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(Hypertension. 2000;36:934.)
© 2000 American Heart Association, Inc.
Scientific Contributions |
Effect of Enalapril on Exhaled Nitric Oxide in Normotensive and Hypertensive Subjects
From the Second Department of Internal Medicine (H.S., T.N., T.T., Y.S., J.H., T.K.), Department of General Medicine (T.K.); Medical Informatics and Decision Sciences (T.S.), Gunma University School of Medicine, Maebashi, Japan; Maebashi-Jonan Hospital, Maebashi, Japan (K.S.); and Department of Cardiovascular Medicine, Graduate School of Medicine, University of Tokyo, Tokyo, Japan (R.N.).
Correspondence to Tetsuya Nakamura, MD, Second Department of Internal Medicine, Gunma University School of Medicine, 3-39-22 Showa-machi, Maebashi, Gunma 371-8511, Japan. E-mail nakamurt{at}news.sb.gunma-u.ac.jp
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Abstract |
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Abstract—We investigated whether an angiotensin-converting enzyme (ACE) inhibitor increases the production of nitric oxide (NO) in exhaled air in normotensive and hypertensive subjects. In study 1, 8 normotensive male subjects received a single oral dose of enalapril (5 mg) or nitrendipine (10 mg) in a crossover manner. Exhaled air was collected at baseline, and at 2, 4, and 8 hours after administration of the drug. In study 2, 10 normotensive subjects (6 men and 4 women) and 10 hypertensive subjects (6 men and 4 women) received a single oral dose of enalapril (5 mg). Exhaled air was collected at baseline and at 2 and 4 hours after administration of the drug. In study 1, enalapril significantly increased the NO release rate from the lung in normotensive subjects (36.9±5.1 pmol/s at baseline versus 58.3±7.3 pmol/s at 4 hours, P<0.01). Nitrendipine did not change the NO release rate. In study 2, enalapril significantly increased the release of NO from the lung in normotensive subjects (40.4±6.0 pmol/s at baseline versus 70.3±11.4 pmol/s at 4 hours, P<0.01) but not in hypertensive subjects. ACE inhibition increased NO production from the lung in normotensive subjects but not in hypertensive patients. The reduction of angiotensin II production and/or the accumulation of bradykinin in the pulmonary tissue may be responsible for increased NO production in components of the lung, such as the pulmonary vascular endothelium, bronchial epithelial cells, macrophages, nasopharyngeal cells, and neurons. However, the effects of ACE inhibition on NO production from the lung differ between hypertensive subjects and normotensive subjects.
Key Words: angiotensin • bradykinin • hypertension, essential • nitric oxide
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Introduction |
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Endothelium-derived relaxing factor (EDRF) has been identified as nitric oxide (NO), a potent vasodilator.1 The attenuated endothelium-dependent vasodilation in patients with essential hypertension2 may be largely mediated by a decrease in the release or activity of NO. Decreased endothelial NO is considered to be either a cause or a consequence of hypertension.
NO is a highly unstable substance with a plasma half-life of only a few seconds3 ; therefore, its direct measurement is difficult, particularly in vivo. Endogenously produced NO is assessed by measuring the serum levels of NOx, the products of NO metabolism, or by measuring endogenous NO present in expired air. The presence of endogenous NO in exhaled air has been demonstrated in humans.4 The cellular source of exhaled NO is not known, but it has been proposed that all NO synthase isoforms in the respiratory system contribute to NO release.5 Therefore, the amount of NO in expired air is an appropriate indicator of endogenously produced NO in the lung. We recently developed a method for measuring NO in exhaled air.6
Angiotensin-converting enzyme (ACE) inhibitors improve impaired endothelium-dependent vascular relaxation in rats,7 but this effect of ACE inhibitors is not always demonstrated in humans.8 9 However, it has not yet been established whether oral administration of ACE inhibitors increase the NO production from the lung or the nitrite/nitrate (NOx) concentrations of systemic circulating venous blood in humans.
In this study, we investigated whether treatment with an ACE inhibitor would increase NO production in exhaled air in normotensive and hypertensive subjects. We measured the NO release rate from the lung before and after administration of enalapril or nitrendipine in normotensive subjects. We also examined the NO release rate from the lung before and after administration of enalapril in normotensive and hypertensive subjects.
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Methods |
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Subjects
Normotensive subjects in both study 1 and study 2 underwent physical examinations to rule out the presence of disease. None of the subjects had evidence of active infection or respiratory disease. None was a smoker. None of the subjects had taken any prior medication. Subjects were also excluded if they had had any clinically relevant illness in the 3 weeks preceding the study or if any clinically relevant abnormality was identified during the screening examination.
Hypertensive subjects in study 2 also underwent a physical examination (Table 1). We also assessed the following laboratory parameters: blood cell count, urinalysis, and serum levels of electrolytes, creatinine, fasting blood sugar, cholesterol, triglycerides, and liver enzymes. Blood pressure was measured on at least 3 different occasions. Hypertension was defined as a systolic or diastolic blood pressure consistently >140 mm Hg or 90 mm Hg, respectively, or both. An ECG, echocardiogram, and chest radiograph were also obtained. Echocardiographic and ECG findings suggestive of left ventricular hypertrophy were present in 2 patients. Mild proteinuria was present in 1 patient and hypercholesterolemia in 3 patients. None of the hypertensive patients had diabetes mellitus or liver dysfunction. No patients were taking antihypertensive medications before the study. None of them was a smoker.
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Alcohol and caffeine were prohibited for 12 hours before and during the study. Antihypertensive drugs were administered after fasting overnight. Subjects were told to maintain a limited-nitrate diet (which excluded foodstuffs containing a high concentration of nitrate such as cured meat, fruit, and, in particular, leafy green vegetables) from 3 days to 14 hours before the administration of antihypertensive drugs. Because tap water contains variable amounts of nitrate, distilled water was provided during the study. Subjects maintained their usual exercise habits throughout the study. All subjects underwent pulmonary function testing (Chestac-55V; Chest M.I.) before beginning the study protocol. The forced vital capacity is expressed as a percentage of the reference value (%VC). The forced expiratory volume in 1 second is expressed as a percentage of the forced expiratory volume (FEV1%). The study protocol was approved by the Institutional Committee on Human Research of Maebashi-Jonan Hospital. Informed consent for participation was obtained from all subjects.
Protocol
Study 1
The effect of enalapril, an ACE inhibitor, and
nitrendipine, a calcium antagonist, on the NO release rate
was examined in 8 male normotensive subjects in a crossover manner.
A single oral dose of enalapril (5 mg) was administered to 4 subjects and a single oral dose of nitrendipine (10 mg) was administered to 4 subjects. Two weeks later, subjects received the alternate study drug. Exhaled air and blood samples were collected and blood pressure and heart rate were measured at baseline after subjects had rested for 30 minutes in the supine position in a quiet room and again at 2, 4, and 8 hours after drug administration. We determined the NO release rate in exhaled air and measured the serum level of NOx and plasma levels of bradykinin and renin activity.
Study 2
The effect of enalapril on the NO release rate was examined in
10 normotensive subjects (6 men and 4 women) and 10 untreated
hypertensive patients (6 men, 4 women).
All subjects received a single oral dose of enalapril (5 mg). After subjects rested for 30 minutes in the supine position in a quiet room, exhaled air and blood samples were collected, and blood pressure and heart rate were measured at baseline and at 2 and 4 hours after drug administration. The NO release rate was determined in exhaled air, and the serum level of NOx and plasma levels of bradykinin and renin activity were measured.
Collection of Exhaled Air
Samples of exhaled air were obtained and NO gas was
analyzed and the rate of NO release determined as previously
described.6 In brief, after application of a nose clip,
air inspired through the mouth was exhaled through the mouth into a 6-L
bag made of polyvinylfluoride film (Tedlar bag, Iuchi). A
Teflon column (15x50 mm) was inserted between the mouthpiece and
the Tedlar bag. The column was packed with 6.7 g of silica gel
(particle size, 1.7 to 4.0 mm, Kanto Chemical). This column was
used to dry the exhaled air sufficiently to prevent the condensation of
vapor on the walls of the Tedlar bag. NO is not adsorbed by the silica
gel and is stable in the Tedlar bag for several hours if the sample is
dry and is not exposed to light. The study was performed only when the
concentration of NO in the room air was <3 parts per billion (ppb).
The room air concentration of NO was 1.2±0.6 ppb (0.6 to 2.8 ppb)
immediately before each measurement.
Analysis of NO and Determination of NO Release Rate in
Exhaled Air
The NO concentration was measured with a chemiluminescence
analyzer (model GLN-32; Denki-Kagaku-Keiki). The flow rate for
sampling was 800 mL/min. The limit of detection for NO was 0.2 ppb. The
coefficient of variation was 2% at 20 ppb of NO.
Subjects were instructed to exhale air after making a full inspiratory effort at 6 flow rates that were determined arbitrarily by each subject. The flow rates ranged from very fast to very slow. Air volume in the 6 efforts corresponded to each person’s vital capacity. Samples were collected in separate bags. The time from the start to the end of each sampling was measured with a stopwatch. Sample volumes were determined on a chart recorder (model 056; Hitachi).
The concentration of NO in exhaled air was positively correlated with the duration of the exhalation. The rate of NO release for each subject was calculated on the basis of the slope of a simple linear regression model of the relation between the concentration of gas and the duration of exhalation as follows: Release rate of NO (pmol/s)=slope (ppb/s)xaverage of 6 sample volumes (L)x1/V(L-1)x103, where V corresponds to the volume of 1 mole of dry air at ambient temperature (24.5 L at 25°C at 760 mm Hg). The release rate was constant (36±4 pmol/s) in 5 control subjects who repeated the protocol 10 times over a 2-week period. In addition, the NO release rate at 0, 2, 4, and 8 hours (37±5 pmol/s, 36±5 pmol/s, 37±3 pmol/s, 36±4 pmol/s, respectively) was not changed for 8 hours in 5 control subjects.
Measurement of Serum Level of NOx
Samples of venous blood were centrifuged at
500g for 10 minutes at 4°C. The resulting serum samples
were stored at -70°C until assayed. For NOx measurements, 0.125 mL
of thawed serum was added to 0.5 mL of 75 mmol/L
ZnSO4 solution, to which 0.625 mL of 55
mmol/L NaOH was then added. The final pH was maintained between 7.0 and
7.5. Treated samples were mixed by vortexing, allowed to stand for 10
minutes, and then centrifuged at 5000g for 10
minutes. The resulting supernatant was applied to a copperized cadmium
reduction column to reduce nitrate to nitrite and subsequently reacted
with the Griess reagent with the use of an autoanalyzer
(TCI-NOX 1000; Tokyo Kasei Kogyo). The absorbance of the reaction
mixture at 540 nm was measured by spectrophotometry. The limit of
nitrite detection was 0.2 µmol/L.
Measurement of Plasma Level of Bradykinin
For measurement of bradykinin, samples were placed in
siliconized vacuum tubes containing aprotinin, soybean trypsin
inhibitor, protamine sulfate, and disodium EDTA. All tubes
were placed in a box filled with ice until they were
centrifuged at 500g for 10 minutes at 4°C.
Supernatants were stored in sealed polypropylene tubes at -80°C
until analysis. The plasma bradykinin level was measured by
radioimmunoassay.10
Measurement of Plasma Level of Renin Activity
Venous blood samples from the contralateral arm were collected
in tubes containing EDTA-2Na (1 mg/mL) and promptly chilled in an ice
bath. After samples of venous blood were centrifuged at
500g for 10 minutes at 4°C and plasma was removed,
aliquots of the plasma sample were stored at -20°C until use. Plasma
renin activity (PRA) was determined by radioimmunoassay with
radioimmunoassay kits obtained from SRL Radioisotope Laboratories,
Tachikawa.
Drugs
Enalapril and nitrendipine were provided by Banyu Pharmaceutical
Co and Yoshitomi Pharmaceutical Co, respectively.
Statistical Analysis
Two-way ANOVA was used to compare measurements of blood
pressure, the NO release rate, the heart rate, the serum level of NOx,
and the plasma levels of bradykinin and renin activity at baseline and
2, 4, and 8 hours after administration of enalapril or nitrendipine in
normotensive subjects in study 1 and at baseline and 2 and 4 hours
after administration of enalapril between normotensive and hypertensive
subjects in study 2. When ANOVA yielded a significant result, the
location of difference was determined by the unpaired or paired
t test. All values are expressed as mean±SEM. A value of
P<0.05 was accepted as statistically significant.
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Results |
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Study 1
Before treatment, there were no differences in blood pressure, heart rate, PRA, plasma bradykinin, and the serum NOx concentration between subjects treated with the ACE inhibitor or the calcium antagonist (Tables 2 and 3). Enalapril significantly increased heart rate (P<0.05) and PRA (P<0.01) at 4 hours compared with baseline levels. Blood pressure, plasma bradykinin, and serum NOx showed no significant changes 8 hours after drug administration. Nitrendipine significantly increased heart rate at 2 hours compared with the baseline level (P<0.05). Blood pressure, PRA, bradykinin, and serum NOx showed no significant changes 8 hours after administration of nitrendipine.
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In enalapril-treated subjects, the NO release rate from the lung was significantly higher at 4 hours (58.3±7.3 pmol/s) than at baseline (36.9±5.1 pmol/s) (P<0.01) (Figure 1). The NO release rate from the lung was not significantly changed 8 hours after administration of nitrendipine (Figure 1).
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, n=8).
Study 2
Before treatment, both systolic (P<0.001) and
diastolic (P<0.001) blood pressures were
significantly higher in hypertensive subjects than in normotensive
subjects (Table 4). There were no
differences in heart rate, PRA, plasma bradykinin, and the serum NOx
concentration between hypertensive and normotensive subjects before
treatment (Tables 4 and 5). In
normotensive subjects, the systolic blood pressure was
significantly decreased at 2 hours (P<0.05) and at 4 hours
(P<0.01) and diastolic blood pressure was
significantly decreased at 4 hours (P<0.05) compared with
the baseline level. The PRA was significantly increased at 4 hours
compared with the baseline level (P<0.01). There were no
changes in diastolic blood pressure, plasma bradykinin, and
serum NOx 8 hours after administration of enalapril. In hypertensive
subjects, systolic blood pressure was significantly decreased
at 4 hours (P<0.01) and diastolic blood
pressure was significantly decreased at 2 hours (P<0.05)
and at 4 hours (P<0.01) compared with the baseline level,
but PRA was significantly increased at 4 hours compared with the
baseline level (P<0.01). Heart rate, plasma bradykinin, and
serum NOx were not significantly changed 8 hours after administration
of enalapril.
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Before treatment, the NO release rate from the lung in hypertensive subjects was significantly lower than in normotensive subjects (P<0.05). The NO release rate from the lung was significantly increased in normotensive subjects at 4 hours (70.3±11.4 pmol/s) compared with baseline (40.4±6.0 pmol/s) (P<0.01) (Figure 2). The NO release rate from the lung was not significantly changed 4 hours after treatment in hypertensive subjects (Figure 2). The NO release rate was significantly higher in normotensive subjects than in hypertensive subjects at 2 and 4 hours (P<0.01 and P<0.01, respectively).
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, n=10). NO release rate at baseline, 2 hours, and 4 hours was significantly higher in normotensive subjects than in hypertensive subjects (
P<0.05, |
Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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The ACE inhibitor enalapril increased NO production from the lung in normotensive subjects. The calcium antagonist nitrendipine did not alter NO production from the lung. Before treatment, NO production from the lung in hypertensive subjects was lower than in normotensive subjects. Enalapril did not increase NO production from the lung in hypertensive subjects.
NO is present in exhaled air, at a stable concentration at rest.4 The level of NO during exhalation differs in various pathophysiological conditions: It is increased in patients with asthma,11 primary lung cancer,12 and systemic lupus erythematosus.13 Exhaled NO levels have also been found to increase with exercise14 and in response to orally administered L-arginine15 and intravenously infused nitroglycerin.16 Conversely, the exhaled NO level is decreased in patients with heart failure,17 hypertension,18 and acute respiratory distress syndrome.19 The exhaled NO level is also reduced by smoking.18 These findings suggest that the level of exhaled NO represents not only its regional production in the airway but also its systemic activity in various physiological or pathological conditions, suggesting that the amount of NO in expired air is a reliable indicator of in vivo NO production.
Schilling et al18 showed that the production of endogenous NO in the lung was impaired in patients with hypertension. Moreover, Forte et al20 reported that whole-body NO production in patients with essential hypertension was diminished under basal condition. Similarly, in the present study, the NO production from the lung in hypertensive subjects was significantly lower than normotensive subjects before treatment.
Haefeli et al21 have demonstrated that quinaprilat
induces arterial vasodilation mediated by NO in humans.
Goldschmidt and Tallarida22 demonstrated that captopril
evoked endothelium-dependent relaxations in rabbit
aortic rings. Mombouli and Vanhoutte23 have suggested that
endothelium-dependent relaxation induced by ACE
inhibitors in perfused canine coronary arteries is
mediated by an increase in local kinins. Although these previous
studies assessed endothelium-dependent vasorelaxant
actions, we measured exhaled NO in the present study. We found that
an ACE inhibitor increased NO production from the
lung in normotensive subjects. Hirooka et al8 have
suggested that captopril may acutely improve impaired
endothelium-dependent forearm vasodilation independent
of a reduction in blood pressure per se in hypertensive patients. In
the present study, however, enalapril did not increase NO
production from the lung in hypertensive subjects. Although
Hirooka et al8 demonstrated an increase in
endothelium-dependent vascular relaxation, they did not
directly measure NO production. Wiemer et al24
reported that the relative increase of carotid
endothelial constitutive NO synthase expression induced
by treatment with low doses of ramipril for 
20 months was markedly
higher for Wistar-Kyoto rats than for spontaneously hypertensive rats.
They speculate that arrangement of NO synthase may differ between
Wistar-Kyoto rats and spontaneously hypertensive rats.
In blood vessels, the converting enzyme is located mainly on the plasma membrane of endothelial cells facing the lumen.25 26 Thus, the endothelium is the principal target organ for ACE inhibitors. Recent studies have reported that the renin-angiotensin27 and kallikrein-kinin systems28 are also present in the vascular wall, especially in endothelial cells. Two possible mechanisms of ACE inhibition–induced increases in NO production have been proposed: (1) The decreased angiotensin II may increase NO production as the result of a decrease in superoxide production. Rajagopalan et al29 have demonstrated that angiotensin II–mediated hypertension in rats increases vascular superoxide production through membrane NADH/NADPH oxidase activation. (2) Bradykinin in the lung tissue increases the generation of NO through B2 receptor activation30 31 and the formation of prostacyclin.32
In the present study, enalapril significantly increased NO production from the lung in normotensive subjects. There was no change in the plasma level of bradykinin or NOx in normotensive or hypertensive subjects. ACE, a carboxy-terminal peptidyl dipeptidase, is more abundant on the luminal surface of pulmonary vascular endothelial cells33 than on other vascular beds. Because the measurement of exhaled NO is directly derived from the lung, it is possible that ACE inhibitors may cause a greater increase in NO release from the lung than in serum NOx in peripheral venous blood. It is possible that NO production in the systemic circulation is also increased by ACE inhibition but that the change is so small that NOx is rapidly excreted in urine without causing changes in the serum level of NOx. It is therefore more advantageous to use the amount of NO measured in expired air as an indicator of the endogenously produced NO levels than the circulating serum level of NOx. Thus, it is likely that increased bioavailability of NO induced by ACE inhibition may result in an increase in NO radicals in exhaled air but not in an increase in NO metabolites, measured as NOx in serum.
In the present study, PRA showed a 4-fold increase at 4 hours,
confirming that enalapril exerts its actions in normotensive men. ACE
inhibitors may increase NO production through
accumulation of bradykinin. Given et al34 and
Johnston et al35 reported that in normotensive and
hypertensive subjects, a single 10-mg dose of enalapril significantly
decreased plasma angiotensin II, inhibited plasma ACE
activity, and increased PRA at 4 hours, but there were no significant
changes in circulating bradykinin during the study. In the present
study, the plasma level of bradykinin was not increased in normotensive
or hypertensive subjects. We suggest that enalapril could not change
circulating plasma bradykinin levels in normotensive and/or
hypertensive groups but that enalapril may increase local bradykinin
levels in pulmonary tissue in those groups. Plasma bradykinin
is quickly degraded by peptidases in plasma and other biological
fluids; the half-life of bradykinin in plasma is reported to be 17
seconds.36 Therefore, ACE inhibitor–induced
increase in bradykinin may persist longer in lung tissue and may
stimulate more NO production in the lung than in the
vasculature.
Exhaled NO may be derived from pulmonary vascular endothelial cells, nerves, alveolar macrophages, and nasopharynx or airway epithelial cells.11 37 38 Decreased angiotensin II may increase NO bioavailability released from these tissues because of the associated decrease in superoxide anions. In addition, it has been reported that bradykinin releases NO from the tracheal epithelium39 and the pulmonary vascular endothelium.40 It is also possible that bradykinin releases NO from other tissues, such as pulmonary nerves, alveolar macrophages, and nasopharynx and airway epithelial cells.
Studies on the relation between calcium channel blockers and EDRF or NO production have yielded some conflicting results. Rubanyi et al41 have found that Bay K 8644, a potent calcium channel activator, and the calcium-ionophore A23187 enhance EDRF synthesis in endothelial cells from canine femoral arteries. Bennett et al42 have shown that amlodipine has no effect on endothelium-dependent relaxation in mesenteric resistance arteries from spontaneously hypertensive rats. In contrast, Gunther et al43 have suggested that vasorelaxation induced by nitrendipine in coronary, basilar, and tail isolated pig arteries may be mediated in part by an increase in the release of NO. These discrepancies may be related to differences in the species, the drugs administered, or the experimental procedure. In the present study, nitrendipine did not alter NO production from the lung or the plasma level of NOx.
In conclusion, enalapril increased NO production from the lung in normotensive subjects but not in hypertensive subjects. The ACE inhibition–induced increase in NO production from the lung may be mediated by inhibition of angiotensin II production and/or the accumulation of bradykinin in lung tissue, such as the pulmonary vascular endothelium, bronchial epithelial cells, macrophages, nasopharyngeal cells, and neurons in the lung. This approach may influence the design of future studies assessing this system in normal subjects and in patients with hypertension and hypertensive complications.
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Acknowledgments |
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We are grateful to Shizuko Saiki and Hiromi Sekiguchi for their technical assistance. We thank Haruyasu Fujita for statistical help.
Received March 15, 2000; first decision April 11, 2000; accepted June 1, 2000.
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References |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
1. Moncada S, Palmer RMJ, Higgs EA. Nitric oxide: physiology, pathophysiology, and pharmacology. Pharmacol Rev. 1991;43:109–142.[Medline] [Order article via Infotrieve]
2.
Linder L, Kiowski W, Buhler FR, Luscher TF. Indirect
evidence for release of endothelium-derived relaxing
factor in human forearm circulation in vivo: blunted response in
essential hypertension. Circulation. 1990;81:1762–1767.
3.
Ignarro LJ. Nitric oxide: a novel signal transduction
mechanism for transcellular communication. Hypertension. 1990;16:477–483.
4. Gustafsson LE, Leone AM, Persson MG, Wiklung NP, Moncada S. Endogenous nitric oxide is present in the exhaled air of rabbits, guinea pigs and humans. Biochem Biophys Res Commun. 1991;181:852–857.[Medline] [Order article via Infotrieve]
5. Gaston B, Drazen JM, Loscalzo J, Stamler JS. State of the art: the biology of nitrogen oxides in the airways. Am J Respir Crit Care Med. 1994;149:538–551.[Abstract]
6.
Sato K, Sakamaki T, Sumino H, Sakamoto H, Hoshino J,
Masuda H, Sawada Y, Mochida M, Ohyama Y, Kurashina T, Nakamura T, Ono
Z. Rate of nitric oxide release in the lung and factors influencing the
concentration of exhaled nitric oxide. Am J Physiol. 1996;270:L914–L920.
7. Dohi Y, Criscione L, Pfeiffer K, Luscher TF. Angiotensin blockade or calcium antagonists improve endothelial dysfunction in hypertension: studies in perfused mesenteric resistance arteries. J Cardiovasc Pharmacol. 1994;24:372–379.[Medline] [Order article via Infotrieve]
8.
Hirooka Y, Imaizumi T, Masaki H, Ando S, Harada S,
Momohara M, Takeshita A. Captopril improves impaired
endothelium-dependent vasodilation in hypertensive
patients. Hypertension. 1992;20:175–180.
9.
Creager MA, Roddy MA. Effect of captopril and
enalapril on endothelial function in hypertensive
patients. Hypertension. 1994;24:499–505.
10. Ando T, Shimamoto K, Nakahashi Y, Nishitani T, Hosoda S, Ishida H, Tanaka S, Iimura O. Blood kinin measurement by sensitive kinin radioimmunoassay and its clinical application. In: Fritz H, Dietze G, Fiedler F, Haberland GL, eds. Recent Progress on Kinins. International Conference: Kinin 81 Munich. Munich, Germany: Birkhauser Verlag; 1982:222–226.
11. Hamid Q, Springall DR, Riveros-Moreno V, Chanez P, Howarth P, Redington A, Bousquet J, Godard P, Holgate S, Polak JM. Induction of nitric oxide synthase in asthma. Lancet. 1993;342:1510–1513.[Medline] [Order article via Infotrieve]
12. Liu CY, Wang CH, Chen TC, Lin HC, Yu CT, Kuo HP. Increased level of exhaled nitric oxide and up-regulation of inducible nitric oxide synthase in patients with primary lung cancer. Br J Cancer. 1998;78:534–541.[Medline] [Order article via Infotrieve]
13. Rolla G, Brussino L, Bertero MT, Colagrande P, Converso M, Bucca C, Polizzi S, Caligaris-Cappio F. Increased nitric oxide in exhaled air of patients with systemic lupus erythematosus. J Rheumatol. 1997;24:1066–1071.[Medline] [Order article via Infotrieve]
14. Bauer JA, Wald JA, Doran S, Soda D. Endogenous nitric oxide in expired air: effects of acute exercise in humans. Life Sci. 1994;55:1903–1909.[Medline] [Order article via Infotrieve]
15. Kharitonov SA, Lubec G, Lubec B, Hjelm M, Barnes PJ. L-arginine increases exhaled nitric oxide in normal human subjects. Clin Sci. 1995;88:135–139.[Medline] [Order article via Infotrieve]
16.
Husain M, Adrie C, Ichinose F, Kavosi M, Zapol WM.
Exhaled nitric oxide as a marker for organic nitrate tolerance.
Circulation. 1994;89:2498–2502.
17.
Sumino H, Sato K, Sakamaki T, Masuda H, Nakamura T,
Kanda T, Nagai R. Decreased basal production of nitric oxide in
patients with heart disease. Chest. 1998;113:317–322.
18. Schilling J, Holzer P, Guggenbach M, Gyurech D, Marathia K, Geroulanos S. Reduced endogenous nitric oxide in the exhaled air of smokers and hypertensives. Eur Respir J. 1994;7:467–471.[Abstract]
19.
Brett SJ, Evans TW. Measurement of
endogenous nitric oxide in the lungs of patients with the
acute respiratory distress syndrome. Am J Respir Crit Care
Med. 1998;157:993–997.
20. Forte P, Copland M, Smith LM, Milne E, Sutherland J, Benjamin N. Basal nitric oxide synthesis in essential hypertension. Lancet. 1997;349:837–842.[Medline] [Order article via Infotrieve]
21.
Haefeli WE, Linder L, Luscher TF. Quinaprilat induces
arterial vasodilation mediated by nitric oxide in humans.
Hypertension. 1997;30:912–917.
22.
Goldschmidt JE, Tallarida RJ. Pharmacological
evidence that captopril possesses an
endothelium-mediated component of vasodilation: effect
of sulfhydryl groups on endothelium-derived relaxing
factor. J Pharmacol Exp Ther. 1991;257:1136–1145.
23. Mombouli JV, Vanhoutte PM. Kinins mediate kallikrein-induced endothelium-dependent relaxations in isolated canine coronary arteries. Biochem Biophys Res Commun. 1992;185:693–697.[Medline] [Order article via Infotrieve]
24.
Wiemer G, Linz W, Hatrik S, Scholkens BA, Malinski T.
Angiotensin-converting enzyme inhibition alters nitric
oxide and superoxide release in normotensive and hypertensive rats.
Hypertension. 1997;30:1183–1190.
25.
Caldwell PRB, Seegal BC, Hsu KC, Das M, Soffer RL.
Angiotensin-converting enzyme: vascular
endothelial localization. Science. 1976;191:1050–1051.
26. Ryan JW, Ryan US, Schultz DR, Whitaker C, Chung A. Subcellular localization of pulmonary angiotensin-converting enzyme (kininase II). Biochem J. 1975;146:497–499.[Medline] [Order article via Infotrieve]
27.
Tang SS, Stevenson L, Dzau VJ.
Endothelial renin-angiotensin pathway:
adrenergic regulation of angiotensin secretion. Circ
Res. 1990;66:103–108.
28.
Saed GM, Carretero OA, MacDonald RJ, Scicli AG.
Kallikrein messenger RNA in rat arteries and veins. Circ
Res. 1990;67:510–516.
29. Rajagopalan S, Kurz S, Munzel T, Tarpey M, Freeman BA, Griendling KK, Harrison DG. Angiotensin II-mediated hypertension in the rat increases vascular superoxide production via membrane NADH/NADPH oxidase activation. J Clin Invest. 1996;97:1916–1923.[Medline] [Order article via Infotrieve]
30.
Sudhir K, Chou TM, Hutchison SJ, Chatterjee K.
Coronary vasodilation induced by
angiotensin-converting enzyme inhibition in vivo:
differential contribution of nitric oxide and bradykinin in conductance
and resistance arteries. Circulation. 1996;93:1734–1739.
31. Linz W, Wiemer G, Scholkens BA. ACE-inhibition induces NO-formation in cultured bovine endothelial cells and protects isolated ischemic rat hearts. J Mol Cell Cardiol. 1992;24:909–919.[Medline] [Order article via Infotrieve]
32. Busse R, Lamontagne D. Endothelium-derived bradykinin is responsible for the increase in calcium produced by angiotensin-converting enzyme inhibitors in human endothelial cells. Naunyn Schmiedebergs Arch Pharmacol. 1991;344:126–129.[Medline] [Order article via Infotrieve]
33.
Ryan JW. Peptidase enzymes of the pulmonary
vascular surface. Am J Physiol. 1989;257:L53–L60.
34. Given BD, Taylor T, Hollenberg NK, Williams GH. Duration of action and short-term hormonal responses to enalapril (MK 421) in normal subjects. J Cardiovasc Pharmacol. 1984;6:436–441.[Medline] [Order article via Infotrieve]
35. Johnston CI, Jackson BJ, Larmour I, Cubella R, Casley D. Plasma enalapril levels and hormonal effects after short- and long-term administration in essential hypertension. Br J Clin Pharmacol. 1984;18:233S–239S.
36. Shima C, Majima M, Katori M. A stable metabolite, arg-pro-pro-gly-phe, of bradykinin in the degradation pathway in human plasma. Jpn J Pharmacol. 1992;60:111–119.[Medline] [Order article via Infotrieve]
37. Kobzik L, Bredt DS, Lowenstein CJ, Drazen J, Gaston B, Sugarbaker D, Stamler JS. Nitric oxide synthase in human and rat lung: immunocytochemical and histochemical localization. Am J Respir Cell Mol Biol. 1993;9:371–377.
38. Gerlach H, Rossaint R, Pappert D, Knorr M, Falke KJ. Autoinhalation of nitric oxide after endogenous synthesis in nasopharynx. Lancet. 1994;343:518–519.[Medline] [Order article via Infotrieve]
39. Figini M, Ricciardolo FLM, Javdan P, Nijkamp FP, Emanueli C, Pradelles P, Folkerts G, Geppetti P. Evidence that epithelium-derived relaxing factor released by bradykinin in the guinea pig trachea is nitric oxide. Am J Respir Crit Care Med. 1996;153:918–923.[Abstract]
40. Shaul PW, Wells LB. Oxygen modulates nitric oxide production selectively in fetal pulmonary endothelial cells. Am J Respir Cell Mol Biol. 1994;11:432–438.[Abstract]
41. Rubanyi GM, Schwartz A, Vanhoutte PM. The calcium agonists Bay K 8644 and (+)202, 791 stimulate the release of endothelial relaxing factor from canine femoral arteries. Eur J Pharmacol. 1985;117:143–144.[Medline] [Order article via Infotrieve]
42. Bennett MA, Hillier C, Thurston H. Endothelium-dependent relaxation in resistance arteries from spontaneously hypertensive rats: effect of long-term treatment with perindopril, quinapril, hydralazine or amlodipine. J Hypertens. 1996;14:389–397.[Medline] [Order article via Infotrieve]
43. Gunther J, Dhein S, Rosen R, Klaus W, Fricke U. Nitric oxide (EDRF) enhances the vasorelaxing effect of nitrendipine in various isolated arteries. Basic Res Cardiol. 1992;87:452–460.[Medline] [Order article via Infotrieve]
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