(Hypertension. 1995;26:847-853.)
© 1995 American Heart Association, Inc.
Articles |
Human Atrial Natriuretic Peptide Gene Delivery Reduces Blood Pressure in Hypertensive Rats
From the Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston.
Correspondence to Lee Chao, PhD, Department of Biochemistry and Molecular Biology, Medical University of South Carolina, 171 Ashley Ave, Charleston, SC 29425.
 |
Abstract |
|---|
 Top Abstract IntroductionMethodsResultsDiscussionReferences |
|---|
Abstract Chronic infusion of atrial natriuretic peptide (ANP) has been shown to cause natriuresis, diuresis, and hypotension in rats and humans. We explored the effect of a continuous supply of ANP by somatic ANP delivery on genetically hypertensive rats. A DNA construct containing the human ANP gene fused to the Rous sarcoma virus 3'-long terminal repeat (RSV-LTR) was injected intravenously into spontaneously hypertensive rats (SHR) through the tail vein. Expression of human ANP in SHR was identified in the heart, lung, and kidney by radioimmunoassay and reverse transcription–polymerase chain reaction followed by Southern blot analysis. A single injection of naked ANP plasmid DNA (12.3 kb) caused a significant reduction of systemic blood pressure in young SHR (4 weeks old), and the effect continued for 7 weeks. The differences were significant at 1 to 2 weeks (n=6, P<.05) and 3 to 6 weeks after injection (n=6, P<.01) A maximal blood pressure reduction of 21 mm Hg in young SHR was observed 5 weeks after injection with ANP DNA (159.4±3.02 mm Hg, mean±SEM, n=6) compared with SHR injected with vector DNA alone (180.2±3.02 mm Hg, mean±SEM; n=6; P<.01). Somatic gene delivery of human ANP DNA had no effect on the blood pressure of adult SHR (12 weeks old). After ANP gene delivery, there were significant increases in urinary volume and urinary potassium output (n=6, P<.05) but not in body weight, heart rate, water intake, urinary sodium output, urinary creatinine, and urinary protein. Antibodies to human ANP or plasmid ANP DNA were not detected in rat sera. These results indicate that somatic delivery of the human ANP gene induces a sustained reduction of systemic blood pressure in young hypertensive rats and raise the feasibility of using ANP gene therapy for the treatment of human hypertension.
Key Words: atrial natriuretic factor • rats, inbred SHR • somatic gene therapy • blood pressure • hypertension
|
Introduction |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
ANP is a 28–amino acid peptide hormone secreted predominantly by atrial cardiomyocytes.1 2 The administration of exogenous ANP resulted in numerous physiological responses, including a rapid natriuresis and diuresis as well as a reduction in arterial blood pressure.3 4 5 6 7 8 9 10 The use of ANP as a therapeutic agent has been explored extensively. ANP has been shown to cause blood pressure reduction in animals and hypertensive human subjects when applied as a bolus injection or in short-term infusions.11 12 13 14 15 16 17 Long-term infusion of ANP often raised ANP concentrations to the upper range of physiological levels and caused a sustained reduction in blood pressure.11 12 13 14 15 16 17 18 When ANP was infused at a low rate of 0.5 to 1.0 pmol/kg per minute, plasma renin activity, aldosterone, and catecholamines were suppressed, with a concomitant reduction of blood pressure.11 18 Infusion of ANP at the rate of 5 to 10 pmol/kg per minute was found to be effective in primary aldosteronism, glomerulonephritis, and renovascular hypertension by reducing blood pressure, lowering plasma aldosterone, and increasing natriuresis.19 Recent studies suggest that transgenic mice overexpressing mouse ANP develop sustained hypotension without causing diuretic and natriuretic effects.20 Monoclonal antibody against ANP was used chronically to block endogenous ANP and to accelerate the development of hypertension in SHR and deoxycorticosterone acetate salt–hypertensive rats.21 A genetic defect in ANP production could lead to salt-sensitive hypertension in mice with a disruption of the mouse ANP gene.22
To investigate the role of ANP in blood pressure regulation in vivo, we applied the human ANP gene linked with Rous sarcoma virus 3'-long terminal repeat (RSV-LTR) to overexpress human ANP in young SHR. In this study, the results revealed that direct delivery of the human gene into SHR via a single intravenous injection led to a sustained lowering of blood pressure for 7 weeks. In addition, the apparent diuretic and slight natriuretic effects occurred 5 weeks after delivery of the human ANP gene. These findings suggest that it is feasible to use gene therapy for introducing ANP DNA to alleviate human hypertensive diseases.
|
Methods |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Materials
The eukaryotic expression vector pREP8 was purchased from Invitrogen. Twelve young SHR (male; 4 weeks old; body weight, 50 to 100 g) and 12 adult SHR (male; 12 weeks old; body weight, 270 to 300 g) were used (Harlan Sprague Dawley, Harlan, Indianapolis, Ind). The rats were housed at a constant room temperature with a 12-hour light/dark cycle and had free access to tap water and rat chow.
RSV-cANP Plasmid DNA Preparation
Human ANP cDNA (cANP) encoding the entire coding
sequence23 (nucleotides 1 through 456) was
amplified from total RNA of human atrium by RT-PCR. The sense primer
used was 5'-ATGAGCTCCTTCTCCACCAC-3' from 1 to 20 of human ANP cDNA and
the antisense primer was 5'-TCAGTACCGGAAGCTGTTAC-3' from 456 to 437 of
the termination codon and exon 2. The amplified product was cloned
into pCR II vector (Invitrogen) according to the manufacturer's
instructions. To construct plasmid RSV-cANP, the human ANP cDNA insert
was released from pCR II vector by Xho I and
HindIII digestion and cloned into the plasmid pREP8 at
Xho I and HindIII sites (Fig 1). The mammalian episomal expression
vector pREP8 includes ori P and EBNA-1 gene (the Epstein-Barr virus
replication origin and nuclear antigen gene), which permit
extrachromosomal replication in a wide variety of primate and canine
cell lines.24 25 26 The expression of human ANP cDNA encoding
the entire coding sequence was under the transcriptional control of the
RSV-LTR promoter in plasmid RSV-cANP.
|
Transient Transfection of Human Hepatoma G2 Cells
Human hepatoma G2 cells (Hep G2 cells) at 80% confluence were
transfected according to the manufacturer's instructions with 10 µg
of plasmid RSV-cANP DNA and pREP8 by Lipofectamine reagent (BRL).
Seventy-two hours after transfection, the transfected Hep G2 cells
were washed with 1x PBS and harvested. Hep G2 cells were lysed by
three cycles of freeze-thawing in PBS. The immunoreactive human ANP
in cell lysates and medium was assayed by a direct RIA specific for
human ANP.
Tissue Preparation
Seven weeks after injection of ANP or vector DNA, rats were
anesthetized intraperitoneally with
pentobarbital at a dose of 50 mg/kg body wt and perfused with normal
saline (0.9% NaCl) by cardiac puncture. Tissues were
homogenized in normal saline with a Polytron (Brinkmann
Instruments). The homogenate was centrifuged at
600g for 10 minutes. The supernatant was incubated in 0.5%
sodium deoxycholate and then centrifuged at 10 000g
for 30 minutes. Total protein in the supernatant was determined by
Lowry's method.27
RIA for Human ANP
The level of human ANP in each tissue extract was determined by
an RIA specific for human ANP. Ten micrograms of human synthetic
ANP-(Ser99-Tyr126) (Sigma Chemical Co) was
labeled with 1 mCi of 125I, which was iodinated
with iodogen for 10 minutes at room temperature. The
iodinated ANP in 250 mmol/L sodium phosphate buffer, pH
7.0, was separated on a reversed-phase C18
high-performance liquid chromatography
column in an acetonitrile gradient. 125I-ANP labeled
tracer, which was eluted from the column at 19 to 20 minutes after
injection, was identified by antibody titration. Serial dilutions of
standard ANP (10 to 1280 pg) or tissue extracts (100 µL) were
incubated with goat anti-human ANP antiserum (1:1500 dilution,
Sigma) in a solution containing 0.01 mol/L PBS (pH 7.4), 0.3% bovine
serum albumin, 0.1% Triton X-100, 0.1 mmol/L EDTA and 0.1%
sodium azide, and 125I-ANP tracer (10 000 cpm in 100 µL)
in a total volume of 400 µL for 18 to 24 hours at 4°C. The reaction
was stopped by adding 800 µL of 25% polyethylene glycol in PBS
containing 0.1% sodium azide and 400 µL of 1% bovine
-globulin in PBS containing 0.1% sodium azide. The
radioactivity of the precipitate was determined in a gamma counter.
RT-PCR Southern Blot Analysis of Human ANP mRNA in
Transfected Hep G2 Cells and in Tissues of SHR
Total RNA was extracted from fresh rat tissues by guanidine
isothiocyanate–cesium chloride gradient
ultracentrifugation.28 The reaction
mixture for RT contained 1 µg of total RNA from SHR, 10 pmol of 3'
primer (5'-CACTGAGCACTTGTGGG-3' located at the second exon of the human
ANP gene), 20 nmol of dNTP, 0.2 µmol of dithiothreitol, 4 µL of 5x
RT buffer (250 mmol/L Tris-HCl, pH 8.3; 375 mmol/L KCl; and 15 mmol/L
MgCl2), and 200 U of Moloney's murine leukemia virus
reverse transcriptase (BRL) in a total volume of 20 µL. The RT
reaction mixture was incubated at 37°C for 1 hour to synthesize the
first strand of cDNA. Ten picomoles of 5' primer
(5'-CACCGTGAGCTTCCTCCTTT-3' from the first exon of the human ANP gene),
5 µL of 10x PCR buffer, and 0.5 U of Taq DNA polymerase
were added to the RT mixture to a total volume of 50 µL followed by
35 cycles of hot-start PCR (94°C, 1 minute; 55°C, 1 minute;
72°C, 1 minute) with wax. Twenty microliters of the RT-PCR
products was subjected to a Southern blot analysis. A
specific oligonucleotide (5'-TAGGTCAGACCAGAGCT-3' from
the first exon of the human ANP gene) was used as an internal probe for
hybridization at 45°C. The filter was washed twice in 6x SSC at room
temperature for 15 minutes each time and then washed in 3x SSC at
45°C for 30 minutes each time. The blot was washed to a final
stringency of 1x SSC with 0.1% sodium dodecyl sulfate at
50°C for 30 minutes once and exposed to Kodak X-Omat film at
-80°C.
Direct DNA Delivery
The plasmid DNA of pREP8 vector and RSV-cANP was purified with a
plasmid purification kit (Qiagen) according to the manufacturer's
instructions. Twelve 4-week-old SHR and twelve 12-week-old SHR
were each divided into two groups. One group of young and adult rats
was injected with a plasmid pREP8 construct through the tail vein, and
the other was injected with RSV-cANP. The constructs were diluted to 1
mg/mL in PBS before injection and administered at a dose of 500 µg
per young rat and 1 mg per adult rat.
Blood Pressure Measurement
Systolic pressure of SHR was measured with a programmed
electrosphygmomanometer PE-300 (Narco Bio-Systems, Division of
International Biomedical, Inc) with the use of the indirect
tail-cuff method.29 Unanesthetized rats
were placed in a plastic holder that was mounted on a thermostatically
controlled warm plate maintained at 37°C during measurement. An
average of 10 readings was taken for each animal.
Assays for Serum Antibodies in Rats
Immunologic responses were monitored by measuring the
production of antibodies against human ANP or ANP plasmid DNA
(RSV-cANP) in the sera of experimental rats. Serum antibodies binding
to human ANP protein or ANP DNA were measured by ELISA. Microtiter
ELISA plates were coated with either synthetic human ANP at 5 µg/mL
in PBS at 4°C or with the purified ANP DNA construct at 5 µg/mL in
1x SSC (150 mmol/L sodium chloride, 15 mmol/L sodium citrate, pH 7.0)
at 37°C overnight.30 Serially diluted rat serum in PBS
containing 0.05% Tween-20 was added to the plates. After incubation
for 45 minutes at room temperature, plates were washed and
peroxidase-conjugated goat anti-rat IgG was added. Substrate
solution was added, and the plates were read at 414 nm on a Titertek
plate reader.
Urine Collection and Analysis of
Physiological Parameters
Twenty-four–hour urine of rats was collected using
metabolic cages 5 weeks after injection. Controls and
ANP-injected animals (n=6 each) were fed regular food for 3 hours
before they were placed in metabolic cages supplied with
drinking bottles. To eliminate contamination of urine samples, animals
received only water during the 24-hour collection period. Urine was
collected 24 hours later and centrifuged in a microfuge at
1000g to remove particles. The volume of the supernatant was
measured and stored for analysis. One milliliter of each sample
was used to measure urinary sodium and potassium output, urinary
creatinine, and total protein.
Statistical Analysis
Data were analyzed with the use of standard statistical
methods. Repeated blood pressure measurements were taken after gene
delivery for comparison between control and RSV-cANP groups with the
use of ANOVA and Fisher's protected least significant difference.
Group data are expressed as mean±SEM. Values were considered
significantly different at a value of P<.05.
|
Results |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
Expression of Human ANP in Hep G2 Cells Transfected with RSV-cANP DNA
Human ANP cDNA construct that was linked to RSV-LTR promoter (RSV-cANP) is shown in Fig 1. The human ANP cDNA construct was transiently transfected in Hep G2 cells, and expression of human ANP was measured by an RIA specific for human ANP. Immunoreactive human ANP secreted from Hep G2 cells into culture medium reached a level of 337±7 pg/mL (n=4). A serial dilution of the culture medium showed parallelism with the human ANP standard, indicating their immunologic identity (Fig 2). No immunoreactive ANP could be detected in the culture medium of Hep G2 cells transfected with control vector DNA.
|
), and serial dilutions of rat tissue
extracts are shown as follows: heart (
), kidney (
), lung
(
), and culture medium (
).
Expression of Human ANP and its mRNA in SHR after Gene
Delivery
Blood pressure was monitored weekly, and rats were killed 7 weeks
after injection. Expression of human ANP in SHR was analyzed by
an RIA for human ANP. The results showed that immunoreactive human ANP
is detected in the heart, lung, and kidney after gene delivery. Linear
displacement curves for immunoreactive human ANP in heart, lung, and
kidney extracts paralleled the human ANP standard curve,
indicating their immunologic identity (Fig 2). A serial
dilution of kidney, lung, and heart extracts from control rats injected
with the vector DNA did not show parallelism with the human ANP
standard. These results indicate that goat anti-human ANP antibody
has some cross-reactivity with rat ANP; however, human and rat ANP
are not immunologically identical and are distinguished in the RIA.
Total RNAs prepared from the heart, lung, liver, and kidney of SHR after gene delivery were analyzed for the human ANP transcript by using specific oligonucleotide probes for human ANP. RT-PCR followed by Southern blot analysis showed that the human ANP gene is expressed in the heart, lung, and kidney of rats receiving human ANP DNA injection (Fig 3). The RT-PCR products from control rats showed weak, nonspecific binding but did not hybridize to the specific human ANP probe. These results indicate that expression of the human ANP gene was detected in SHR after somatic ANP gene delivery.
|
Lack of Immunoresponse With Intravenous Injection of
Human ANP DNA
Direct delivery of the human ANP gene into SHR induces expression
of exogenous human ANP. To examine the possibility of antibody
production against human ANP or its DNA in rats, we used ELISA
to measure antibody levels in rat sera injected with ANP DNA and vector
DNA. Using serial dilutions of rat sera from 1:10 to 1:1000, we did not
detect any antibodies against either human ANP protein or ANP DNA at 7
weeks after injection. From our previous ELISA assays using the same
procedures, the lower limit of detecting the concentration of antibody
for human kallistatin antibody is 5 ng IgG/mL.
Hypotensive Effect of ANP Gene Delivery in Young but not
Adult SHR
The effect of human ANP DNA (500 µg) on the blood pressure of
young SHR (4 weeks old) was monitored weekly from 1 to 7 weeks after
intravenous injection. The plasmid DNA of pREP8 vector was
injected intravenously as a control. The results show that
the ANP construct produced a significant reduction in the
systolic pressure 1 to 7 weeks after injection compared with
control rats receiving vector DNA injection (Fig 4). The differences were significant at 1
to 2 weeks (n=6, P<.05) and 3 to 6 weeks (n=6,
P<.01) after injection. A maximal blood pressure reduction
of 21 mm Hg in young SHR was observed 5 weeks after injection with ANP
DNA (159.4±3.02 mm Hg, mean±SEM, n=6) compared with SHR injected
with vector DNA alone (180.2±3.02 mm Hg, mean±SEM, n=6,
P<.01). However, there is no significant difference of
blood pressure in adult SHR (12 weeks old) injected with 1 mg human ANP
DNA versus pREP8 vector DNA (Fig 5). The
hypotensive effects of ANP gene delivery in young SHR were observed in
three separate experiments.
|
P<.01,
*P<.05, RSV-cANP vs pREP8 control group (n=6).
|
Effects of Human ANP Gene Delivery on the
Physiological Parameters in
SHR
The Table shows results of
physiological analysis of urine samples of
young SHR injected with RSV-cANP compared with control rats receiving
vector DNA at 5 weeks after injection. At the time of urine collection,
a reduction of blood pressure was observed from 180.2±3.02 mm Hg in
the control group to 159.4±3.02 mm Hg (n=6, P<.01) in the
experimental group. Significant increases of urine volume (5.62±0.96
versus 3.68±0.53 mL/100 g body wt per day, mean±SEM; n=6,
P<.05) and urinary potassium output (0.90±0.06 versus
0.76±0.05 mmol per rat per day, mean±SEM; n=6, P<.05)
were observed in SHR after delivery of the ANP DNA. No apparent changes
in heart rate, body weight, water intake, urinary sodium output,
urinary creatinine, and urinary protein levels were
observed in SHR after delivery of the human ANP gene.
|
|
Discussion |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
The present study shows that somatic gene delivery of naked human ANP DNA resulted in a sustained decrease in the systolic pressure of young SHR (4 weeks old) without having an effect on the blood pressure of adult SHR (12 weeks old). The maximal reduction of blood pressure was 21 mm Hg after ANP gene delivery compared with control rats receiving vehicle DNA injection. Hypotension was sustained for 7 weeks after a single injection of ANP DNA, and the expression of human ANP was detected in the heart, lung, and kidney of SHR by an RIA and by RT-PCR Southern blot analysis. Human ANP gene delivery resulted in a significant increase in diuresis. These findings suggest that it is feasible to apply ANP gene therapy for treating human hypertensive diseases.
Previous studies suggest that ANP administration causes several biological responses: reduction in arterial blood pressure and rapid natriuresis and diuresis.3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 Garcia et al31 reported that chronic infusion of active ANP (ANP-[Arg101-Tyr126]) reduced blood pressure and increased diuresis and natriuresis in conscious one-kidney, one-clip hypertensive rats. Hamet and colleagues evaluated the effects of prolonged ANP infusion on blood pressure and humoral parameters in normotensive and hypertensive African green monkeys (Cercopithecus aethiops). They also found that prolonged ANP infusion caused a significant decrease in blood pressure, plasma renin activity, aldosterone, and hematocrit in normotensive and hypertensive monkeys without increasing plasma cGMP levels.32 Furthermore, recent studies have shown that transgenic mice overexpressing mouse ANP exhibit sustained hypotension,20 whereas ANP knockout mice are hypertensive after salt loading.22 The present study shows that a continuous supply of ANP by somatic gene delivery has a prolonged effect on blood pressure reduction. Collectively, these findings are consistent with our recent studies of other vasodilators of the tissue kallikrein-kinin system. Previously, we showed that transgenic mice overexpressing human tissue kallikrein are hypotensive29 and that somatic gene delivery of human tissue kallikrein into SHR by intravenous and intramuscular injection induces reduction of blood pressure in these rats.30 33 The present studies showed that ANP and kallikrein gene therapies could potentially be used to treat complex hypertensive diseases.
It is interesting to note that direct gene delivery of human ANP causes a reduction in the blood pressure of young SHR (4 weeks old) without causing any effect on adult SHR (12 to 14 weeks old). Our results are comparable with those reported by Mulvany,34 who showed that a synthetic ANP induces dilatation of isolated renal resistance vessels in young but not in adult SHR. We injected human ANP DNA construct into young SHR and observed a blood pressure–lowering effect 1 week after gene delivery that lasted for 7 weeks. This result is consistent with a previous study by Harrap et al,35 who showed that an angiotensin-converting enzyme inhibitor prevents full expression of hypertension in 6- to 10-week-old SHR as a result of permanent reduction in total peripheral resistance.36 It has been suggested that 6- to 10-week-old SHR are in the most critical phase in the development of hypertension.36 At the present time, it is not known whether ANP receptors gradually alter their sensitivity to ANP on renal resistance vessels during the development of hypertension in SHR. It is interesting to observe that tissue kallikrein gene delivery into SHR induces a sustained reduction of blood pressure in adult SHR.30 33 These results suggest that therapeutic usage of both ANP and tissue kallikrein gene delivery are effective in reducing blood pressure, but each gene construct may be unique in exerting the greatest impact during a specific developmental stage.
Rats receiving a single intravenous injection of human ANP DNA have a 65% increase in daily urine production and a significant increase of urinary potassium output. Although there is a slight increase of urinary sodium output and water consumption in RSV-cANP–injected SHR, no significant differences were detected in water consumption, urinary sodium output, urinary creatinine, and urinary protein. These results are similar to those of Steinhelper et al,20 who showed that several physiological parameters including water intake and daily sodium output of ANP transgenic mice are not significantly different from those of control littermates. Since SHR injected with ANP were fed a normal salt diet during the experimental period, it is possible that sodium excretion is not in excess as a result of bodily fluid and systemic sodium homeostasis. Therefore, salt-sensitive hypertensive rats might serve as a good model for studying the relation between natriuretic effects and human ANP expression.
Somatic gene transfer techniques using various constructs and vectors have been developed extensively in recent years.37 38 39 40 41 In this study, we show that a single intravenous injection of unprotected human ANP DNA construct produced a sustained reduction in blood pressure. The RSV-cANP construct harbors the EBNA-1 gene, which makes it possible to replicate as an episome in primate and canine cells but not in rodent cells.24 25 26 Therefore, somatic delivery of RSV-cANP construct in human gene therapy could prolong the expression period even more. One possible way to achieve long-term expression is to use retrovirus-mediated gene transfer, which promotes chromosomal integration. However, the site of integration is random and carries the risk of gene inactivation.42 In SHR injected with the human ANP gene construct, there were no obvious changes in body weight, heart rate, or rat activity, indicating that DNA injection was nontoxic to the recipient rats. In comparison with long-term daily drug intake or human ANP infusion for controlling hypertensive symptoms, a major therapeutic advantage of ANP gene therapy is that a single injection provides a long-lasting effect without causing any apparent side effects or immunologic responses.
These findings suggest that ANP gene delivery could be an effective and feasible alternative for treating human hypertensive diseases. Efficiency and uptake of naked ANP plasmid DNA by direct intravenous injection might be quite low. Other methods such as liposome-mediated delivery or virus vector-mediated transfer for improving efficiency of gene delivery and expression will be the subject of future studies.
|
Selected Abbreviations and Acronyms |
|---|
|
|
Acknowledgments |
|---|
This work was supported by National Institutes of Health grants HL-29397 and DE-09731. We thank Dr Carmelann Zintz for critical review of the manuscript.
Received May 22, 1995; first decision June 14, 1995; accepted July 25, 1995.
|
References |
|---|
|
TopAbstractIntroductionMethodsResultsDiscussionReferences |
|---|
1. de Bold AJ, Borenstein HB, Veress AT, Sonnenberg H. A rapid and potent natriuretic response to intravenous injection of atrial myocardial extract in rats. Life Sci. 1981;28:89-94. [Medline] [Order article via Infotrieve]
2.
de Bold AJ. Atrial natriuretic
factor: a hormone produced by the heart. Science. 1985;230:767-770.
3.
Needleman P, Adams SP, Cole BR, Currie MG, Geller DM,
Michener ML, Saper CB, Schwartz D, Standaert DG. Atriopeptins as
cardiac hormones. Hypertension. 1985;7:469-482.
4. Laragh JH. Atrial natriuretic hormone, the renin-aldosterone axis, and blood pressure-electrolyte homeostasis. N Engl J Med. 1985;313:1330-1340. [Abstract]
5.
Cantin M, Genest J. The heart and the atrial
natriuretic factor. Endocr Rev. 1985;6:107-127.
6. Needleman P, Greenwald JE. Atriopeptin: a cardiac hormone intimately involved in fluid, electrolyte, and blood-pressure homeostasis. N Engl J Med. 1986;314:828-834. [Medline] [Order article via Infotrieve]
7. Sonnenberg H. Renal effects of atrial natriuretic factor. ISI Atlas of Science: Pharmacology. 1988:171-174.
8. Trippodo NC. An update on the physiology of atrial natriuretic factor. Hypertension. 1987;10(suppl I):I-122-I-127.
9.
Brenner BM, Ballermann BJ, Gunning ME, Zeidel
ML. Diverse biological actions of atrial natriuretic
peptide. Physiol Rev. 1990;70:665-699.
10. Atlas S, Maack T. Atrial natriuretic factor. In: Windhager EE, ed. Handbook of Physiology: Renal Physiology. New York, NY: Oxford University Press; 1992:1577-1673.
11.
Janssen WM, de Zeeuw D, van der Hem GK, de Jong
PE. Antihypertensive effect of a 5-day infusion of atrial
natriuretic factor in humans.
Hypertension. 1989;13:640-646.
12. Granger JP, Opgenorth TJ, Salazar J, Romero JC, Burnett JC Jr. Long-term hypotensive and renal effects of atrial natriuretic peptide. Hypertension. 1986;8(suppl II):II-112-II-116.
13. Spokas EG, Suleymanov OD, Bittner SE, Campion JG, Gorczynski RJ, Lenaers A, Walsh GM. Cardiovascular effects of chronic high-dose atriopeptin III infusion in normotensive rats. Toxicol Appl Pharmacol. 1987;91:305-314. [Medline] [Order article via Infotrieve]
14.
Pares DG, Coghlan JP, McDouggali JG, Scoggins
BA. Long-term hemodynamic actions of atrial
natriuretic factor (99-126) in conscious sheep.
Am J Physiol. 1988;254:H811-H815.
15.
Harrison-Bernard LM, Vari RC, Holleman WH, Trippodo NC,
Barbee RW. Chronic vs acute hemodynamic effects
of atrial natriuretic factor in conscious rats.
Am J Physiol. 1991;260:R247-R254.
16. Garcia R, Thibault G, Gutkowska J, Horky K, Hamet P, Cantin M, Genest J. Chronic infusion of low doses of atrial natriuretic factor (ANF Arg 101-Tyr 126) reduces blood pressure in conscious SHR without apparent changes in sodium excretion. Proc Soc Exp Biol Med. 1985;179:396-401. [Medline] [Order article via Infotrieve]
17.
De Mey JG, Cuthbert C, von Szendroi KG, van Malder G,
Roba J. Smooth muscle relaxing, acute and long-term blood
pressure lowering effect of atriopeptins: structure-activity
relationship. J Pharmacol Exp Ther. 1987;240:937-943.
18. Cusson JR, Thibault G, Cantin M, Larochelle P. Prolonged low dose infusion of atrial natriuretic factor in essential hypertension. Clin Exp Hypertens. 1990;12:111-135.
19.
Hirata Y, Ishii M, Sugimoto T, Matsuoka H, Fukui K,
Sugimoto T, Yamakado M, Tagawa H, Miyata A, Kangawa K, Matsuo H.
Hormonal and renal effects of atrial natriuretic peptide in
patients with secondary hypertension.
Circulation. 1988;78:1401-1410.
20.
Steinhelper ME, Cochrane KL, Field LJ.
Hypotension in transgenic mice expressing atrial
natriuretic factor fusion genes.
Hypertension. 1990;16:301-307.
21. Itoh H, Nakao K, Mukoyama M, Yamada T, Hosoda K, Shirakami G, Morii N, Sugawara A, Saito Y, Shiono S, Arai H, Yoshida I, Imura H. Chronic blockade of endogenous atrial natriuretic polypeptide (ANP) by monoclonal antibody against ANP accelerates the development of hypertension in spontaneously and deoxycorticosterone acetate-salt-hypertensive rats. J Clin Invest. 1989;84:145-154.
22.
Simon WM, Krege JH, Oliver PM, Hagaman JR, Hodgin JB,
Pang SC, Flynn TG, Smithies O. Genetic decreases in atrial
natriuretic peptide and salt-sensitive
hypertension. Science. 1995;267:679-681.
23. Greenberg BD, Bencen GH, Seilhamer JJ, Lewicki JA, Fiddes JC. Nucleotide sequence of the gene coding human atrial natriuretic factor precursor. Nature. 1984;312:656-658. [Medline] [Order article via Infotrieve]
24. Yates JL, Warren N, Sugden B. Stable replication of plasmids derived from Epstein-Barr virus in various mammalian cells. Nature. 1985;313:812-815. [Medline] [Order article via Infotrieve]
25.
Hauer CA, Getty RR, Tykocinski ML. Epstein-Barr
virus episome-based promoter function in human myeloid
cells. Nucleic Acids Res. 1989;17:1989-2003.
26.
Margolskee RF, Kavathas P, Berg P. Epstein-Barr
virus shuttle vector for stable episomal replication of cDNA expression
libraries in human cells. Mol Cell Biol. 1988;8:2837-2847.
27.
Lowry OH, Rosebrough NJ, Farr AL, Randall RJ.
Protein measurement with the Folin phenol reagent.
J Biol Chem. 1951;193:265-275.
28. Sambrook J, Fritsch EF, Maniatis T. Molecular Cloning: A Laboratory Manual. Plainview, NY: Cold Spring Harbor Laboratory Press; 1989:7.19-7.22.
29.
Wang J, Xiong W, Yang Z, Davis T, Dewey MJ, Chao J,
Chao L. Human tissue kallikrein induces hypotension in
transgenic mice. Hypertension. 1994;23:236-243.
30. Wang C, Chao L, Chao J. Direct gene delivery of human tissue kallikrein reduces blood pressure in spontaneously hypertensive rats. J Clin Invest. 1995;95:1710-1716.
31. Garcia P, Gutkowska J, Genest J, Cantin M, Thibault G. Reduction of blood pressure and increased diuresis and natriuresis during chronic infusion of atrial natriuretic factor (ANF Arg 101-Tyr 126) in conscious one-kidney, one-clip hypertensive rats. Proc Soc Exp Biol Med. 1985;179:539-545. [Medline] [Order article via Infotrieve]
32. Hamet P, Testaert E, Palmour R, Larochelle P, Cantin M, Gutkowska J, Langlois Y, Ervin F, Tremblay J. Effect of prolonged infusion of ANF in normotensive and hypertensive monkeys. Am J Hypertens. 1989;2:690-695.[Medline] [Order article via Infotrieve]
33.
Xiong W, Chao J, Chao L. Muscle delivery of
human kallikrein gene reduces blood pressure in hypertensive
rats. Hypertension. 1995;25:1-5.
34. Mulvany MJ. Enhanced dilatation by atrial natriuretic peptide of renal arcuate arteries from young, but not adult, spontaneously hypertensive rats. Clin Exp Hypertens. 1987;9:1789-1801.
35.
Harrap SB, Van der Merwe WM, Griffin SA, Macpherson F,
Lever AF. Brief angiotensin converting enzyme
inhibitor treatment in young spontaneously hypertensive
rats reduces blood pressure long-term.
Hypertension. 1990;16:603-614.
36.
Unger T, Rettig R. Development of genetic
hypertension: is there a `critical phase'?
Hypertension. 1990;16:615-616.
37. Flotte T R. Prospects for virus-based gene therapy for cystic fibrosis. J Bioenerg Biomembr. 1993;25:37-42. [Medline] [Order article via Infotrieve]
38.
Wolff JA, Malone RW, Williams P, Chong W, Acsadi G,
Jani A, Felgner PL. Direct gene transfer into mouse muscle in
vivo. Science. 1990;247:1465-1468.
39.
Barr E, Leiden JM. Systemic delivery of
recombinant proteins by genetically modified myoblasts.
Science. 1991;254:1507-1509.
40. Wolff JA, Williams P, Acsadi G, Jiao S, Jani A, Chong W. Conditions affecting direct gene transfer into rodent muscle in vivo. Biotechniques. 1991;11:474-485.[Medline] [Order article via Infotrieve]
41.
Dhawan J, Pan LC, Pavlath GK, Travis MA, Lanctot AM,
Blau HM. Systemic delivery of human growth hormone by injection
of genetically engineered myoblasts. Science. 1991;254:1509-1512.
42. Nabel EG, Pompili VJ, Plautz GE, Nabel GJ. Gene transfer and vascular disease. Cadiovasc Res. 1994;28:445-455.
This article has been cited by other articles:
 |
|
 |
|
  M. K. Raizada and S. D. Sarkissian Potential of Gene Therapy Strategy for the Treatment of Hypertension Hypertension, January 1, 2006; 47(1): 6 - 9. [Full Text] [PDF]
|
|
|
|
 |
|
 K. J. Schillinger, S. Y. Tsai, G. E. Taffet, A. K. Reddy, A. J. Marian, M. L. Entman, K. Oka, L. Chan, and B. W. O'Malley Regulatable atrial natriuretic peptide gene therapy for hypertension PNAS, September 27, 2005; 102(39): 13789 - 13794. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Pan, R. Gulati, C. S. Mueske, T. A. Witt, A. Lerman, J. C. Burnett Jr., and R. D. Simari Gene transfer of a novel vasoactive natriuretic peptide stimulates cGMP and lowers blood pressure in mice Am J Physiol Heart Circ Physiol, June 1, 2004; 286(6): H2213 - H2218. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Q. Miao, J. Agata, L. Chao, and J. Chao Kallistatin is a new inhibitor of angiogenesis and tumor growth Blood, October 16, 2002; 100(9): 3245 - 3252. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Massfelder, N. Taesch, S. Fritsch, A. Eichinger, M. Barthelmebs, A. F. Stewart, and J.-J. Helwig Type 1 Parathyroid Hormone Receptor Expression Level Modulates Renal Tone and Plasma Renin Activity in Spontaneously Hypertensive Rat J. Am. Soc. Nephrol., March 1, 2002; 13(3): 639 - 648. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K.-F. Lin Human Atrial Natriuretic Peptide Gene Delivery Reduces Blood Pressure in Hypertensive Rats Hypertension, December 1, 2001; 38 (6): e37 - e37. [Full Text] [PDF]
|
|
|
|
|
|
A. S. Pachori, M. J. Huentelman, S. C. Francis, C. H. Gelband, M. J. Katovich, and M. K. Raizada The Future of Hypertension Therapy: Sense, Antisense, or Nonsense? Hypertension, February 1, 2001; 37(2): 357 - 364. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Gardon, M. K Raizada, M. J Katovich, K. H Berecek, and C. H Gelband Gene therapy for hypertension and restenosis Journal of Renin-Angiotensin-Aldosterone System, September 1, 2000; 1(3): 211 - 216. [PDF]
|
|
|
|
 |
|
 J. Zicha and J. Kunes Ontogenetic Aspects of Hypertension Development: Analysis in the Rat Physiol Rev, October 1, 1999; 79(4): 1227 - 1282. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. K. Raizada, M. J. Katovich, H. Wang, K. H. Berecek, and C. H. Gelband Is antisense gene therapy a step in the right direction in the control of hypertension? Am J Physiol Heart Circ Physiol, August 1, 1999; 277(2): H423 - H432. [Full Text] [PDF]
|
|
|
|
 |
|
 I. J. Kullo, R. D. Simari, and R. S. Schwartz Vascular Gene Transfer : From Bench to Bedside Arterioscler Thromb Vasc Biol, February 1, 1999; 19(2): 196 - 207. [Full Text] [PDF]
|
|
|
|
|
|
M. I. Phillips Is Gene Therapy for Hypertension Possible? Hypertension, January 1, 1999; 33(1): 8 - 13. [Full Text] [PDF]
|
|
|
|
|
|
K.-F. Lin, J. Chao, and L. Chao Atrial Natriuretic Peptide Gene Delivery Reduces Stroke-Induced Mortality Rate in Dahl Salt-Sensitive Rats Hypertension, January 1, 1999; 33(1): 219 - 224. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Mohuczy, C. H. Gelband, and M. I. Phillips Antisense Inhibition of AT1 Receptor in Vascular Smooth Muscle Cells Using Adeno-Associated Virus-Based Vector Hypertension, January 1, 1999; 33(1): 354 - 359. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K.-F. Lin, L. Chao, and J. Chao Prolonged Reduction of High Blood Pressure With Human Nitric Oxide Synthase Gene Delivery Hypertension, September 1, 1997; 30(3): 307 - 313. [Abstract] [Full Text]
|
|
|
|
|
|
M. I. Phillips Antisense Inhibition and Adeno-Associated Viral Vector Delivery for Reducing Hypertension Hypertension, January 1, 1997; 29(1): 177 - 187. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. I. Phillips, D. Mohuczy-Dominiak, M. Coffey, S. M. Galli, B. Kimura, P. Wu, and T. Zelles Prolonged Reduction of High Blood Pressure With an In Vivo, Nonpathogenic, Adeno-Associated Viral Vector Delivery of AT1-R mRNA Antisense Hypertension, January 1, 1997; 29(1): 374 - 378. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||