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(Hypertension. 1995;25:796-802.)
© 1995 American Heart Association, Inc.

Articles

Angiotensin-(1-7) and Nitric Oxide Interaction in Renovascular Hypertension

Hidetomo Nakamoto; Carlos M. Ferrario; Stanley B. Fuller; David L. Robaczewski; Eric Winicov; Richard H. Dean

From the Hypertension Center and the Department of General Surgery, The Bowman Gray School of Medicine of Wake Forest University, Winston-Salem, NC.

Correspondence to Carlos M. Ferrario, MD, Hypertension Center, Bowman Gray School of Medicine of Wake Forest University, Medical Center Blvd, Winston-Salem, NC 27157-1032.

	Abstract

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Abstract New studies suggest that vasodilator systems may play an important role in restraining the rise in peripheral vascular resistance associated with the evolution of arterial hypertension. We characterized in conscious dogs the hemodynamic and hormonal effects of 4 weeks of feeding either the nitric oxide synthase inhibitor N-nitro-L-arginine (3 mg · kg^-1 · d^-1) or the nitric oxide precursor L-arginine (0.3 mg · kg^-1 · d^-1) during the evolution of two-kidney, one clip hypertension. Inhibition of nitric oxide production elicited a form of hypertension more severe than that produced in placebo-fed two-kidney, one clip dogs. The higher levels of blood pressure were accompanied by lower levels of plasma renin activity and lower angiotensin II concentrations. During the chronic phase of renovascular hypertension, the fall in blood pressure produced by acute systemic injections of lisinopril or losartan was significantly reduced in dogs given the nitric oxide inhibitor. In contrast, chronic administration of L-arginine had no effect on the magnitude of hypertension or on the increases in renin activity and hyperangiotensinemia associated with the evolution of renal hypertension. Likewise, the fall in blood pressure produced by pharmacological blockade of angiotensin II was not different from that recorded in untreated renal hypertensive dogs. The vasodilator component of the blood pressure response due to intravenous injections of angiotensin-(1-7) (1 to 100 nmol/kg) was augmented in both untreated and L-arginine–treated two-kidney, one clip hypertensive dogs, but was significantly attenuated in hypertensive dogs fed the nitric oxide synthase inhibitor. These experiments demonstrated an important contribution of nitric oxide in modulating the increased activity of the peripheral renin-angiotensin system during the evolution of renovascular hypertension. Furthermore, our data show that the evolution of this form of experimental renal hypertension is accompanied by a magnification of the vasodilator actions of angiotensin-(1-7). Activation of endothelium-derived relaxing factors and angiotensin-(1-7) mechanisms may act in synergy to buffer the increase in vascular resistance produced by chronic renal ischemia.

Key Words: angiotensins • angiotensin II • losartan • hypertension, renal • nitric oxide • vascular resistance

	Introduction

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Endothelium-derived relaxing factors constitute an area of intense research because these hormonal regulators provide a strong underpinning to the concept that tissue perfusion pressure is determined by a balance between systemic vasoconstrictor and local vasodilator hormones.¹ The availability of agents that inhibit the action of nitric oxide synthase has allowed extensive studies of the physiology of nitric oxide and its interaction with other vasopressor and vasodepressor systems. It has been reported that nitric oxide may modulate the constrictor activity of angiotensin II (Ang II) in both isolated blood vessels² and intact animals.^{2 3} Furthermore, a dysfunction of the endocrine activity of endothelium-derived relaxing factors has been linked to the evolution of some forms of experimental arterial hypertension⁴ and the antihypertensive actions of angiotensin-converting enzyme (ACE) inhibitors and Ang II receptor antagonists.^{5 6 7}

While multiple studies link nitric oxide to the long-term regulation of peripheral vascular resistance, our laboratory has been investigating novel functions of angiotensin fragments in the regulation of blood pressure. The heptapeptide angiotensin-(1-7) [Ang-(1-7)]⁸ differs from Ang II in that it is devoid of any significant constrictor activity. However, Ang-(1-7) displays an important vasodilator activity that is mediated by stimulation of vasodilator prostaglandins,^{9 10} the release of nitric oxide,^{11 12} or both. Because current work from this laboratory suggested that the actions of Ang-(1-7) were readily evidenced in conditions associated with increased Ang II activity, we investigated the participation of Ang-(1-7) in the evolution of a well-characterized canine model of renovascular hypertension, in the presence and in the absence of chronic systemic inhibition of nitric oxide synthase. The experimental strategies used in these studies allowed the first direct characterization of the chronic effect of nitric oxide synthesis inhibition on the evolution of hypertension due to chronic renal ischemia.

	Methods

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Experiments were performed in 17 conscious, conditioned mongrel male dogs weighing an average of 20±1 kg. Dogs were fed a solid diet (Science Dog Food, Hill's Pet Nutrition Inc) and canned meat (Hill's Science Diet, Hill's Pet Nutrition Inc) containing a total of 65 mmol Na⁺ and 50 mmol K⁺ per day, and they had free access to tap water. Protocols were carried out in strict accordance with the guidelines of the National Institutes of Health¹³ and were approved by the Institutional Animal Care and Use Committee of Wake Forest University.

Surgery and Animal Preparation
Surgery was performed in animals in which inhalation anesthesia with 1% halothane (Ayerst Laboratories) was preceded by induction with a combination of tiletamine HCl, zolazepam HCl (Aveco Co, Inc; 8 mg/kg IM), and atropine sulfate (Elkins-Sinn, Inc; 0.4 g/kg IM). After surgery, dogs convalesced for at least 1 week in individual pens and were cared for by trained veterinarians who administered medications and obtained daily records of body temperature, weight, and food intake.

Tygon catheters (Norton Plastics & Synthetic Division) were positioned in an external iliac artery and vein through an incision in the lower abdominal quadrant, as described elsewhere.^{14 15} Catheter tips were advanced into the lower portion of the abdominal aorta (below the renal arteries) and vena cava, respectively; the opposite ends were tunneled under the skin and exteriorized at the nape of the neck. The two-kidney, one clip (2K1C) form of experimental hypertension was produced by the procedure described by Masaki et al.¹⁶ In brief, the left renal artery was constricted to 50% of its original diameter with an externally adjustable stainless steel clamp (Catalogue No. 484414, Keystone Automatic Tech) through an incision in the left flank. Two weeks later, the previously constricted renal artery was totally occluded from the outside under fluoroscopic imaging in dogs lightly anesthetized with 1% halothane. It has been amply documented that the two-step procedure, as developed by our laboratory, results in a reproducible and long-lasting form of renovascular hypertension.^{16 17 18}

Experiment Protocols
Seven to 10 days after placement of catheters, dogs were trained to lie quietly in a cage placed in a darkened laboratory isolated from environmental noises. Phasic and mean arterial pressure and heart rate were recorded, usually between 7 and 8 AM. At the completion of a 14-day control period, dogs were randomly assigned to one of three groups at the time of surgical induction of 2K1C hypertension. Six dogs (group 1; placebo-control) were fed a placebo supplement to their diet (see below), and 5 other dogs were given 3 mg · kg^-1 · d^-1 of the nitric oxide synthase inhibitor N-nitro-L-arginine (group 2; L-NA–treated). Six additional dogs were fed 0.3 g · kg^-1 · d^-1 L-arginine (group 3; L-Arg–treated). Capsules of either agent were hand-fed to the dogs inside meatballs prepared from canned meat (100 g each, Hill's Science Diet, Hill's Pet Nutrition, Inc). Dogs received the agents or the placebo (meatball only) for 4 weeks after constriction of a renal artery. The quantities of L-NA and L-Arg fed to the dogs each day were purposely chosen to cause no effect on baseline arterial pressure. In experiments preliminary to those described here, we determined that these agents did not cause significant changes in the resting mean arterial pressure of conscious dogs for up to 14 days of administration.

Repeated measures of the hemodynamic response to intravenous injections of Ang-(1-7), lisinopril, or losartan potassium were obtained in all three groups of dogs during the course of the studies. Circulatory responses to intravenous injections of Ang-(1-7) (1 to 100 nmol/kg) were assessed before and during the first and third weeks after onset of renovascular hypertension, whereas the actions of lisinopril (0.5 mg/kg IV) or losartan potassium (0.5 mg/kg IV) were measured on days alternating with those in which dogs were injected with Ang-(1-7). All agents were dissolved in 10 mL sterile saline, and the drugs were given in a random order at a rate of 1 mL/s for 10 seconds. Injections of either the inhibitors or Ang-(1-7) were spaced at least 30 to 60 minutes apart while the dogs rested quietly and were unaware of the procedure.

Measurement of Hormone Levels
Venous blood was collected in prechilled tubes in the presence of either heparin sulfate or a mixture of protease inhibitors (see below). After centrifugation at 4°C, the plasma was quickly frozen on dry ice and stored at -80°C until assay. Separate aliquots of the blood samples were assayed for concentrations of electrolytes by flame photometry (IL943, Instrumentation Laboratory). ACE activity was assayed using a radioassay provided by Hycor Biomedical Inc. The limit of this assay for detection of histadine-glycine was 2.1 nmol · mL^-1 · min^-1. The intra-assay and interassay coefficients of variation were 5.3% and 11.9%, respectively. Plasma concentrations of the second messenger of nitric oxide, guanosine-3',5'-monophosphate (cyclic GMP), were assayed, as described elsewhere,¹⁹ with a radioimmunoassay kit from Du Pont Co. Blood samples were extracted in pure ethanol, dried, and reconstituted. The intra-assay coefficient of variation determined in 20 control samples averaged 14.2%.

Angiotensin peptides were determined by immunoassays from venous blood collected in a cocktail of protease inhibitors, as described previously.^{20 21} Plasma was extracted using Sep-Pak columns activated with 5-mL sequential washes of a mixture of ethanol/water/4% acetic acid (83:13:4), methanol, ultrapure water, and 4% acetic acid. After the sample was applied to the column, it was washed with ultrapure water and acetone and eluted with two 1-mL washes and one 1.5-mL wash of an ethanol/water/4% acetic acid mixture. The sample was eluted, reconstituted, and split for the three radioimmunoassays. Ang II samples were reconstituted in an assay buffer, and Ang I and Ang-(1-7) samples were reconstituted in a Tris buffer solution with 0.1% bovine serum albumin. Recoveries of radiolabeled angiotensins added to the sample and followed through the extraction were 92% (n=23). Samples were corrected for recoveries. Ang I was measured using a modification of the commercially available New England Nuclear radioimmunoassay kit (RIANEN, Du Pont Co). Ang II was measured using the Nichols Institute radioimmunoassay, and Ang-(1-7) was measured using the antibody previously described.²¹ The minimum levels detectable by use of the assays were 2.5 pg per tube for Ang-(1-7), 4 pg per tube for Ang II, and 1.25 pg per tube for Ang I. Values at or below the minimum detectable level of the assay were arbitrarily assigned that value for statistical analysis. The intra-assay coefficient of variation was 18% for Ang I, 12% for Ang II, and 8% for Ang-(1-7).

Data Analysis
All data are expressed as mean±SEM. One-way and two-way ANOVA, followed by Dunnet's test and Student's t test for paired data, were used for statistical analysis. A value of P<.05 was considered statistically significant.

Drugs
Ang-(1-7) was from Bachem Bioscience Inc, losartan (DuP 753) was kindly provided by Du Pont, and lisinopril was a kind gift from Merck Sharp & Dohme Research Laboratories. L-NA was purchased from Sigma Chemical Co.

	Results

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Characteristics of 2K1C Hypertension in Placebo-Control Dogs
As in previous studies,^{16 17 18} partial constriction of a renal artery in placebo-control dogs produced a gradual increase in mean arterial pressure that reached a hypertensive plateau by the third week (Table). The early stage of 2K1C hypertension was accompanied by tachycardia, whereas bradycardia followed the more severe hypertension produced by total occlusion of a renal artery (Table; week 3). In confirmation of previous findings,¹⁶ the evolution of 2K1C hypertension in placebo-control dogs was associated with significant elevations in plasma renin activity and plasma levels of Ang I and Ang II (Table). Ang-(1-7) circulated in the blood of normal dogs at concentrations comparable to those determined for Ang II (Table). Although plasma levels of Ang-(1-7) did not change at either the early or later stages of 2K1C hypertension (Table), the Ang-(1-7)/Ang II ratio decreased significantly from 1.034 before to 0.284 3 weeks after onset of 2K1C hypertension (P<.01). The 73% decrease in the Ang-(1-7)/Ang II ratio suggests a reduced production of Ang-(1-7) in terms of Ang II²² during the chronic phase of 2K1C hypertension in placebo-treated dogs.

View this table: [in this window] [in a new window]   Table 1. Hemodynamic and Hormonal Effects of Two-Kidney, One Clip Hypertension

Chronic Inhibition of Nitric Oxide Synthase Aggravates 2K1C Hypertension
The Table also shows that oral administration of L-NA produced a statistically significant and sustained increase in the magnitude of the hypertensive response produced by constriction of a renal artery. The higher blood pressures in L-NA–treated dogs were accompanied by sustained bradycardia throughout the 3 weeks of observation. Hypertension in these dogs was accompanied by a blunted rise in plasma renin activity and lower levels of plasma Ang I and Ang II compared with animals given placebo or fed L-Arg (Table). In contrast, dogs fed L-Arg developed a form of 2K1C hypertension that did not differ significantly from that characterized in dogs given the placebo diet. Moreover, the pattern of activation of the renin-angiotensin system in L-Arg–treated dogs was similar to that observed in dogs fed the placebo-control diet (Table).

In placebo-treated 2K1C hypertensive dogs, plasma levels of cyclic GMP rose gradually, averaging 16.5% (P<.05) and 82.5% (P<.01) above prebanding value at week 1 and week 3, respectively (Table). Plasma levels of cyclic GMP were significantly higher in hypertensive dogs fed L-Arg. In contrast, dogs given L-NA showed significantly lower concentrations of cyclic GMP at week 3 after constriction of a renal artery (Table).

Interplay Between the Angiotensin System and Nitric Oxide
In Fig 1, the effects of acute interruption of the activity of Ang II in the three groups of hypertensive animals are compared. Intravenous lisinopril caused a large fall in mean arterial pressure in both control and L-Arg–treated dogs at weeks 1 and 3 after onset of renovascular hypertension. However, the fall in mean arterial pressure produced by lisinopril in L-NA–treated animals (week 3) was significantly less than that determined in control or L-Arg–treated dogs or in L-NA–treated animals at week 1 after renal artery occlusion. Similar effects were produced by systemic administration of losartan, although the magnitude of the depressor responses produced by the type 1 angiotensin receptor antagonist was consistently lower than that of responses obtained with lisinopril at the dose used in these experiments.

View larger version (37K): [in this window] [in a new window]   Figure 1. Bar graphs show decreases in mean arterial pressure (MAP) after bolus intravenous injection of either lisinopril (0.5 mg/kg) or losartan (0.5 mg/kg) before (open bars) and during the first (shaded bar) and third week (solid bar) after onset of two-kidney, one clip hypertension. Values are mean±SEM of data obtained in dogs given placebo (control; n=6), N-nitro-L-arginine (L-NA; n=5), or the nitric oxide synthase substrate L-arginine (L-Arg; n=6). *P<.05, **P<.01, compared with baseline values obtained before production of two-kidney, one clip hypertension; +P<.05 compared with effects obtained during the first week.

Fig 2 summarizes the changes in plasma levels of Ang I, Ang II, and Ang-(1-7) and in ACE activity produced by administration of either lisinopril or losartan in control, L-Arg–treated, and L-NA–treated dogs at week 3 after development of 2K1C hypertension. Characteristically, the general pattern of the hormonal response produced by acute administration of lisinopril in all three groups of dogs consisted of an almost complete inhibition of ACE activity, a marked decrease in plasma Ang II levels, and a large rise in plasma levels of Ang I and Ang-(1-7). Importantly, however, the increases in Ang-(1-7) produced by acute inhibition of ACE were significantly blunted in L-NA–treated dogs (Fig 2). The hormonal effects associated with administration of losartan were directionally similar to those reported previously.⁷ In the current experiments, acute blockade of type 1 angiotensin receptors did not change plasma levels of Ang I or Ang-(1-7) or ACE activity. Losartan augmented plasma levels of Ang II, but the differences were not statistically significant.

View larger version (32K): [in this window] [in a new window]   Figure 2. Bar graphs show differential effects of acute inhibition of angiotensin-converting enzyme (by lisinopril) or type 1 angiotensin II receptors (by losartan) on plasma concentrations of angiotensin peptides and converting-enzyme activity in untreated (control), L-arginine–treated (L-Arg), and N-nitro-L-arginine–treated (L-NA) two-kidney, one clip hypertensive dogs. Open bars denote values before injection of the agents and solid bars denote hormone values 2 hours after injection. *P<.05, **P<.01, compared with baseline values.

Hemodynamic Effects of Ang-(1-7)
As in previous studies,²³ systemic injections of Ang- (1-7) produced a biphasic response composed of a short-lasting rise followed by a longer-lasting fall in mean arterial pressure. Before production of 2K1C hyper-tension, the depressor component of the hemodynamic response to Ang-(1-7) was small in magnitude (-3.0±0.4 mm Hg). After development of renovascular hypertension, the initial pressor component of the response remained unchanged, while the depressor component was significantly magnified (-10.4±0.7 mm Hg, P<.05) compared with baseline values obtained before 2K1C hypertension. Fig 3 shows that there were no differences in the peak pressor effects produced by intravenous injection of Ang-(1-7) among the three groups of animals. In contrast, the depressor component of the response to Ang-(1-7) was significantly attenuated in the group of hypertensive dogs given L-NA.

View larger version (13K): [in this window] [in a new window]   Figure 3. Dose-response curve for intravenous administration of angiotensin-(1-7) in conscious dogs at 3 weeks after induction of two-kidney, one clip hypertension. Solid lines with closed circles denote averages from animals given placebo (control; n=6). Broken lines with open squares denote averages in two-kidney, one clip hypertensive dogs chronically treated with N-nitro-L-arginine (n=5). Broken lines with stars denote values for two-kidney, one clip hypertensive dogs exposed to L-arginine (n=6).

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
Our studies both confirmed and extended the concept that inhibition of nitric oxide synthesis facilitates vasoconstriction and blood pressure elevation by removing an apparently active vasodilator tone. In addition, our experiments revealed that chronic inhibition of nitric oxide synthase had a sustained effect on the evolution of this renin-dependent form of experimental hypertension. The higher blood pressures in L-NA–treated dogs were associated with attenuation of the increases in plasma renin activity and plasma Ang II concentrations. In addition, the enhanced vasoconstrictor state due to chronic inhibition of nitric oxide was accompanied by significant blunting of the hypotensive effects produced by acute inhibition of ACE or blockade of type 1 angiotensin receptors. Potentiation of the vasodepressor action of Ang-(1-7) after development of 2K1C hypertension suggested that this angiotensin peptide may oppose the vasopressor actions of Ang II by a nitric oxide–dependent mechanism.

Several studies have demonstrated that administration of nitric oxide inhibitors, acutely or chronically, raises blood pressure,^{24 25} impairs renal function,⁴ and deteriorates glomerular hemodynamics in ischemic kidneys.^{24 26 27} To our knowledge, the present experiments are the first to evaluate the effect of chronic nitric oxide synthase inhibition on the evolution of 2K1C hypertension in conscious animals. L-NA was given to the dogs at the time of induction of renal hypertension and at a dose verified to have no direct effect on the blood pressure of conscious normotensive dogs. This strategy prevented a hypertensive response in normal animals from obscuring the characterization of the endogenous contribution of nitric oxide after renal artery constriction. Sequential measurements of the second messenger cyclic GMP provided corroborative evidence that L-NA treatment was effective in inhibiting nitric oxide. Although plasma levels may not totally reflect the degree of inhibition in tissues, Dundore et al²⁸ found a significant correlation between plasma and aortic levels of cyclic GMP.

The characteristics of the hypertension in untreated 2K1C dogs did not deviate from those extensively described by us.^{16 17 18} However, chronic administration of L-NA produced a more severe form of hypertension, accompanied by sustained bradycardia and a lesser degree of activation of the peripheral renin-angiotensin system, as gauged by the changes in plasma renin activity and plasma levels of angiotensin peptides. Pharmacological evaluation of the contribution of the renin-angiotensin system to the maintenance of this form of hypertension was done by measuring the hemodynamic and hormonal responses to inhibition of ACE or type 1 angiotensin receptors. The blood pressure response to systemic administration of either agent was significantly reduced during the established phase of 2K1C hypertension only in L-NA–treated dogs. These data provide further evidence that development of 2K1C hypertension is accompanied by an enhanced modulation of vascular resistance by a nitric oxide–dependent mechanism produced by the vascular endothelium, nerve endings, or other sites. The increases in cyclic GMP found in placebo-treated dogs during the evolution of 2K1C hypertension is in keeping with this interpretation.

It had been surmised that removal of the regulatory action of nitric oxide on renal function stimulated renin release and aggravated Ang II–dependent forms of hypertension. Serial measurements of plasma renin activity, levels of angiotensin peptides, and pharmacological responses to blockade of Ang II activity performed in these experiments did not confirm this possibility. It may be suggested that the suppression of renin results from an enhanced sodium retention due to inhibition of nitric oxide. This interpretation is not supported by cur-rent experiments performed in L-NA–treated dogs. In preliminary experiments that are extensions of studies showing that chronic inhibition of nitric oxide in 2K1C dogs caused a significant suppression of renal function in the ischemic and unclipped kidney,²⁹ we found reduced urinary sodium excretion during week 1 but negative sodium balance during week 3 (unpublished observations, 1994). However, the lower levels of plasma renin activity and lower concentrations of angiotensin peptides in L-NA–treated dogs may be accounted for by a reduced contribution of the sympathetic control of renal function, brought about in part by a baroreceptor-mediated response to the higher pressures. Although additional work will be required to evaluate these possibilities, Bank et al³⁰ found that the hypertension and reduced renal blood flow caused by chronic nitric oxide inhibition in normal rats was a direct effect of reduced nitric oxide availability.

We have previously suggested that smaller fragments of Ang II may play alternative roles in the regulation of arterial pressure.⁸ A series of studies conducted by this laboratory showed that Ang-(1-7) stimulates release of prostaglandins both in vitro and in vivo.^{31 32 33} The vasodilator actions of Ang-(1-7) in the periphery and the cerebral circulation are prevented by administration of indomethacin or a nitric oxide synthase inhibitor.^{11 23 34} Although we did not determine whether the residual vasodilator component of the Ang-(1-7) response may be mediated by stimulation of prostaglandins, our findings are in keeping with the observation that acute inhibition of nitric oxide synthase abolished the vasodilator response to Ang-(1-7) in the mesenteric circulation of cats.¹² Importantly, Pörsti et al¹¹ reported that the concentration-dependent dilator response (ED₅₀>2 µmol/L) produced by Ang-(1-7) in porcine coronary artery rings was markedly attenuated by the nitric oxide synthesis inhibitor L-NA and abolished after removal of the endothelium. In their experiments, the Ang-(1-7)–induced relaxation was not affected by type 1 angiotensin or type 2 angiotensin receptor antagonists but was augmented by the ACE inhibitor quinaprolat. Our results and those reported by others suggest that the vasodilator action of Ang-(1-7) is mediated, at least in part, by release of nitric oxide from the endothelium through activation of an angiotensin receptor other than type 1 angiotensin or type 2 angiotensin receptors.

The differential effects of ACE inhibition on plasma Ang-(1-7) levels are another indication for a relationship between Ang-(1-7) and nitric oxide. Recent studies by ourselves³⁵ and others³⁶ suggest that Ang-(1-7) contributes to the vasodilator actions of ACE inhibitors by aug-menting the release of vasodilator prostaglandins and possibly of nitric oxide. Schini et al³⁷ found that Ang-(1-7) elicits release of vasoactive kinins from the coronary endothelium.

In summary, our experiments showed an important contribution of endothelium-derived relaxing factor in modulating the increase in the activity of the renin-angiotensin system during the evolution of 2K1C hypertension. The enhanced endogenous vasoconstrictor influence activated by chronic renal ischemia stimulates vasodilator mechanisms that include an enhanced contribution of nitric oxide and Ang-(1-7) mechanisms. These vasodilator influences may act independently to buffer the elevation of blood pressure or may be linked by receptor mechanisms yet to be defined.

	Acknowledgments

 
This study was supported by grants 1PO1-HL-51952 and RO1-HL-50066 from the National Heart, Lung, and Blood Institute of the National Institutes of Health. We thank Deanna G. Brown, Thomas H. Edwards, Cynthia A. Andrews, Carolyn F. Kiger, and Charles D. Springs for their excellent technical contributions and Sherri L. Miller for her secretarial expertise.

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