1 Department of Pharmacology, Boyer Center for Molecular Medicine, Yale University School of Medicine, New Haven 06536; 2 Section of Digestive Diseases, Department of Internal Medicine, Yale University School of Medicine, New Haven 06520; and 3 Hepatic Hemodynamic Laboratory, Veterans Affairs Connecticut Healthcare System, West Haven, Connecticut 06516
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ABSTRACT |
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Systemic vasodilation is the
initiating event of the hyperdynamic circulatory state, being most
likely triggered by increased levels of vasodilators, primarily nitric
oxide (NO). Endothelial NO synthase (eNOS) is responsible for this
event. We tested the hypothesis that gene deletion of eNOS and
inducible NOS (iNOS) may inhibit the development of the hyperdynamic
circulatory state in portal hypertensive animals. To test this
hypothesis, we used mice lacking eNOS (eNOS/
) or eNOS/iNOS
(eNOS/iNOS
/
) genes. A partial portal vein ligation (PVL) was used
to induce portal hypertension. Sham-operated animals were used as a
control. Hemodynamic characteristics were tested 2 wk after surgery. As
opposed to our hypothesis, PVL also caused significant reduction in
peripheral resistance in eNOS
/
compared with sham animals
(0.33 ± 0.02 vs. 0.41 ± 0.03 mmHg · min · kg body wt · ml
1;
P = 0.04) and in eNOS/iNOS
/
animals with PVL
compared with that of the sham-operated group (0.44 ± 0.02 vs.
0.54 ± 0.04; P = 0.03). This demonstrates that,
despite gene deletion of eNOS, the knockout mice developed hyperdynamic
circulation. Compensatory vasodilator molecule(s) are upregulated in
place of NO in the systemic and splanchnic circulation in portal
hypertensive animals.
liver diseases; nitric oxide; vasodilatation; and portal vein ligation.
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INTRODUCTION |
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HYPERDYNAMIC CIRCULATORY state is known as a hallmark of portal hypertension in liver cirrhosis. It is characterized by such hemodynamic abnormalities as generalized systemic vasodilation with lowered mean arterial pressure and systemic vascular resistance and subsequent blood volume expansion with elevated cardiac index and regional blood flows (28). Systemic vasodilation is the initiating event of this hyperdynamic circulatory state and is most likely triggered by increased levels of vasodilators, primarily nitric oxide (NO) (13, 14, 21-23). Inhibition of NO production has been shown to ameliorate the hyperdynamic circulatory state in patients with cirrhosis (12) as well as in animal models of cirrhosis and/or portal hypertension (14).
NO is produced by three distinct isoforms of NO synthase (NOS), two of which are constitutively expressed [endothelial NOS (eNOS), which is involved in regulating basal vasodilation, and neuronal NOS (nNOS)] and one that is inducible (iNOS) and produces NO in response to such stimuli as LPS and cytokines. It is known that eNOS is the major isoform responsible for excessive NO production in the systemic and splanchnic circulation of cirrhotic animals and humans (4, 5, 15, 27, 28).
The goal of the present study was to elucidate further the role of eNOS as well as iNOS in the development of the hyperdynamic circulatory state. To achieve this goal we used eNOS knockout mice as well as both eNOS and iNOS knockout mice. The utilization of those mice lacking eNOS and iNOS genes allowed us to investigate the effects of NO, or the lack thereof, without administering exogenous inhibitors that may not be specific enzymatically and may induce other unwanted hemodynamic effects that may obscure the sole effect of a deficient NOS. Furthermore, this is the first study to use mice for the study of the hyperdynamic circulatory syndrome in portal hypertension. Because the vast majority of gene deletion studies have been achieved in murine models, this study will expand the possibility of the usage of mice in the study of portal hypertension.
We found that knockout mice lacking eNOS and both eNOS and iNOS still developed similar hemodynamic characteristics to those seen in wild-type animals with portal hypertension. Our results strongly suggest that other vasodilator molecule(s) may compensate for the lack of NO. Additionally, this finding may suggest that the long-term inhibition of NO may not be enough to treat the vasodilatory syndrome observed in cirrhosis. The blockade of other vasodilator(s), besides NO, would be necessary for the effective long-term treatment of the hyperdynamic syndrome of chronic liver disease.
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MATERIALS AND METHODS |
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Animals
Knockout mice lacking the gene for eNOS (eNOSInduction of Portal Hypertension
A prehepatic portal hypertensive animal model extensively studied in our laboratory (6) was used. Portal vein ligation (PVL) to induce portal hypertension in mice was performed (16). In brief, the animals were anesthetized with ketamine hydrochloride (Ketalar, 100 mg/kg body wt; Parke-Davis, Avon, CT) and xylazine (10 mg/kg body wt; Phoenix Pharmaceutical, St. Joseph, MO). After a midline abdominal incision, the portal vein was freed from surrounding tissue. A ligature (silk gut 6-0) was placed around a 27-gauge blunt-tipped needle lying along the portal vein. Subsequent removal of the needle yielded a calibrated stenosis of the portal vein. In sham-operated mice, the same operation was performed, with the exception that, after the portal vein was isolated, no ligature was placed. After the operation, the animals were housed in plastic cages and allowed free access to food and water. Studies were performed 14 days after operation.Western Blotting
To confirm the absence of eNOS and iNOS protein in knockout mice, aorta from eNOSHemodynamic Studies
On the day of experimentation, animals were weighed and anesthetized with ketamine hydrochloride (100 mg/kg) and fastened to a surgical board. Mean arterial pressure (MAP) was measured by cannulating the exposed left femoral artery with a polyethylene (PE)-10 (intravascular) catheter joined to a PE-50 (extravascular) tubing (Clay Adams; Becton Dickinson, Parsippany, NJ) connected to a pressure transducer (Hewlett-Packard, Andover, MA). The external zero reference was placed at the midportion of the mice. Cardiac output was then measured by the thermodilution technique. Briefly, a thermistor (F.1) was placed in the aortic arch by way of the left carotid artery, and the thermal indicator (20 µl of normal saline maintained at a temperature of 15° or more below body temperature) was injected into the right atrium through a PE-10 catheter placed into the right jugular vein. The aortic thermistor was connected to a cardiac output computer (Columbus Instruments, Columbus, OH). Body temperature was maintained at 37.0 ± 0.2°C. At least three thermodilution curves were obtained for each cardiac output measurement, discarding those curves with unusual morphology. A typical curve had a rapid upslope and a smooth decay. The final cardiac output value was obtained from the arithmetic mean of at least three cardiac output measurements. Cardiac index was calculated as cardiac output per 100 g body wt. Systemic vascular resistance was calculated from MAP divided by cardiac index. Right atrial pressure was regarded as negligible. Portal pressure (PP) was measured by inserting the tip of a 30-gauge needle into the superior mesenteric vein. The needle length was joined to a short length of PE-10 tubing, which in turn was joined to PE-50 tubing and connected to a Hewlett-Packard pressure transducer. All hemodynamic readings were monitored and saved on a computer using the analog-to-digital MacLab system (ADInstruments, Milford, MA).To further confirm the absence of the eNOS gene in the double knockout
mice, an injection of
N-nitro-L-arginine
(L-NNA) (Sigma) dissolved in normal saline (12 mg/kg body
wt) was made into the jugular vein catheter before death of the
knockout mice and control. The subsequent effect of NNA on MAP was noted.
Additionally, to exclude the possibility of nNOS induction in eNOS/
or eNOS/iNOS
/
with PVL surgery, L-NNA was also injected in those animals. The changes in MAP were determined after
L-NNA injection.
Portal-Systemic Shunting
Portal-systemic shunting was estimated in at least 10 animals in each group by the splenic pulp injection of ~30,000 141Ce-labeled microspheres (15.5 ± 0.1 µm; New England Nuclear, Boston, MA), mixed in 0.1 ml of normal saline as previously described (6).Statistics
Results were expressed as means ± SE. Statistical analyses were performed using the unpaired Student's t-test and the Bonferroni-Dunn ANOVA. ![]() |
RESULTS |
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A total of 32 wild-type control mice (eNOS+/+), 31 eNOS/
knockout mice, 28 wild-type controls for eNOS/iNOS
/
mice
(eNOS/iNOS+/+), and 35 eNOS/iNOS
/
mice were studied. Besides
genotyping, Western blot analysis for eNOS or iNOS confirmed the
knockout genotypes of the breeders that bred the mice used in the
experiments (Fig. 1). Mean body weight of
the wild-type control mice was no different from that of the eNOS
/
mice (30.2 ± 0.75 vs. 30.2 ± 2.58 g). Similarly, mean
body weight of eNOS/iNOS
/
mice (27.1 ± 1.17 g) was no
different from that of the wild-type control mice (27.4 ± 1.29 g).
|
We also tested the hemodynamic characteristics of wild-type control and
knockout mice. Both types of knockout mice were hypertensive with
elevated MAP, as also reported by others (3, 10, 20): MAP
of wild-type control (eNOS+/+) and knockout eNOS/
mice were 77.27 ± 1.4 and 124.3 ± 5.6 mmHg (P = 0.0001), respectively; MAP of wild-type control (eNOS/iNOS+/+)
and knockout eNOS/iNOS
/
mice were 117.2 ± 4.4 and 151.9 ± 7.1 mmHg (P = 0.001), respectively. Perfusion of the
NOS inhibitor (L-NNA) raised the MAP of all the wild-type
animals tested, whereas that of knockout mice did not change,
confirming the lack of NO production in knockout animals.
Expression of eNOS Protein in PVL Animals
It has been shown that eNOS protein expression is upregulated in the splanchnic circulation in portal hypertensive rats and rabbits (4, 5, 15, 27, 28). It is not known whether this is also the case for a mouse model of PVL. Western blot analysis indicated that PVL significantly increased eNOS protein expression in the SMA compared with that of sham-operated mice (P < 0.05). Similar to SMA of rats, eNOS protein is significantly upregulated in the splanchnic circulation in mice with chronic portal hypertension (Fig. 1).Effect of PVL on Hemodynamic Characteristics
Wild-type control for eNOS/
mice.
Portal-systemic shunting increased in the PVL group compared with the
sham-operated group (91.8 ± 4.3 vs. 0.2 ± 0.1%,
P = 0.0001). The PVL resulted in significantly
increased PP compared with the sham-operated group (8.1 ± 0.6 vs.
4.7 ± 0.3 mmHg, P = 0.003). Similarly, the PVL
group showed a significantly increased cardiac index (CI) compared with
that of the sham-operated group (534.0 ± 25.9 vs. 407.5 ± 33.9 mmHg, P = 0.008). The systemic vascular resistance
(SVR) of the PVL group significantly decreased compared with the
sham-operated group (0.133 ± 0.008 vs. 0.192 ± 0.03 mmHg · min · kg body wt · ml
1,
P = 0.03). These data strongly suggest that, similar to
rats (7, 26), mice developed the hyperdynamic circulatory
state as a result of PVL (Fig. 2).
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eNOS knockout mice.
Portal-systemic shunting significantly increased in the PVL group
compared with the sham-operated group (58.6 ± 15.7 vs. 0.3 ± 0.17%, P = 0.03). We then compared factors
associated with the hyperdynamic circulatory state, including MAP, CI,
SVR, and PP, between sham-operated and PVL groups (Fig.
3). PVL caused a significant twofold
increase in PP (P = 0.0001) compared with that of the sham-operated group (8.1 ± 0.5 vs. 4.6 ± 0.1 mmHg). CI of
the PVL group significantly increased compared with that of the
sham-operated group (369.3 ± 16.9 vs. 311.4 ± 11.4 ml · min1 · kg body wt
1,
P = 0.01). The SVR of the PVL group was significantly
lower than that of sham-operated eNOS
/
group (0.33 ± 0.02 vs.
0.41 ± 0.03 mmHg · min · kg body
wt · ml
1, P = 0.04).
Collectively, these data demonstrate that eNOS
/
mice also developed
the hyperdynamic circulatory state as a result of PVL.
|
Wild-type control for
eNOS/iNOS/
mice.
Portal-systemic shunting increased in the PVL group compared with the
sham-operated group (72.0 ± 18.4 vs. 0.4 ± 0.13%,
P = 0.0046). The PVL resulted in significantly
increased PP compared with the sham-operated group (7.1 ± 0.8 vs.
4.9 ± 0.2 mmHg, P = 0.015). Similarly,
the PVL group showed a significantly increased CI compared with that of
the sham-operated group (474.1 ± 21.9 vs. 416.4 ± 14.3 mmHg, P = 0.04). The SVR of the PVL group
significantly decreased compared with the sham-operated group
(0.242 ± 0.009 vs. 0.284 ± 0.009 mmHg · min · kg body wt · ml
1,
P = 0.005). These data strongly suggest that, similar
to rats (7, 26), these wild-type mice also developed the
hyperdynamic circulatory state as a result of PVL (Fig.
4).
|
eNOS/iNOS/
mice.
As also seen in eNOS
/
mice, PVL resulted in the developed
hyperdynamic circulatory state in eNOS/iNOS
/
mice (Fig.
5). Increased portal-systemic shunting
was observed in the PVL group compared with the sham-operated group
(84.8 ± 12.1 vs. 1.1 ± 0.7%, P = 0.002).
PVL resulted in a significant increase in PP compared with that of the
sham-operated group (6.3 ± 0.3 vs. 5.2 ± 0.3 mmHg,
P = 0.016). PVL significantly increased CI compared
with the sham group (370.2 ± 22.8 vs. 287.4 ± 11.0 ml · min
1 · kg body
wt
1, P = 0.004). The peripheral
resistance of the PVL group significantly decreased compared with the
sham group (0.44 ± 0.02 vs. 0.54 ± 0.04 mmHg · min · kg body wt · ml
1,
P = 0.03). Collectively, these data suggest that PVL
also resulted in the development of the hyperdynamic circulatory state
in eNOS/iNOS
/
mice.
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Magnitude of Development of Hyperdynamic Circulation
Values of hemodynamic characteristics at their baseline levels are different between wild-type and knockout mice (see Table 2). To compare the levels of the development of the hyperdynamic circulation between the wild-type controls and their corresponding knockout mice, we determined the percent changes in MAP, CI, PP, and SVR after the PVL operation, which were then compared between the wild-type and knockout mice (Table 1). The percent changes in those factors were no different between wild-type and knockout animals, suggesting that knockout mice developed the hyperdynamic circulatory state to an extent similar to that observed in wild-type control mice. Collectively, these data strongly suggest that mice lacking eNOS and iNOS still developed the hyperdynamic circulatory state.
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Effects of a NOS Inhibitor on MAP
To test the involvement of nNOS in knockout mice with PVL, L-NNA (a nonspecific NOS inhibitor) was injected, and MAP was measured. L-NNA did not increase MAP in either eNOS
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DISCUSSION |
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We found that mice lacking eNOS or eNOS/iNOS genes still developed the hyperdynamic circulatory state after partial PVL. Our results may suggest that involvement of another vasodilator(s), besides NO, are involved in the development of the hyperdynamic circulatory state, a hallmark of portal hypertension. Furthermore, when NO is lacking, this vasodilator(s) plays a significant role in enhanced vasodilatation in the systemic and splanchnic circulation in portal hypertensive animals.
NO is a vasodilator that regulates vascular tone (11).
eNOS is the key NOS isoform that regulates blood pressure
(10). Thus knockout mice lacking the eNOS gene demonstrate
abnormally increased vascular resistance; thereby, they are arterial
hypertensive (Table 1). In contrast, mice lacking the iNOS gene only do
not develop hypertension. However, to further rule out the possibility of iNOS involvement in arterial vasodilation in portal hypertensive animals, we also studied the effects of PVL on mice lacking both eNOS
and iNOS genes. The partial portal vein ligation is a commonly used
method to study hemodynamic characteristics of portal hypertension and
has been used by our laboratory and others in rats (7, 9, 13, 19,
22-24, 26, 28) and by us in mice (16). Animals
with PVL produce similar hemodynamic characteristics to those seen in
chronic liver diseases with portal hypertension. Those characteristics
include reduced peripheral resistance due to increased vasodilatation
owing to an excessive NO production in the splanchnic and systemic
circulation (1, 15). Of the three isoforms, eNOS, not
iNOS, plays a central role in vasodilatation in the splanchnic and
systemic circulation and contributes to the development of the
hyperdynamic circulatory state (4, 5, 15, 27, 28). Thus we
hypothesized that knockout mice lacking eNOS could be resistant to the
development of the hyperdynamic circulation due to the lack of vascular
NO production. In contrast to our hypothesis, PVL still led to the
development of the hyperdynamic circulatory state in knockout mice to a
similar extent to that observed in wild-type control animals
(Table 2).
|
We also tested the possibility of compensatory NO production by nNOS. L-NNA, known to produce arterial hypertensive responses in mice, did not cause any increase in arterial pressure in PVL knockout mice (Fig. 6). If nNOS had a significant role in the compensatory mechanism observed in PVL knockout mice, L-NNA would have induced an increase in arterial pressure. Therefore, a compensatory role of nNOS is unlikely to account for our results.
Until now, in experimental animals, studies about the hyperdynamic state have been done mainly in rats. To our knowledge, this is the first demonstration of a study of the hyperdynamic state using a mouse model. Utilization of murine models will enable us to explore the role of specific gene products in the hyperdynamic circulatory state. In rats with chronic portal hypertension, studies have shown an upregulation of eNOS protein expression in the splanchnic circulation. We demonstrated that in wild-type mice there is a significant upregulation of eNOS protein expression, similar to the rat model of portal hypertension, suggesting the similarity in the effects of PVL between rats and mice.
Baseline hemodynamic characteristics (such as MAP, CI, and resistance) as expected are significantly different between wild-type and knockout mice. Thus the percent changes in each factor between sham-operated and PVL may be a better indicator for the evaluation of the development of the hyperdynamic circulatory state (Table 2). The percent changes in each hemodynamic factor as a result of PVL were not different between wild-type and knockout animals, suggesting that knockout mice developed the hyperdynamic circulatory state to an extent similar to that observed in wild-type animals.
Our results suggest that, in the absence of NO, one or more compensatory vasodilator(s) seems to be upregulated and play a role in the reduction of peripheral resistance in portal hypertensive animals. The presence of a vasodilator(s) distinct from NO has been suggested in vessels of both wild-type and eNOS knockout mice (2, 8, 17, 18, 25). A compensatory role by the endothelium-dependent hyperpolarization factor (EDHF) in the deficiency of NO has been suggested in mesenteric vessels (17, 18) and mouse hindlimb (2). In coronary circulation and skeletal muscle arterioles, endothelial vasodilator prostaglandins are upregulated in the absence of eNOS (8, 25). Considering this evidence, it is highly possible that compensatory vasodilators, such as prostalgandins, EDHF, or another molecule, may be upregulated and consequently reduce the peripheral resistance in eNOS and eNOS/iNOS knockout mice with PVL in our study.
In conclusion, a compensatory vasodilator molecule seems to be upregulated in place of NO in the systemic and splanchnic circulation in portal hypertensive knockout animals. Although studies have shown the beneficial effects of NO inhibitors for the treatment of the hyperdynamic circulation in portal hypertension in both human and animal models (12, 14), it would be important to take into account this compensatory response by vasodilators that seems to replace the chronic absence of NO production and to lead to the development of the hyperdynamic circulation. Thus an inhibition of NO may not be enough for the chronic treatment of hyperdynamic circulatory syndrome observed in portal hypertension. This compensatory mechanism in an NO-depleted vasculature may need to be determined for the development of effective pharmacological agents that can reduce the occurrence of the hyperdynamic circulatory syndrome.
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ACKNOWLEDGEMENTS |
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Y. Iwakiri and G. Cadelina contributed equally to this work.
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FOOTNOTES |
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This work is supported by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Liver Center Molecular Biology and Imaging Cores P30-DK-34989, NIDDK Hepatology Training Grant T32-DK-07356-23 to Y. Iwakiri, and Veterans Affairs Merit Review Grant to R. J. Groszmann. W. C. Sessa is an Established Investigator of the American Heart Association.
Address for reprint requests and other correspondence: R. J. Groszmann, Hepatic Hemodynamic Laboratory/111J, Veterans Administration Medical Center, 950 Campbell Ave., West Haven, CT 06516 (E-mail: roberto.groszmann{at}yale.edu).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
July 31, 2002;10.1152/ajpgi.00145.2002
Received 15 April 2002; accepted in final form 17 July 2002.
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REFERENCES |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
1.
Atucha, NM,
Shah V,
Garcia-Cardena G,
Sessa WE,
and
Groszmann RJ.
Role of endothelium in the abnormal response of mesenteric vessels in rats with portal hypertension and liver cirrhosis.
Gastroenterology
111:
1627-1632,
1996[ISI][Medline].
2.
Brandes, RP,
Schmitz-Winnenthal FH,
Feletou M,
Godecke A,
Huang PL,
Vanhoutte PM,
Fleming I,
and
Busse R.
An endothelium-derived hyperpolarizing factor distinct from NO and prostacyclin is a major endothelium-dependent vasodilator in resistance vessels of wild-type and endothelial NO synthase knockout mice.
Proc Natl Acad Sci USA
97:
9747-9752,
2000
3.
Busse, R,
and
Mulsch A.
Calcium-dependent nitric oxide synthesis in endothelial cytosol is mediated by calmodulin.
FEBS Lett
265:
133-136,
1990[ISI][Medline].
4.
Cahill, PA,
Foster C,
Redmond EM,
Gingalewski C,
Wu Y,
and
Sitzmann JV.
Enhanced nitric oxide synthase activity in portal hypertensive rabbits.
Hepatology
22:
598-606,
1995[ISI][Medline].
5.
Cahill, PA,
Redmond EM,
Hodges R,
Zhang S,
and
Sitzmann JV.
Increased endothelial nitric oxide synthase activity in the hyperemic vessels of portal hypertensive rats.
J Hepatol
25:
370-378,
1996[ISI][Medline].
6.
Chojkier, M,
and
Groszmann RJ.
Measurement of portal-systemic shunting in the rat by using gamma-labeled microspheres.
Am J Physiol Gastrointest Liver Physiol
240:
G371-G375,
1981
7.
Colombato, LA,
Albillos A,
and
Groszmann RJ.
Temporal relationship of peripheral vasodilatation, plasma volume expansion and the hyperdynamic circulatory state in portal-hypertensive rats.
Hepatology
15:
323-328,
1992[ISI][Medline].
8.
Godecke, A,
and
Schrader J.
Adaptive mechanisms of the cardiovascular system in transgenic micelessons from eNOS and myoglobin knockout mice.
Basic Res Cardiol
95:
492-498,
2000[ISI][Medline].
9.
Hori, N,
Wiest R,
and
Groszmann RJ.
Enhanced release of nitric oxide in response to changes in flow and shear stress in the superior mesenteric arteries of portal hypertensive rats.
Hepatology
28:
1467-1473,
1998[ISI][Medline].
10.
Huang, PL,
Huang Z,
Mashimo H,
Bloch KD,
Moskowitz MA,
Bevan JA,
and
Fishman MC.
Hypertension in mice lacking the gene for endothelial nitric oxide synthase.
Nature
377:
239-242,
1995[ISI][Medline].
11.
Ignarro, LJ,
Buga GM,
Wood KS,
Byrns RE,
and
Chaudhuri G.
Endothelium-derived relaxing factor produced and released from artery and vein is nitric oxide.
Proc Natl Acad Sci USA
84:
9265-9269,
1987[Abstract].
12.
La Villa, G,
Barletta G,
Pantaleo P,
Del Bene R,
Vizzutti F,
Vecchiarino S,
Masini E,
Perfetto F,
Tarquini R,
Gentilini P,
and
Laffi G.
Hemodynamic, renal, and endocrine effects of acute inhibition of nitric oxide synthase in compensated cirrhosis.
Hepatology
34:
19-27,
2001[ISI][Medline].
13.
Lee, FY,
Albillos A,
Colombato LA,
and
Groszmann RJ.
The role of nitric oxide in the vascular hyporesponsiveness to methoxamine in portal hypertensive rats.
Hepatology
16:
1043-1048,
1992[ISI][Medline].
14.
Lee, FY,
Colombato LA,
Albillos A,
and
Groszmann RJ.
N-nitro-L-arginine administration corrects peripheral vasodilation and systemic capillary hypotension and ameliorates plasma volume expansion and sodium retention in portal hypertensive rats.
Hepatology
17:
84-90,
1993[ISI][Medline].
15.
Niederberger, M,
Gines P,
Martin PY,
Tsai P,
Morris K,
McMurtry I,
and
Schrier RW.
Comparison of vascular nitric oxide production and systemic hemodynamics in cirrhosis versus prehepatic portal hypertension in rats.
Hepatology
24:
947-951,
1996[ISI][Medline].
16.
Pons, HA,
Morgan JS,
Hutchinson ML,
Rojkind M,
Groszmann RJ,
and
Stadecker MJ.
Resistance to reinfection in experimental murine schistosomiasis: role of porto-hepatic hemodynamics.
Am J Trop Med Hyg
41:
189-197,
1989[ISI][Medline].
17.
Ruiz-Marcos, FM,
Ortiz MC,
Fortepiani LA,
Nadal FJ,
Atucha NM,
and
Garcia-Estan J.
Mechanisms of the increased pressor response to vasopressors in the mesenteric bed of nitric oxide-deficient hypertensive rats.
Eur J Pharmacol
412:
273-279,
2001[ISI][Medline].
18.
Scotland, RS,
Chauhan S,
Vallance PJ,
and
Ahluwalia A.
An endothelium-derived hyperpolarizing factor-like factor moderates myogenic constriction of mesenteric resistance arteries in the absence of endothelial nitric oxide synthase-derived nitric oxide.
Hypertension
38:
833-839,
2001
19.
Shah, V,
Wiest R,
Garcia-Cardena G,
Cadelina G,
Groszmann RJ,
and
Sessa WC.
Hsp90 regulation of endothelial nitric oxide synthase contributes to vascular control in portal hypertension.
Am J Physiol Gastrointest Liver Physiol
277:
G463-G468,
1999
20.
Shesely, EG,
Maeda N,
Kim HS,
Desai KM,
Krege JH,
Laubach VE,
Sherman PA,
Sessa WC,
and
Smithies O.
Elevated blood pressures in mice lacking endothelial nitric oxide synthase.
Proc Natl Acad Sci USA
93:
13176-13181,
1996
21.
Sieber, CC,
and
Groszmann RJ.
In vitro hyporeactivity to methoxamine in portal hypertensive rats: reversal by nitric oxide blockade.
Am J Physiol Gastrointest Liver Physiol
262:
G996-G1001,
1992
22.
Sieber, CC,
and
Groszmann RJ.
Nitric oxide mediates hyporeactivity to vasopressors in mesenteric vessels of portal hypertensive rats.
Gastroenterology
103:
235-239,
1992[ISI][Medline].
23.
Sieber, CC,
Lopez-Talavera JC,
and
Groszmann RJ.
Role of nitric oxide in the in vitro splanchnic vascular hyporeactivity in ascitic cirrhotic rats.
Gastroenterology
104:
1750-1754,
1993[ISI][Medline].
24.
Sikuler, E,
Kravetz D,
and
Groszmann RJ.
Evolution of portal hypertension and mechanisms involved in its maintenance in a rat model.
Am J Physiol Gastrointest Liver Physiol
248:
G618-G625,
1985
25.
Sun, D,
Huang A,
Smith CJ,
Stackpole CJ,
Connetta JA,
Shesely EG,
Koller A,
and
Kaley G.
Enhanced release of prostaglandins contributes to flow-induced arteriolar dilation in eNOS knockout mice.
Circ Res
85:
288-293,
1999
26.
Vorobioff, J,
Bredfeldt JE,
and
Groszmann RJ.
Hyperdynamic circulation in portal-hypertensive rat model: a primary factor for maintenance of chronic portal hypertension.
Am J Physiol Gastrointest Liver Physiol
244:
G52-G57,
1983
27.
Wiest, R,
Das S,
Cadelina G,
Garcia-Tsao G,
Milstien S,
and
Groszmann RJ.
Bacterial translocation in cirrhotic rats stimulates eNOS-derived NO production and impairs mesenteric vascular contractility.
J Clin Invest
104:
1223-1233,
1999
28.
Wiest, R,
Shah V,
Sessa WC,
and
Groszmann RJ.
NO overproduction by eNOS precedes hyperdynamic splanchnic circulation in portal hypertensive rats.
Am J Physiol Gastrointest Liver Physiol
276:
G1043-G1051,
1999