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INTEGRATIVE |
The Pennsylvania State University, Noll Laboratory,
1 Department of Kinesiology
2 Graduate Physiology Program, University Park, PA 16802, USA
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Abstract |
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%CVCmax between the control and NOS-I site was calculated as the difference between C and NOS-I sites. Maximal CVC was attenuated in the HTN subjects by 
25% compared with AMN subjects (P < 0.001). Throughout, whole body heating %CVCmax was not different between the groups (HTN, 43 ± 3%CVCmax
versus AMN, 45 ± 3%CVCmax, P > 0.05). NOS-I significantly decreased %CVCmax in both groups but %CVCmax was greater in the HTN group (HTN, 32 ± 4%CVCmax
versus AMN, 23 ± 3%CVCmax, P < 0.05). The %CVCmax between the control and NOS-I sites was attenuated at Tor > 0.5°C in the HTN group (P < 0.001 versus AMN). A-I alone augmented %CVCmax only in the HTN group (HTN, 65 ± 5%CVCmax
versus AMN, 48 ± 3%CVCmax, P < 0.05). L-Arg alone did not affect %CVCmax in either group (HTN, 49 ± 5%CVCmax
versus AMN, 49 ± 3%CVCmax, P > 0.05). Combined A-I +
L-arg augmented %CVCmax in both subject groups compared with their respective control sites (HTN, 60 ± 7%CVCmax
versus AMN, 61 ± 3%CVCmax, both P < 0.05 versus respective control sites). Vasodilatation is attenuated with HTN due to decreased NO-dependent vasodilatation and can be augmented with arginase inhibition but not L-arg supplementation, suggesting that arginase is up-regulated with HTN.
(Received 23 January 2007;
accepted after revision 1 March 2007;
first published online 8 March 2007)
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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Essential hypertension is associated with attenuated cutaneous vasodilatation during local (Carberry et al. 1992) and systemic thermal stress (Kenney et al. 1984). Chronically elevated systemic vascular resistance causes impairments in vasodilatory responses resulting from reduced NO-dependent vasodilatation and structural maladaptations including vascular smooth muscle hypertrophy (Taddei et al. 1998). The incidence of essential hypertension increases with advancing age (AHA, 2006), suggesting that hypertensive pathology-associated decreases in NO bioavailability coupled with healthy age-related deficits in non-NO-dependent mechanisms (Holowatz et al. 2003) may combine to attenuate reflex cutaneous vasodilatation. However, the precise contribution of NO to reflex cutaneous vasodilatation and the involvement of mechanisms limiting NO bioavailability in hypertensive human skin remain unclear.
One potential mechanism limiting NO-dependent vasodilatation with hypertension is the up-regulation of vascular arginase activity. Arginase is constitutively expressed in two isoforms and catalyses the conversion of L-arginine to L-ornithine and urea in the final step of the urea cycle. Furthermore, up-regulated arginase is mechanistically linked to the pathogenesis of vascular dysfunction with hypertension through increases in the polyamine and proline precursor L-ornithine, which contributes to vascular smooth muscle cell proliferation and intimal thickening (Wu & Morris, 1998; Durante et al. 2001, 2006). Arginase is also capable of reciprocally regulating NO synthesis through preferentially utilizing the common NO-synthase substrate L-arginine. In several different animal models of hypertension, inhibition of arginase augments vasodilatory responses to endothelium-dependent agonists through NO-dependent mechanisms (Johnson et al. 2005; Zhang et al. 2004; Demougeot et al. 2005, 2006). Additionally, in aged human skin acute inhibition of arginase augments cutaneous vasodilatation (Holowatz et al. 2006a,b). Taken together, these data suggest that up-regulated arginase activity may limit L-arginine availability for NO synthesis in hypertensive vasculature.
Therefore, the purpose of this study was to determine the role of arginase in reflex cutaneous vasodilatation in an unmedicated essential hypertensive subject sample. Since arginase is up-regulated in the skin with primary human ageing (65–85 years) (Holowatz et al. 2006b), we sought to control for this by investigating the role of arginase in reflex vasodilatation in an age- and sex-matched healthy control group. We hypothesized that (1) reflex vasodilatation in hypertensive subjects would be attenuated due to a reduced NO contribution and (2) acute arginase inhibition alone or with concurrent L-arginine supplementation would significantly augment reflex vasodilatation in hypertensive skin while only modestly increasing reflex vasodilatation in the age-matched control group.
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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 nine age- and sex-matched control subjects (57 ± 3 years, 6 men, 3 women) and eight unmedicated subjects with essential hypertension (57 ± 4 years, 6 men, 2 women). Each subject reported to the laboratory on three separate occasions at least 1 week apart for blood pressure measurements via brachial auscultation with a mercury sphygmomanometer before experimental protocols were performed. During each blood pressure measurement visit the subject sat quietly with their feet on the floor and underwent three serial blood pressure measurements with 5 min between readings. Subjects were considered hypertensive if two of the three measurements during each visit was greater than 140/90 mmHg. After determining the subject's blood pressure status each subject underwent a complete medical screening, including blood chemistry, lipid profile evaluation (Quest Diagnostics Nichol Institute, Chantily, VA, USA), resting electrocardiogram, and physical examination. All subjects were screened for the presence of cardiovascular disease other than hypertension, dermatological, and neurological disease. Subjects were normally active, non-diabetic, healthy non-smokers who were currently not taking medications, including aspirin therapy, hormone replacement therapy or oral contraceptives. All premenopausal female subjects were studied on days 2–7 of the follicular phase of their menstrual cycle.
Instrumentation and measurements
All protocols were performed in a thermoneutral laboratory with the subject in the semi-supine position with the experimental arm at heart level. Upon arrival at the laboratory, 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, IN, USA) 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 (MAP).
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 thermistor placed in the sublingual sulcus as an index of body core temperature. The subjects were instructed to keep the thermistor 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 from 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 body temperature. During whole body heating, 50°C water was perfused through the suit to raise subject's Tor 1.0°C above baseline body temperature. Local skin temperature over each microdialysis site was maintained at 33°C during baseline and whole body heating (SH02, Moor Instruments).
Experimental protocol
RBC flux over each microdialysis site was monitored during the insertion trauma resolution period (60–90 min). Following this period, microdialysis sites were randomly assigned to receive: (1) 10.0 mM
NG.-nitro-L-arginine (L-NAME) to inhibit NO production by NO-synthase (Kellogg et al. 1999; Minson et al. 2002; Holowatz et al. 2005); (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 (Holowatz et al. 2006b) (Calbiochem, San Diego, CA, USA); (3) 10.0 mM L-arginine (Sigma) to supplement the substrate for NO-synthase and arginase (Holowatz et al. 2006b); or (4) 5.0 mM BEC + 5.0 mM nor-NOHA + 10.0 mM L-arginine to inhibit arginase and supplement the substrate for NO-synthase and arginase. A fifth microdialysis site was perfused with only lactated Ringer solution to serve as control. All pharmacological solutions were mixed just prior to usage, dissolved in lactated Ringer solution, and sterilized using syringe microfilters (Acrodisc, Pall, Ann Arbor, MI, USA).
A cocktail of arginase inhibitors was used to ensure that both isoforms of arginase that are present in human skin were adequately inhibited. Neither nor-NOHA nor BEC inhibit NOS, making them beneficial for the study of arginase NOS interactions (Tenu et al. 1999; Colleluori & Ash, 2001). Additionally, the binding characteristics of this cocktail of inhibitors is ideal for quick-onset, long-lasting acute arginase inhibition (Colleluori & Ash, 2001). BEC is a slow-binding, long-lasting, competitive inhibitor of arginase I and II (Cox et al. 1999), while nor-NOHA is a quick-acting, potent, non-specific arginase inhibitor (Tenu et al. 1999). Additionally, extensive pilot work was conducted to ensure that the concentrations of arginase inhibitors maximally inhibited the arginase pathway. Briefly, varying concentrations (0.1, 1.0, 2.5, 5.0 and 10.0 mM) of each BEC + nor-NOHA were delivered to different skin microdialysis sites during a standardized local heating protocol described elsewhere (Minson et al. 2001). Increasing concentrations above 2.5 mM BEC + 2.5 mM nor-NOHA did not further increase the NO-dependent plateau phase of the local heating response.
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 over each microdialysis site simultaneously with SNP infusion to ensure maximal CVC had been obtained.
Data acquisition and analysis
Data were acquired using Labview software and 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). Absolute maximal CVC in each microdialysis site was calculated as the average of the stable plateau in laser-Doppler flux during 28 mM SNP infusion and local heating to 43°C divided by mean arterial pressure. The CVC (%maximal) between the control site and the NO-synthase-inhibited site was calculated at every 0.1°C rise in body core temperature.
Student's unpaired t tests were used to determine significant differences between the groups for physical characteristics. Two-way repeated measures analysis of variance (ANOVA) was conducted to detect (1) differences due to blood pressure and pharmacological treatment on maximal CVC and (2) differences due to blood pressure on the %CVCmax between the control and the NO-synthase-inhibited sites for every 0.1°C rise in Tor. A mixed models three-way repeated measures ANOVA was conducted to detect differences in %CVCmax between subject groups at the pharmacological treatment sites over the rise in Tor (SAS, version 8.01). 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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Tor > 0.7°C (P < 0.05) compared with the normotensive group. In the normotensive group, arginase inhibition did not change %CVCmax compared with the control site. In contrast, arginase inhibition significantly increased %CVCmax compared with the control site in the hypertensive group at Tor > 0.6°C (Fig. 1A). There were no significant differences between the control site and the L-arginine-supplemented site in either subject group with the rise in Tor (Fig. 1B: P > 0.05). Combined arginase inhibition +
L-arg significantly increased %CVCmax compared with control sites in both subject groups starting at Tor > 0.2°C in the normotensive and Tor > 0.4°C in the hypertensive group, respectively (Fig. 1C: both P < 0.05).
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%CVCmax between the control site and the NO-synthase inhibited site across the rise in body core temperature to illustrate the relative NO contribution to reflex cutaneous vasodilatation. The %CVCmax was attenuated in the hypertensive group with Tor > 0.5°C compared with the normotensive group (P < 0.001).
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Discussion |
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Tor > 0.2°C. These findings suggest that arginase is up-regulated in the skin of hypertensive subjects and contributes to reduced NO-dependent vasodilatation by limiting intracellular L-arginine availability of NO synthesis. Since direct L-arginine supplementation in hypertensive skin failed to result in an increase in cutaneous vasodilatation, these data suggest that either (1) freely exchangeable extracellular L-arginine does not limit NO synthesis, (2) there is diminished transport of L-arginine through the cationic amino acid transporter (CAT), or (3) caveolar NO-synthase activity associated with the CAT is decreased in hypertensive skin.
Our results confirm earlier reports that hypertensive humans have attenuated reflex vasodilatation during systemic hyperthermia. While there were no significant differences between the groups in the control site when data are expressed as a percentage of maximal CVC, the hypertensive group exhibited reduced absolute maximal CVC. Therefore, reflex cutaneous vasodilation is attenuated in the hypertensive group but this reduction is masked when data are normalization to a percentage of maximal vasodilatation. Due to capillary density and site-to-site variability in raw laser-Doppler flux measurements (Braverman et al. 1990), we chose to represent the data as a percentage of maximal CVC. Using a different experimental protocol to induce hyperthermia, we have previously demonstrated that unmedicated humans with essential hypertension have attenuated skin blood flow (Kenney et al. 1984). However, similar to the present study, others (Kellogg et al. 1998b) have failed to demonstrate attenuated reflex vasodilatation during passive heat stress when data are represented as a percentage of maximal CVC, but have shown reduced maximal CVC during whole arm local heating with laser-Doppler and forearm blood flow measurements (Carberry et al. 1992). Similar reductions in absolute maximal CVC (20–25%) are observed in other disease states associated with microvascular dysfunction, such as type II diabetes (Wick et al. 2006; Sokolnicki et al. 2007). Collectively, our data show that reflex vasodilatation is attenuated in humans with essential hypertension due to impairments in vascular signalling. Moreover, the reduction in maximal CVC probably reflects additional structural alterations in the cutaneous vasculature that limit absolute vasodilator capacity
Our data show that there is an attenuated reduction in %CVCmax with NO-synthase inhibition (Figs 1 and 2) and that the %CVCmax between the control site and the NO-synthase inhibited site is reduced (Fig. 3) in hypertensive subjects. Hence, cutaneous NO-dependent vasodilatation is reduced in humans with hypertension. There are several putative mechanisms that may contribute to decreased NO production in hypertensive skin including (1) up-regulated arginase activity, and (2) decreased L-arginine availability in relation to intracellular NO-synthase localization.
Our findings implicate a role for up-regulated vascular arginase in limiting cutaneous vasodilatation in humans with established essential hypertension. Arginase is also up-regulated with ageing-related endothelial dysfunction (Berkowitz et al. 2003). In aged human skin, arginase inhibition also augments reflex cutaneous vasodilatation (Holowatz et al. 2006b); however, the precise stimulus mediating the up-regulation of vascular arginase with either ageing or hypertension is unknown. It is likely that there are several inducers of arginase expression and/or agents that modify arginase activity that are unique to the vascular diseased state whether it is ageing or hypertension. Recently, up-regulated expression and activity of vascular arginase has been observed prior to the onset and throughout the development of hypertension in the spontaneously hypertensive rat (SHR) model, implicating arginase in the pathogenesis of essential hypertension. Further, pharmacologically preventing the rise in blood pressure blunted arginase up-regulation, suggesting that increased haemodynamic forces act as an inducer of arginase expression (Demougeot et al. 2006). However, increased haemodynamic forces alone did not fully explain the hypertension-associated increase in vascular arginase expression.
In addition to haemodynamic forces mediating the up-regulation of arginase, there is another recently discovered mechanism that stimulates arginase activation. In cultured endothelial cells, arginase is activated by dissociation from the microtubule cytoskeleton (Ryoo et al. 2006). There are several mediators capable of causing microtubule disruption with hypertension including activation of the small GTPase, Rho kinase. Rho kinase also modulates Ca2+ sensitivity in vascular smooth muscle and is capable of down-regulating NO-synthase (Ming et al. 2002; Wettschureck & Offermanns, 2002) and arginase (Ming et al. 2004) expression and activity. Further, Rho kinase is known to be up-regulated with human essential hypertension (Masumoto et al. 2001). In relation to human cutaneous vasculature, we have recently found that Rho kinase mediates cutaneous vasoconstriction (Thompson-Torgerson et al. 2006). Collectively, these data point to a potential mechanism for activation of arginase through Rho kinase-mediated disruption of the microtubule cytoskeleton.
In the present study we found that although NO-dependent vasodilatation is attenuated in hypertensive human skin, exogenous L-arginine supplementation directly to the cutaneous vasculature through intradermal microdialysis did not significantly alter the %CVCmax during whole body heating. One potential explanation for this finding is that the dose of L-arginine delivered to the cutaneous vasculature through intradermal microdialysis may have been insufficient to observe an increase in skin blood flow during hyperthermia. However, the dose of L-arginine per gram of tissue delivered through intradermal microdialysis was comparable, or greater than, what is commonly administered during whole-limb arterial infusion studies (Taddei et al. 1997). Additionally, we have previously used this dose of L-arginine using the same experimental techniques and we observed augmented cutaneous vasodilatation in a healthy aged population (Holowatz et al. 2006b). In the present study we also observed a significant effect of L-arginine treatment when added to arginase inhibition in the normotensive control group suggesting that the dose of L-arginine delivered through the microdialysis fibre was efficacious. Thus, although it is possible, it is unlikely that higher doses of L-arginine would have produced different results.
A more likely explanation for the inability of exogenous L-arginine supplementation to augment cutaneous vasodilatation involves the CAT transporters and the cellular localization of microdomains of L-arginine accessible to NO-synthase. There are at least three potential microdomains of L-arginine including: (1) a domain that is associated with the CAT that is freely exchangeable with the extracellular space and associated with caveolar NO-synthase, (2) a domain in the cytosolic fraction where arginase is localized when activated that is non-freely exchangeable (Topal et al. 2006), and (3) an intracellular domain consisting of L-arginine synthesized from conversion of L-citrulline through argininosuccinate synthase (McDonald et al. 1997; Flam et al. 2001; Huynh & Chin-Dusting, 2006; Ryoo et al. 2006). In our experimental design, localized cutaneous L-arg supplementation most probably affected the freely exchangeable microdomain of L-arginine whereas arginase inhibition probably increased the availability of L-arginine in the cytosolic microdomain not associated with the CAT. Our results indicate that either the concentration of L-arginine in the freely exchangeable pool is sufficient to support NO production through caveolar-associated NO-synthase, although caveolar-associated NO-synthase may be decreased with hypertension (Forstermann & Munzel, 2006), and/or that L-arginine transport through the CAT is impaired with hypertension. Radiotracer studies in the human forearm muscle circulation have demonstrated that subjects with essential hypertension, and those genetically predisposed to hypertension, have impaired L-arginine transport through the CAT (Schlaich et al. 2004). Future investigations in the cutaneous circulation measuring NO-synthase expression and activity, and L-arginine transport through the CAT are necessary to resolve these questions.
In the age-matched normotensive subject group, we found that although arginase inhibition or L-arginine supplementation did not affect cutaneous vasodilatation independently, the combination of these treatments significantly augmented vasodilatation with relatively small increases in body core temperature (Tor > 0.2°C). In middle-aged subjects L-arginine availability appears sufficient to support full expression of reflex vasodilatation. Therefore, it was unexpected that combined L-arginine supplementation and arginase inhibition would augment cutaneous vasodilatation. These data suggest that it takes a robust increase in L-arginine in potentially multiple microdomains to augment cutaneous vasodilatation in middle-aged humans. In contrast, we have previously reported that these combined treatments did not result in a further increase in skin blood flow greater than the individual treatments in healthy aged skin (65–85 years) (Holowatz et al. 2006b). However, the subjects from the previous ageing study were significantly older and had a greater attenuation in skin blood flow under control conditions compared with the age-matched normtensive subjects from the present study. In addition to age-related decreases in L-arginine availability, another possible explanation for this difference is that there is greater vasodilatory reserve in subjects of advanced age.
Our present data show that middle-aged normotensive subjects rely heavily on NO-dependent mechanisms to increase skin blood flow during hyperthermia. In young healthy human subjects, NO contributes approximately 30–40% to the total reflex cutaneous vasodilatory response (Kellogg et al. 1998a; Shastry et al. 1998). Subjects of more advanced age display an impaired co-transmitter contribution to reflex vasodilatation and also rely heavily on NO-dependent mechanisms to increase skin blood flow. Similar to subjects of advanced age, our data show that deficits in co-transmitter contribution are evident in healthy middle-aged skin.
Limitations
We performed extensive pilot work to determine the dosage of the arginase inhibitors we utilized in the present study. The concentration that we delivered through the microdialysis fibre was significantly greater than the highest dose commonly used in in vitro preparations (5 x 10–3 M versus 10 x 10–5 M) that maximally inhibit the arginase pathway (Berkowitz et al. 2003). Because of the inherent uncertainly of the concentration of the inhibitor delivered through the microdialysis fibre that reaches the intradermal space, we chose in increase the concentration of arginase inhibitors to ensure that an efficacious dose would be administered. The results of our pilot testing suggest that the arginase pathway was fully inhibited at concentrations greater than 2.5 x 10–3 M, but there is the possibility that the arginase pathway was not completely inhibited with the concentrations utilized in this investigation.
We did not directly show that the interventions employed in this study augmented cutaneous vasodilatation via NO-dependent mechanisms. However, our chosen pharmacological treatments specifically targeted the arginase–L-arginine–NO pathway (Cox et al. 1999; Tenu et al. 1999). Although we did not quantify the NO contribution within each microdialysis treatment site, we did evaluate the time course of the interventions. Additional data from NO-synthase inhibition during the plateau phase of the rise in skin blood flow would have helped to clarify the pharmacological action of our chosen arginase inhibitors.
Summary
In summary, humans with essential hypertension exhibit attenuated reflex cutaneous vasodilatation due to a reduced NO-dependent vasodilatation. Acute arginase inhibition but not L-arginine supplementation augmented reflex vasodilatation in hypertensive skin. These data suggest that arginase is up-regulated in hypertensive vasculature and that L-arginine supplementation alone is insufficient to augment cutaneous vasodilatation suggesting either (1) L-arginine concentrations in the freely exchangeable microdomain are sufficient to support NO production through the available NO-synthase, or (2) the CAT is dysfunctional and limits L-arginine transport into the cell with hypertensive pathology. Finally, in aged-matched normotensive control subjects L-arginine supplementation or arginase inhibition individually did not alter the skin blood flow response during hyperthermia but a combination of these two treatments significantly augmented reflex vasodilatation.
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) and nitric oxide synthase (NOS)-inhibited site (
). B shows the L-arginine (L-arg) supplemented site (
). C shows the combined L-arg + arginase-inhibited site (
). CVC (%maximal) during the rise in oral temperature (
) is illustrated in all of the panels for comparison. Arginase inhibition and combined arginase inhibition +
L-arg supplementation augmented %CVCmax in essential hypertensive subjects. Arginase inhibition +
L-arg supplementation combined but not the individual treatments augmented CVC in the age-matched normotensive subjects. *P < 0.05 significant difference versus the control site within subject groups.
P < 0.001 significant versus control site hypertensive group, 
P < 0.001 significant versus control site age-matched normotensive group.
