor-NOHA) to inhibit arginase (Calbiochem, San Diego, CA, USA), (3) 10.0 mM
L-Arg (Sigma) to supplement the substrate for NOS and arginase, and (4) 5.0 mM BEC + 5.0 mM nor-NOHA + 10.0 mM
L-Arg to inhibit arginase and supplement the substrate for NOS and arginase. All pharmacological agents were dissolved in lactated Ringer solution. A fifth microdialysis site was perfused with only lactated Ringer solution to serve as a control.
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All microdialysis sites were perfused with assigned pharmacological agents continuously for at least 60 min prior to the start of the baseline, and during the baseline and heating periods, at a rate of 2.0 µl min–1. Baseline data were collected for 20 min prior to the start of whole-body heating. After the baseline data collection period, whole-body heating was conducted to raise Tor by 1.0°C. At the end of the heating protocol, each microdialysis site was perfused with 28.0 mM sodium nitroprusside (SNP; Nitropress; Abbot Laboratories, Chicago, IL, USA) at a rate of 4.0 µl min–1 to achieve maximal CVC. Local heating of the skin to 43°C was conducted simultaneously with SNP infusion to ensure maximal CVC had been obtained.
Data acquisition and analysis
Data were acquired using Labview software and the National Instruments data acquisition system (Austin, TX, USA). The data were collected at 40 Hz, digitized, recorded and stored on a personal computer for further analysis. CVC data were averaged over 3 min periods for baseline and every 0.1°C rise in Tor, and are presented as a percentage of maximal CVC (%CVCmax). Two reviewers blinded to the age of the subjects and to the pharmacological treatment of the microdialysis sites visually identified the absolute Tor and delta Tor (
Tor) at which the threshold for reflex cutaneous vasodilatation was initiated in each microdialysis site.
Student's t tests were used to determine significant differences between the young and older groups for physical characteristics and baseline Tor. A two-way repeated measures analysis of variance (ANOVA) was conducted to detect age and pharmacological treatment effects on the threshold Tor (absolute Tor and Tor) for reflex cutaneous vasodilatation. A three-way repeated measures ANOVA was conducted to detect differences between subject groups at the pharmacological treatment sites over the rise in Tor (SAS, version 8.01). Planned comparison tests, including Tukey post hoc tests, were performed when appropriate to determine where differences between groups and drug treatments occurred. The level of significance was set at 
= 0.05. Values are presented as means ±
S.E.M.
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Results |
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(P
= 0.002). Total cholesterol and low density lipoprotein levels were significantly higher in the older subject group (P
= 0.001 for both), but there was no difference in high density lipoproteins between the age groups.
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Tor 0.4°C; this difference was observed in the aged subject group at Tor 0.6°C (P < 0.001 between groups). There was no difference in the %CVCmax responses in the arginase-inhibited compared with the control site in the young subject group (Fig. 3A). However, in the older subject group, arginase inhibition significantly increased %CVCmax above the level of the control site at Tor 0.7°C. Similarly, CVC in the L-Arg-supplemented (Fig. 3B) and the arginase-inhibited +
L-Arg-supplemented (Fig. 3C) site was not significantly different from the control site in young subjects, but was significantly augmented compared with the control site in the older subject group starting at Tor 0.7°C. Moreover, arginase inhibition, L-Arg supplementation, and arginase inhibition +
L-Arg supplementation in the older subject group increased cutaneous vasodilatation such that there was no difference between these microdialysis sites compared with the young subject group's control site (P > 0.05).
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Discussion |
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Our results indicate that NO bioavailability is compromised in aged human skin, and that pharmacological interventions specifically targeting the L-Arg–NO pathway can increase cutaneous blood flow during hyperthermia. In young human subjects, NO is required for full expression and contributes approximately 40–50% to the total reflex cutaneous vasodilatory response (Kellogg et al. 1998a; Shastry et al. 1998); additionally both VIP and H1 receptor activation mediate vasodilatation through NO-dependent mechanisms (Wilkins et al. 2004; Wong et al. 2004). Furthermore, NO is capable of mediating cutaneous vasodilatation synergistically with sympathetic cotransmitters, resulting in a combined vasodilatation that is greater than the sum of the individual contributions (Wilkins et al. 2003). In the context of human ageing, we have previously shown that older subjects have an impaired cotransmitter contribution to cutaneous vasodilatation with significant increases in body core temperature. Instead, the aged rely on an impaired NO-dependent mechanism to increase blood flow to the skin during thermal stress. Our current findings suggest that in aged human skin, the intracellular stores of L-Arg available for NOS and NO-dependent vasodilatation are insufficient to support the full expression of the increase in skin blood flow during hyperthermia. Alternatively, the interventions employed in the present investigation affecting the L-Arg–NO pathway may have capitalized on the synergistic relationship between NO and the cotransmitter(s) mediating reflex cutaneous vasodilatation; by increasing the amount of bioavailable NO in the cutaneous vasculature, the total vasodilatory response of both NO- and non-NO-mediated vasodilatation may have been augmented.
Our data show that the cutaneous vasodilatation in the combined treatment site was not significantly different compared with the arginase-inhibited or L-Arg-supplemented treatments alone, indicating that the effects of the individual treatments were not additive. One potential explanation for this finding is that the individual drug treatments were sufficient to replenish intracellular L-Arg for NO synthesis through NOS, such that the L-Arg–NOS pathway was operating near Vmax. Another possibility is that we maximized the capacity of the cutaneous vessels to vasodilate at this level of hyperthermic stress (1.0°C), approaching a ‘ceiling effect’ with our individual drug treatments, and that increasing the degree of hyperthermic stress may have unmasked further vasodilatation in the combined treatment site.
There are several putative mechanisms affecting the L-Arg–NO pathway and subsequent NO-dependent vasodilatation that may be impaired in aged skin. The most plausible mechanisms directly alter the intracellular availability of L-Arg for NOS and include augmented arginase activity, the subcellular distribution of L-Arg in relation to NOS, and age-related increases in endogenous NOS inhibitors. Additionally, these mechanisms have also been suggested as possible explanations for the L-Arg paradox where the intracellular concentration of L-Arg far exceeds the Km for NOS, but the addition of exogenous L-Arg augments NO-dependent vasodilatation.
Our in vivo findings implicate a role for augmented arginase activity limiting the availability of L-Arg for NOS and subsequent NO-dependent cutaneous vasodilatation in humans. These results are in agreement with in vitro isolated vessel investigations where arginase I is capable of reciprocal regulation of endothelial NOS, and its activity is upregulated in aged vessels (Berkowitz et al. 2003; White et al. 2006). These authors found that pretreatment with arginase inhibitors directly restored NO signalling and L-Arg responsiveness in aged vessels. Similarly, our data also demonstrate that the age-associated decline in cutaneous vasodilatory function was restored by arginase inhibition. However, in contrast to the study by Berkowitz et al. (2003) we were able to induce augmented cutaneous vasodilatation with L-Arg supplementation alone in the absence of concurrent arginase inhibition. These divergent findings may be due to species, tissue, and vascular tree differences, and methodological differences including the dose of L-Arg delivered to the vasculature. Alternatively, another explanation involves the intracellular compartmentalization of L-Arg available for NO synthesis in relation to NOS localization. In young endothelial cells, intracellular L-Arg is sequestered in several pools including (1) a pool associated with the cationic amino acid transporter (CAT) that is freely exchangeable with the extracellular space and associated with calveolar NOS, and (2) a pool in the cytosolic fraction where arginase I is localized that is non-freely exchangeable (McDonald et al. 1997; Flam et al. 2001). Localized cutaneous L-Arg supplementation most probably affected the calveolar associated pool of L-Arg, whereas arginase inhibition probably increased the availability of L-Arg in the cytosolic pool.
Another putative explanation for the L-Arg paradox is the accumulation of endogenous NOS inhibitors. Asymmetric dimethylarginine (ADMA) is the most abundant of the endogenous NOS inhibitors in humans, and both hyperlipidaemia and age-related impairments in microvascular function and subsequent NO bioavailability have been linked to increases in ADMA (Miyazaki et al. 1999; Kielstein et al. 2003). The mechanisms mediating increased ADMA are twofold, and include an increase in its formation and a decrease in degradation via oxidative stress (Fliser, 2005). In vivo human studies have demonstrated that ADMA-mediated NOS inhibition in the forearm circulation is reversible by the administration of L-Arg (Kielstein et al. 2005). In the context of the current study, an increase in endogenous NOS inhibitors in the aged subjects could help explain why cutaneous vasodilatation was significantly augmented with L-Arg supplementation in the absence of arginase inhibition.
Our findings show that direct L-Arg supplementation to the cutaneous vasculature through intradermal microdialysis significantly improves cutaneous vasodilatory function during hyperthermia in aged humans. Other investigations examining the effects of L-Arg supplementation on vasodilatory responsiveness have reported mixed results depending on the dose, duration and route of administration. Consistent with our data, L-Arg infusion into forearm and coronary vascular beds has more consistently demonstrated an increase in NO bioavailability and improved endothelium-dependent vasodilatation (Chauhan et al. 1996; Pernow et al. 2003; Perticone et al. 2005). In contrast, recent evidence from a clinical trail examining the effects of oral L-Arg supplementation (9 mg day–1) on non-invasive measures of resting vascular function (pulse pressure, arterial compliance, pulse wave velocity and arterial elastance) in patients following acute myocardial infarction failed to demonstrate a significant effect of L-Arg treatment (Schulman et al. 2006). These non-specific tests of arterial stiffness during resting conditions may have not been sufficient to observe significant differences between treatment and placebo groups. Both, in vitro and in vivo human data in the forearm circulation suggest that potent vasodilatory stimuli enhance L-Arg transport through CAT-1, significantly increasing NO production (Parnell et al. 2004). In the present study we stimulated the cutaneous microvasculature to induce pronounced vasodilatation through whole-body hyperthermia; in this construct it is feasible that a sufficient vasodilatory stimulus to the vasculature is necessary to observe increased vasodilatation with L-Arg supplementation.
Limitations
Our aim in the present study was to investigate the role of arginase and L-Arg availability in the regulation of cutaneous blood flow during systemic hyperthermia. We chose to use five separate microdialysis treatment sites in each subject during passive whole-body heat stress and compare between sites. Furthermore, our chosen pharmacological treatments specifically target the arginase pathway and are therefore instrumental in studying the interplay between arginase and NO (Cox et al. 1999; Tenu et al. 1999). However, we did not choose to inhibit NOS subsequent to the established plateau in skin blood flow to quantify the NO contribution within each microdialysis treatment site due to the longer duration of whole-body heating and associated increased cardiovascular risk and discomfort for the aged subjects. This additional data would have helped to clarify the pharmacological action of our chosen arginase inhibitors and the synergistic role between NO and cotransmitter-mediated vasodilatation during reflex cutaneous vasodilatation.
Our findings that the aged subjects had attenuated cutaneous vasodilatation in the control site and rely on impaired NO-dependent vasodilatation are consistent with our previous investigations. However, in both the aged and young subjects, we observed systematically attenuated levels of cutaneous vasodilatation (30%CVCmax) with increasing core body temperature in comparison with our previous study (Holowatz et al. 2003). In our previous studies, we induced maximal vasodilatation by infusion of 28 mM SNP, whereas in the present study we induced maximal vasodilatation by both infusion of this dose of SNP and by simultaneously locally heating the skin to 43°C. The most likely explanation for this discrepancy between studies is that we obtained a truer level of maximal vasodilatation with our current protocol, accounting for the consistent difference in cutaneous vascular conductance across age groups. It is likely that our higher maximal CVC values attained in this study account for the lower normalized CVC values.
Summary
In conclusion, this study demonstrated that both arginase inhibition and direct L-Arg supplementation through intradermal microdialysis in the cutaneous vasculature selectively augment reflex cutaneous vasodilatation in aged humans. Moreover, these data suggest that NO bioavailability is decreased in aged skin due to limited L-Arg availability by an age-related upregulation of vascular arginase activity. The age-related impairment in cutaneous vasodilatation during whole-body heat stress can be restored by replenishing the available pool of L-Arg for NO synthesis through NOS.
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P < 0.001, significant versus control site young subject group; 
P < 0.001, significant versus control site older subject group.