Gen. Pharmac. Vol. 24, No. 3, pp. 531-537, 1993 Printed in Great Britain. All rights reserved
0306-3623/93 $24,00 + 0.00 Copyright © 1993 Pergamon Press Ltd
MINIREVIEW R E G U L A T I O N OF V A S C U L A R S M O O T H M U S C L E C O N T R A C T I O N BY E X T R A C E L L U L A R N a ÷ ROBERT M. RAPOPORT Veterans Affairs Medical Center and the Department of Pharmacology and Cell Biophysics, University of Cincinnati, College of Medicine, Cincinnati, OH 45267-0575, U.S.A. [Tel. (513) 558-2376; Fax (513) 558-1169] (Received 8 January 1993) Abstract--l. The effects of extracellular Na + removal on agonist-induced contraction of vascular smooth muscle/n vitro are reviewed. 2. The effects of extracellular Na + removal on contraction vary depending upon the agonist and vessel. 3. Factors that may influence the effects of extracellular Na + removal on agonist-induced contraction include the compound substituted for Na +, time of tissue exposure to lowered extracellular Na +, concentration of extracellular Na +, agonist concentration, presence of the vascular endothelium and presence of basal tone. 4. The potential influence of these factors needs to be determined and minimized, in studies that investigate the role of extracellular Na + in agonist-induced contraction.
that tested the effects of extracellular Na + removal on agonist-induced contraction of vascular smooth muscle. Secondly, the review identifies several factors that may obscure the role of Na÷-dependent processes in the regulation of agonist-induced contraction following lowering of the extracellular Na ÷ concentration. These factors need to be controlled for in studies that utilize removal of extracellular Na ÷ as a tool to investigate Na÷-dependent processes in the regulation of agonist-induced contraction.
There are numerous mechanisms whereby extracellular Na + may regulate vascular smooth muscle contraction. These mechanisms include Na+-dependent exchange processes, such as Na +/H ÷, Na ÷- Ca 2÷ and Na÷-dependent CI-/HCO 3- exchange, as well as sarcolemmal channels that regulate Na ÷ influx. The functional role of many of these processes in the regulation of agonist-induced contraction of vascular smooth muscle is not clear. One experimental approach widely taken to elucidate the functional role of these processes in the regulation of smooth muscle contraction has been to expose the isolated vascular tissue to lowered concentrations of extracellular Na +. This approach, however, has yielded varied results. The reasons for these varied results likely relate, in some way, to the different functional roles of the Na ÷- dependent processes in the regulation of smooth muscle contraction. However, additional effects of lowered extracellular Na +, that are not directly related to the effects of the Na+-dependent processes on agonist-induced contraction, may obscure the role of these processes in the regulation of contraction. The purpose of this review is two-fold. First, it is the intention that this review serve as a springboard for future studies that investigate the role of Na +dependent processes in the regulation of agonistinduced contraction of vascular smooth muscle through exposure of isolated vascular tissue to lowered extracellular Na ÷ concentrations. To this purpose, the review summarizes reports in the literature GP
REGULATION OF VASCULAR SMOOTH MUSCLE CONTRACTION BY EXTRACELLULAR N a +
dgonist It is clear that agonists may utilize different signal transduction pathways to greater or lesser extents to elicit contraction. It would not be surprising, therefore, to expect that extracellular Na ÷ removal differentially effects contraction induced by different agonists (Table 1). Hinke and Wilson (1962) demonstrated that Na + substituted with sucrose was without effect on contractions of the rat tail artery to norepinephrine and epinephrine, while contractions to angiotensin II and vasopressin were decreased. Others demonstrated that Na + substitution with sucrose potentiated contractions of the rabbit coelic and mesenteric arteries to epinephrine and angiotensin II, while contractions to KCI remained unaltered (Novelli et al., 1983). Araki et aL (1975) demonstrated using the rabbit pulmonary artery that substitution of Na ÷ with Li + inhibited contractions 531
ROBERT M. RAPOPORT Table 1. Effect of extracellular Na + on agonist-induced contraction [Na+]cxt Na + (mM) substitute
Time in Na + substitute (rain)
,[, 1' (%) or N.C.
1.2 6 24 36 95 6 24 36 95
NMDG Li + Li + Li + Li ÷ Sucrose Sucrose Sucrose Sucrose
15 15 15 15 15 15 15 15 15
KCI NE NE NE NE NE NE NE NE
40raM 0.5/aM 0.5/aM 0.5/aM 0.5/aM 0.5/aM 0.5/aM 0.5/aM 0.5/aM
43T 13,[ I1,[ 5,[ N.C. 43,[ 18`[ 55 N.C.
Salvaterra (1989) DeMey and Vanhoutte (1980)
80 80 2 0
Tris Tris 3 Li + Sucrose
60 15 184 55
Epi Epi Epi Epi
0.23/aM 0.23/aM 4.6ng 4 9.1 ng4
50,[ 79,[ 38`[ 68,[
Sitrin and Bohr (1971)
10/aM 5 mM
~85 37 37 0 0 0 0 0 0 0 0 0 0 0 0 71.5 0 80
Sucrose Sucrose Choline Sucrose Sucrose Sucrose Choline Choline Choline Li ÷ Tris Sucrose Li + Tris Sucrose Sucrose Li + Sucrose Sucrose Sucrose Li + Choline 3 TMA 3 Choline Choline 3 NMDG NMDG Li + Choline Li + Li ÷ Sucrose Sucrose Sucrose Li + Li + Li + Li +3
20 60 60 150 150 150 150 150 150 5 5 5 5 5 5 18 0.5 60 60 60 20-30 N.R. N.R. 15 25 N.R. 30-120 30-120 30-120 20-30 0.5 60 60 60 40 40 40 40
Li + Choline Tris Mannitol Urea Sucrose Li + NMDG NMDG NMDG Li + Choline
N.R. N.R. 30 30 30 30 30 15 151 15 ~ 90 90
19 0 0 6 6 79.9 25 25 25 19 0 80
25 25 84 84 84 84 84 30 2 0 20 20
Waugh et al. (1962)
Itoh et al. (1981)
Richards et al. (1989)
Woolfson et al. (1990)
Epi Epi Epi Epi Hist ACh Epi Hist ACh KCI KCI KCI NE NE NE NE NE Epi Angll KCI ACh Hist Hist NE NE NE NE NE NE NE NE Epi Angll KCI NE Ba 2+ KCI Ca 2+
9nM 15/aM 15 # M 30#M 326pM 4.4 mM 30 # M 326/aM 4.4 mM N.R. N.R. N.R. 0.01-1/aM 0.01-1/aM 0.01-1/aM 0.78/aM 0.05#M 0.15/aM 0.05/aM 36 mM 0.01-10/aM 10/aM 10/aM 1/ag4 1/ag4 1/aM I/aM I/aM 1/aM 0.01-4).1/aM 0.01/aM 0.15/aM 0.05/aM 36 mM 0.1/aM 0.2mM 2 mM N.R.
50T N.C. N.C. 100,[ 100,[ 100,[ 100,[ 100,[ 100j, N.C. TI T~ 50,[2 160T2 T~ N.C. 20T 29T 22 T N.C. 18,[ 13,[ 20,[ 8,[ 20,[ N.C. N.C. N.C. 69,[ N.C. 2 50T 32T 15T N.C. 29,[ 31,[ N.C. 100~,
Bohr et al. (1958) Briggs and Melvin (1961)
0.3/aM 0.3/aM 1-100 mM 1-100 mM 1-100 mM 1-100 mM 1-100 mM 5 mM 10/aM 10/aM 1/aM I/aM
N.C. N.C. 25~ 2 60~2 10T2 45T 2 75Tz5 100T 15,[ 20J, 20], 20,~
Ando et al. (1991)
NE NE KCI KCI KCI KCI KCI Caf Phe Phe NE NE
Dodd and Daniel (1960)
Karaki and Urakawa (1977)
Nash et al. (1965) Bohr et aL (1969) Novelli et al. (1983)
Foley (1984) Droogmans and Casteels (1979) Hiraoka et al. (1968) Bevan et al. (1990) Bevan and Joyce (1990)
Foley (1984) Bohr et al. (1969) Novelli et al. (1983)
Araki et al. (1975)
Altura et aL (1990)
Ashida and Blaustein (1987a) Reynolds et al. (1988) Schoeffter and Miller (1986) --continued
Na + and vascular smooth muscle contraction Table l--Continued
Time in Na + [Na+}e~t Na + substitute (mM) substitute (min) Agonist
,L, T (%) or N.C.
25 Choline 2 NE 2/~M 80J, Mulvany et aL (1984) 25 Choline 2 KCI 30 mM 50T 25 Sucrose 2 NE 2#M 80J, 25 Sucrose 2 KCI 30 mM 50T Tail 72 Sucrose N,R. NE 1.6/~M N.C. Hinke and Wilson (1962) 72 Sucrose N.R. Epi 0.5/JM N.C. 72 Sucrose N.R. Angll 0.3/~g/ml ~l 72 Sucrose N,R. Vaso 2.5 mU/ml ,~ 26 Sucrose N.R. NE 1.6/~M N.C. 72 Li+ N.R. NE 1.6~M Tt 26 Li+ N.R. NE 1.6 gM T~ 95 Choline N.R. NE 1.6 ,uM TI 72 Choline N.R. NE 1.6/tM Tj 26 Choline N.R. NE 1.6/tM TI ~Values necessary for quantitation not reported. 2Approximated from EC~0. 3Also in Ca2+-free or low Ca2+ solution. 4Bolus. 5Maximal response decreased. NE, norepinephrine; Epi, epinephrine; Angll, angiotensin II; Hist, histamine; ACh, acetyleholine; Caf. caffeine; Endo, endothelin; Vaso, vasopressin; N.C., no change; N.R., not reported.
to n o r e p i n e p h r i n e , Ba 2+ a n d Ca 2+, while KCI contractions r e m a i n e d unaltered. C o n t r a c t i o n s o f rat mesenteric resistance vessels to n o r e p i n e p h r i n e were decreased, a n d to KC1 were increased, following exposure to solution in which N a + was substituted for choline or sucrose ( M u l v a n y et al., 1984). A l t h o u g h n u m e r o u s additional c o m p a r i s o n s can be m a d e between the different studies listed in Table 1, caution should be used in m a k i n g these comparisons, since experimental conditions vary. Vessel It is expected t h a t the role o f N a + - d e p e n d e n t processes in the regulation o f c o n t r a c t i o n varies with different vessels. It would be predicted, therefore, t h a t the effect o f lowered extracellular N a + o n agonist-induced c o n t r a c t i o n also varies with different vessels (Table 1). Only two investigations have, thus far, investigated the effects o f extracellular N a + removal o n agonist-induced c o n t r a c t i o n in different vessels. B o h r et al. (1969) d e m o n s t r a t e d t h a t norepinephrineinduced c o n t r a c t i o n s o f the r a b b i t mesenteric artery were p o t e n t i a t e d to a greater m a g n i t u d e t h a n those o f the r a b b i t a o r t a 0.5 m i n following complete substit u t i o n o f N a + with Li +. In contrast, c o n t r a c t i o n s o f the r a b b i t coeliac a n d mesenteric arteries to epinephrine a n d angiotensin II were p o t e n t i a t e d to similar m a g n i t u d e s following removal o f extracellular N a + a n d substitution with sucrose (Novelli et al., 1983). Again, a l t h o u g h n u m e r o u s c o m p a r i s o n s o f the effects of extraceilular N a + removal can be m a d e between the studies listed in Table 1, the n u m b e r o f variabilities, including N a + substitute, exposure time to lowered extracellular solution, c o n c e n t r a t i o n o f extracellular N a + a n d the presence or absence o f basal tone, m a k e such c o m p a r i s o n s difficult.
EXPERIMENTAL CONDITIONS THAT MAY INFLUENCE AGONIST-INDUCED CONTRACTION IN LOWERED EXTRACELLULAR N a + C o m p o u n d substituted f o r N a + N u m e r o u s c o m p o u n d s have been used as substitutes for N a + (Table 1). These include isoosmotic substitutes, such as sucrose, m a n n i t o l a n d urea, a n d cationic substitutes, such as N-methyl-D-glucamine + (NMDG), Li +, Tris +, t e t r a m e t h y l a m m o n i u m + ( T M A ) a n d choline +. T h e c o m p o u n d substituted for N a + has a clear impact on the agonist-induced contraction. K a r a k i a n d U r a k a w a (1977) d e m o n s t r a t e d t h a t complete substitution of Li + for N a + inhibited contractions o f the r a b b i t a o r t a to norepinephrine, while contractions were p o t e n t i a t e d when Tris or sucrose were used as substitutes. Using bovine femoral artery, substitution of N a + with sucrose inhibited n o r e p i n e p h r i n e - i n d u c e d c o n t r a c t i o n s to a greater m a g n i t u d e t h a n substitution with Li + ( D e M e y a n d V a n h o u t t e , 1980). Bevan a n d Joyce (1990) also showed t h a t N a + substitution with choline + , but n o t with N M D G or Li +, inhibited norepinephrineinduced c o n t r a c t i o n o f r a b b i t ear resistance vessels. The sensitivity of the rat a o r t a to KC! decreased w h e n Tris or m a n n i t o l were substituted for N a ÷, while the sensitivity was increased w h e n urea, sucrose or Li ÷ were substituted (Altura et aL, 1990). In this latter study, however, only N a + substitution with Li + inhibited the m a x i m a l contractile response to KC1 (Altura et al., 1990). Others d e m o n s t r a t e d t h a t while removal o f extracellular N a + a n d replacement with T M A or choline caused similar magnitudes of inhibition o f the histamine-induced transient c o n t r a c t i o n o f the r a b b i t ear artery elicited in C a 2+-free solution, the rate o f relaxation o f the transient histamine
contraction was significantly less in choline containing solution as compared to TMA or normal Na ÷ containing solution (Droogmans and Casteels, 1979). Clearly, the compounds substituted for Na ÷ exert differential effects on the signal transduction pathways utilized by the various agonists to elicit contraction. T i m e o f tissue e x p o s u r e to lowered extracellular N a ÷ solution
Another variable that may come into play in the determination of the effects of lowered extracellular Na + on agonist-induced contraction is the time of tissue exposure to the lowered extracellular Na ÷ solution. Itoh et al. (1981), using the guinea pig mesenteric artery, demonstrated that 20 min following exposure to Na+-free solution containing choline the contractile response to norepinephrine was increased 2-fold, while after 30 min the response was somewhat less, at 1.7-fold. A greater effect of time of exposure to lowered extracellular Na ÷ was observed by Araki et al. (1975), who demonstrated potentiation of the contractile responses of the rabbit pulmonary artery to KCI, norepinephrine, Ba2+ and Ca ~÷ immediately (actual time not reported) following Na ÷ removal and replacement with Li ÷ , and inhibition of the contractile responses 30 or 40 min following Na ÷ removal. Nash et aL (1965) also observed a potentiation of the contractile response of the rabbit aorta to norepinephrine in solution containing 0.08 mM Ca 2÷ 1 min following Na + replacement with sucrose, while no effect on norepinephrine contraction was observed after 18 min. In potential contrast, the contractile response of the rabbit ear artery to norepinephrine in the absence of extracellular Ca 2÷ was decreased approx. 60 and 20%, 5 and 25 min respectively, following replacement of extracellular Na ÷ with choline (Hiraoka et al., 1968). Dodd and Daniel (1960) demonstrated that the contractile response of the rabbit aorta to epinephrine, histamine and acetylcholine decreased over a 150min period following Na + replacement with sucrose or choline. Thus, it appears that numerous factors come into play at different times following exposure to Na+-free solution. To add to this complication, the factors, and the magnitudes of the effects of the factors, may depend on the Na ÷ substitute. Concentration o f extracellular N a +
The effects of different concentrations of extracellular Na + on agonist-induced responses have not been studied in detail. Presumably, different processes will be affected to various magnitudes depending on the Na + concentration. Furthermore, these processes will likely influence the contractile event to different
magnitudes depending upon the vessel. DeMey and Vanhoutte (1980) reported that removal of extracellular Na ÷ and substitution with Li ÷ or sucrose inhibited norepinephrine-induced contractions of the bovine femoral artery in a concentration-dependent manner. Additional studies on the effects of different extracellular Na ÷ concentration on agonist-induced contractions are required to more fully examine this variable. A g o n i s t concentration
An additional parameter that may contribute to some of the variable effects of extracellular Na ÷ removal on agonist-induced contraction is that, in many instance, complete concentration-response curves were not performed. Karaki and Urakawa (1977), using rabbit aorta, and DeMey and Vanhoutte (1980), using bovine femoral artery, demonstrated that contractions to lower norepinephrine and/or KCI concentrations were inhibited to greater magnitudes than contractions to higher concentrations of these agonists following substitution of extracellular Na ÷. Nash et al. (1965) demonstrated that the potentiation of the contractile response of the rabbit aorta to norepinephrine 1 min following removal of extracellular Na ÷ was not observed at a high norepinephrine concentration. Thus, experiments that investigated the effects of lowered extracellular Na ÷ on agonist-induced contraction, but tested only relatively low or high agonist concentrations, may overestimate and underestimate, respectively, the effects of lowered extracellular Na +. Endothelium
The presence of the endothelium may influence the effects of extracellular Na + removal on agonistinduced contraction since it is known that removal of extracellular Na + inhibits agonist-induced endothelium-dependent relaxation (DeMey and Vanhoutte, 1980; Schoeffter and Miller, 1986; Ando et al., 1991), and that agents and procedures that inhibit endothelium-dependent relaxation potentiate the contractile response mediated through activation of numerous receptors (Carrier and White, 1985; Martin et al., 1986). Indeed, the endothelium was present in the blood vessels used in several of the studies listed in Table 1 that investigated the effects of removal of extracellular Na + (DeMey and Vanhoutte, 1980; Schoeffter and Miller, 1986; Reynolds et al., 1988; Ando et al., 1991). Furthermore, in the remaining investigations listed in Table 1, no attempt was made to remove the endothelium, although some of the endothelium may have been incidently removed during preparation of the vessel for study.
Na + and vascular smooth muscle contraction
The characteristics of the tone induced by lowered extracellular Na ÷ can be quite different (Table 2). In rabbit ear resistance arteries, lowered extracellular
Na ÷ and substitution with N M D G or Li ÷ induced an immediate phasic contraction, while substitution with choline induced a tonic contraction (Bevan and Joyce, 1990). A phasic followed by a tonic contraction was observed in the guinea pig aorta following
Table 2. Effect of extracellular N a + on basal tone Tone observed when sympathetic blockade is Species
Na + substitute
NMDG TMA Tris
N.R. N.R. N.R.
Yes Yes Yes
Ashida and Blaustein (1987a,b)
Choline Choline Sucrose Choline Choline Sucrose Li ÷ Choline
Yes Yes Yes Yes Yes Yes No Yes
Yes N.R. Yes N.R. Yes N.R. N.R. N.R.
Toda (1978) Toda (1978) Maseki et al. (1990) Toda (1978) Toda (1978) Briggs and Melvin (1961)
Li + Sucrose Choline Choline Sucrose
N.R. N.R. N.R. Yes Yes
Yes Yes Yes NR. N.R.
Ozaki and Orakawa (1981)
Renal Guinea pig
Itoh et al. (1981)
Subcutaneous resistance Cerebral
Woolfson et al. (1990) Toda (1978)
Choline Li ÷
Rembold et al. (1992)
Choline Li + Sucrose Choline Sucrose Choline Li + Tris Sucrose Li + Choline Sucrose Choline TMA NMDG Li + Choline Li + Li + Choline Sucrose
Yes Yes Yes Yes Yes Variable Yes Yes Yes Yes Yes Yes N.R. N.R. Yes Yes Yes Yes Yes Yes Yes
N.R. N.R. N.R. N.R. N.R. N.R. No Yes Yes N.R. N.R. N.R. Yes Yes N.R. N.R. N.R. N.R. N.R. N.R. N.R.
Tris Mannitol Urea Sucrose Li ÷ Choline NMDG Tris TMA Li ÷ Choline Sucrose Tris Choline Sucrose Li + Choline
No No No No No Yes N.R. N.R. N.R. N.R. N.R. N.R. Yes Yes No No Yes
N.R. N.R. N.R. N.R. N.R. N.R. Yes Yes Yes No Yes Yes N.R. N.R. N.R. N.R. N.R.
Ear Ear resistance
Mesenteric resistance Tail
Bohr et al. (1958) Briggs and Melvin (1961) Dodd and Daniel (1960) Karaki and Urakawa (1977)
Reuter et al. (1973)
Droogmans and Casteels (1979) Bevan and Joyoe (1990)
Araki et al. (1975) Reuter et al. (1973)
Altura et al. (1990)
Ashida and Blaustein (1987a,b)
Mulvany et al. (1984) Friedman and Friedman (1964) Hinke and Wilson (1962)
removal of extracellular Na + and substitution with sucrose, while only a tonic contraction was observed when Li ÷ or choline were used as substitutes (Ozaki and Urakawa, 1981). A phasic followed by a tonic contraction was also observed in guinea pig mesenteric artery (Itoh et al., 1981) and rabbit pulmonary artery (Araki et al., 1975) after replacement of Na ÷ with choline, sucrose or Li ÷. In rat portal vein, removal of extracellular Na ÷ and replacement with choline resulted in a tonic contraction with accompanying phasic contractions, while only phasic contractions were observed following Na ÷ replacement with Li ÷ (Yamamoto and Hotta, 1985). Although the reasons for the varied contractile response characteristics of basal tone due to lowered extracellular Na ÷ are not clear, it is apparent that the factors responsible for the increased tone are numerous, and include both direct effects on the smooth muscle, as well as indirect effects due to norepinephrine release from sympathetic nerve terminals within the vessels. This latter effect was demonstrated by Karaki and Urakawa (1977), who reported that the increased basal tone of the rabbit aorta due to lowered extracellular Na ÷ was inhibited by exposure to an ~t-adrenergic receptor antagonist, surgical removal of the sympathetic nerves, or following reserpinization of the rabbit. In contrast, ~t-adrenergic receptor antagonists were without effect on the increased basal tone due to lowered extracellular Na ÷ in canine cerebral, mesenteric (Toda, 1978), and coronary arteries (Maseki, 1990). One of the factors that appears to influence basal tone through a direct effect on the smooth muscle is the compound substituted for Na ÷. In the rat aorta and tail artery, Na ÷ substitution with choline, but not with Tris, mannitol, urea, sucrose or Li ÷, increased basal tone (Hinke and Wilson, 1962; Altura et al., 1990). Na n substitution with T M A induced a much greater increase in basal tone than substitution with choline in rabbit ear artery (Droogmans and Casteels, 1979). In canine mesenteric artery and rabbit aorta, Na ~ substitution with sucrose, but not Li ÷, increased basal tone (Waugh, 1962; Karaki and Urakawa, 1977). An additional factor that also appears to influence whether removal of extracellular Na ÷ increases basal tone is the Na+/K+-ATPase, since exposure to ouabain, which inhibits the Na÷/K+-ATPase, potentiated and/or was required to observe an increase in basal tone following removal of extracellular Na n (Ozaki and Urakawa, 1981; Mulvany et al., 1984; Toda, 1978; Ashida and Biaustein, 1987a; Maseki et al., 1990). Since ouabain increases the intracellular Na ÷ concentration, these results may suggest a role of N a + - C a 2+ exchange in producing the tone.
Others have reported that caffeine was required to observe an increase in tone following removal of extracellular Na ÷ (Ashida and Blaustein, 1987a, b). Thus, Ca 2+ uptake by the sarcoplasmic reticulum may also influence whether tone is observed following extracellular Na ÷ removal. Membrane potential is an additional factor that may influence whether removal of extracellular Na ÷ results in an increase in basal tone, since KC1 potentiated the increase in basal tone in canine coronary artery (Maseki et al., 1990), bovine tail artery (Ashida and Blaustein, 1987a), and rabbit pulmonary artery and aorta (Reuter et al., 1973). SUMMARY
This review illustrates the varied effects of extracellular Na + concentration on agonist-induced contraction. This variation is not unexpected between different agonists, or different vessels. However, the review also identifies a number of experimental conditions that may greatly influence the effects of extracellular Na ÷ removal on agonist-inducted contraction. A lack of appreciation for these factors may also account for some of the wide variations in the reported effects of extracellular Na n removal. The potential influence of some of these factors may be determined, and minimized, by testing different Na n substitutes and time of exposure to lowered extracellular Na ÷, reducing increased basal tone through sympathetic blockade and, possibly, the use of Ca 2÷ channel antagonists, performing complete agonist concentration-contraction curves, and removing the endothelium from the vessel. Where possible studies that use extracellular Na n removal as a tool to investigate the role of Na÷-dependent processes in the regulation of agonist-induced contraction need to control for these factors. In this manner, the role of Na÷-dependent processes in agonist-induced contraction may be more clearly elucidated. Acknowledgements--The author thanks Rita Eveleigh and Gerald Chambers for manuscript preparation. This work was supported in part by grants from the VA and AHA SW Ohio Chapter. REFERENCES
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