Evidence That Reduced Renal Medullary NOS Activity of Dahl S Rats Enables Small Elevations of Avp to Produce Sustained Hypertension

Hypertension ◽  
2000 ◽  
Vol 36 (suppl_1) ◽  
pp. 682-682
Author(s):  
Baozhi Yuan ◽  
Allen W Cowley
Keyword(s):  
Nitric Oxide ◽  
Control Level ◽  
Renal Medulla ◽  
Renal Tissue ◽  
Brown Norway ◽  
Experimental Hypertension ◽  
Chronic Hypertension ◽  
No Production ◽  
Potent Vasoconstrictor ◽  
Plasma Arginine

27 It remains unclear why sustained elevations of plasma arginine vasopressin (AVP), a potent vasoconstrictor and fluid retaining hormone, do not generally result in hypertension. Related to this, there have been 4 general observations: 1) AVP is elevated in many forms of human and experimental hypertension, including Dahl S rats; 2) AVP can stimulate nitric oxide synthases (NOS) and nitric oxide (NO) production in the renal medulla of normal rats; 3) AVP stimulated NO production can buffer AVP induced reductions of medullary blood flow; 4) partial reduction of medullary NOS activity (via medullary L-NAME infusion) unmasks chronic hypertensive effects of small elevations of plasma AVP (Hypertension. 2000; 35:740-745). In the present study, we hypothesize that Dahl salt-sensitive rats (DS) have reduced capacity to synthesize medullary NO which sensitizes them to the hypertensive effects of small elevations of circulating AVP. DS and Brown Norway (BN) rats with implanted arterial and venous catheters were fed a 0.4% salt diet and infused continuously for 14 days with a chronic “subpressor” dose of AVP (2 ng/kg/min). Conscious mean arterial pressure (MAP) was measured 2 hours daily with rats maintained in their home cages. MAP in DS rats increased during day1 of AVP infusion from a control level of 127 ± 0.9 mmHg to an average of 147 ± 1.6 mmHg after 14 days. MAP did not return to control values even within three days following the end of AVP infusion. BN rats showed no changes of MAP during 14 days of AVP infusion (90.4 ± 0.6 mmHg and 92.3 ± 0.4 mmHg). Northern blot analysis of renal tissue from vehicle (saline) infused rats demonstrated that NOS I and NOS III mRNA expression was significantly less in DS rats in the renal outer medulla compared to BN rats. We conclude that small, normally subpressor elevations of plasma AVP can produce chronic hypertension in DS rats, a phenomenon probably related to reduced renal medullary NO synthesis.

Renal medullary nitric oxide deficit of Dahl S rats enhances hypertensive actions of angiotensin II

2002 ◽  
Vol 283 (1) ◽  
pp. R266-R272 ◽  
Author(s):  
Mátyás Szentiványi ◽  
Ai-Ping Zou ◽  
David L. Mattson ◽  
Paulo Soares ◽  
Carol Moreno ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Intravenous Infusion ◽  
Renal Medulla ◽  
Brown Norway ◽  
Ang Ii ◽  
Outer Medulla ◽  
Doppler Flowmetry ◽  
Medullary Blood Flow ◽  
Induced Hypertension ◽  
Renal Medullary Blood Flow

Studies were designed to examine the hypothesis that the renal medulla of Dahl salt-sensitive (Dahl S) rats has a reduced capacity to generate nitric oxide (NO), which diminishes the ability to buffer against the chronic hypertensive effects of small elevations of circulating ANG II. NO synthase (NOS) activity in the outer medulla of Dahl S rats (arginine-citrulline conversion assay) was significantly reduced. This decrease in NOS activity was associated with the downregulation of protein expression of NOS I, NOS II, and NOS III isoforms in this region as determined by Western blot analysis. In anesthetized Dahl S rats, we observed that a low subpressor intravenous infusion of ANG II (5 ng · kg−1 · min−1) did not increase the concentration of NO in the renal medulla as measured by a microdialysis with oxyhemoglobin trapping technique. In contrast, ANG II produced a 38% increase in the concentration of NO (87 ± 8 to 117 ± 8 nmol/l) in the outer medulla of Brown-Norway (BN) rats. The same intravenous dose of ANG II reduced renal medullary blood flow as determined by laser-Doppler flowmetry in Dahl S, but not in BN rats. A 7-day intravenous ANG II infusion at a dose of 3 ng · kg−1 · min−1 did not change mean arterial pressure (MAP) in the BN rats but increased MAP in Dahl S rats from 120 ± 2 to 138 ± 2 mmHg ( P< 0.05). ANG II failed to increase MAP after NO substrate was provided by infusion of l-arginine (300 μg · kg−1 · min−1) into the renal medulla of Dahl S rats. Intravenous infusion ofl-arginine at the same dose had no effect on the ANG II-induced hypertension. These results indicate that an impaired NO counterregulatory system in the outer medulla of Dahl S rats makes them more susceptible to the hypertensive actions of small elevations of ANG II.

scholarly journals Luminal flow induces eNOS activation and translocation in the rat thick ascending limb

2004 ◽  
Vol 287 (2) ◽  
pp. F274-F280 ◽  
Author(s):  
Pablo A. Ortiz ◽  
Nancy J. Hong ◽  
Jeffrey L. Garvin
Keyword(s):  
Nitric Oxide ◽  
Apical Membrane ◽  
Renal Medulla ◽  
Cytochalasin D ◽  
No Synthase ◽  
No Production ◽  
Thick Ascending Limb ◽  
Loop Of Henle ◽  
Luminal Flow ◽  
Nos Inhibitor

Nitric oxide (NO) produced by endothelial NO synthase (eNOS) acts as an autacoid to inhibit NaCl absorption in the thick ascending limb of the loop of Henle (THAL). In the vasculature, shear stress activates eNOS. We hypothesized that increasing luminal flow activates eNOS and enhances NO production in the THAL. We measured NO production by isolated, perfused THALs using a NO-sensitive microelectrode. Increasing luminal flow from 0 to 20 nl/min increased NO production by 43.1 ± 4.1 pA/mm of tubule ( n = 10, P < 0.05), and this response was blunted (92%) by the NOS inhibitor l-ωnitro-methylarginine ( P < 0.05). We studied the effect of flow on eNOS subcellular localization. In the absence of flow, eNOS was diffusely localized throughout the cell (basolateral = 33 ± 4%; middle = 27 ± 3%; apical = 40 ± 4% of total eNOS). Increasing luminal flow induced eNOS translocation to the apical membrane, as evidenced by a 60% increase in eNOS immunoreactivity in the apical membrane (from 40 ± 4 to 65 ± 2%; n = 6; P < 0.05). Disrupting the actin cytoskeleton with cytochalasin D (10 μM) reduced flow-induced NO production by 62% (from 37.1 ± 3.4 to 14.0 ± 2.4 pA/mm tubule, n = 7, P < 0.04) and blocked flow-induced eNOS translocation. Flow also increased the amount of phosphorylated eNOS (Ser1179) at the apical membrane (from 25 ± 2 to 56 ± 2%; P < 0.05). We conclude that increasing luminal flow induces eNOS activation and translocation to the apical membrane in THALs. These are the first data showing that flow regulates eNOS in epithelial cells. This may be an important mechanism for regulation of NO levels in the renal medulla.

scholarly journals Vascular Dysfunction as Target Organ Damage in Animal Models of Hypertension

2012 ◽  
Vol 2012 ◽  
pp. 1-6 ◽  
Author(s):  
Mario Fritsch Neves ◽  
Daniel Arthur B. Kasal ◽  
Ana Rosa Cunha ◽  
Fernanda Medeiros
Keyword(s):  
Endothelial Dysfunction ◽  
Vascular Reactivity ◽  
Vascular Dysfunction ◽  
Target Organ Damage ◽  
Organ Damage ◽  
Experimental Hypertension ◽  
Chronic Hypertension ◽  
No Production ◽  
Response Curves ◽  
Spontaneously Hypertensive

Endothelial dysfunction is one of the main characteristics of chronic hypertension and it is characterized by impaired nitric oxide (NO) bioactivity determined by increased levels of reactive oxygen species. Endothelial function is usually evaluated by measuring the vasodilation induced by the local NO production stimulated by external mechanical or pharmacological agent. These vascular reactivity tests may be carried out in different models of experimental hypertension such as NO-deficient rats, spontaneously hypertensive rats, salt-sensitive rats, and many others. Wire myograph and pressurized myograph are the principal methods used for vascular studies. Usually, increasing concentrations of the vasodilator acetylcholine are added in cumulative manner to perform endothelium-dependent concentration-response curves. Analysis of vascular mechanics is relevant to identify arterial stiffness. Both endothelial dysfunction and vascular stiffness have been shown to be associated with increased cardiovascular risk.

scholarly journals Role of nitric oxide in rat nephrotoxic nephritis: comparison between inducible and constitutive nitric oxide synthase.

1997 ◽  
Vol 8 (11) ◽  
pp. 1712-1721 ◽  
Author(s):  
V Bremer ◽  
A Tojo ◽  
K Kimura ◽  
Y Hirata ◽  
A Goto ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Early Stage ◽  
Renal Tissue ◽  
Macrophage Infiltration ◽  
Intercellular Adhesion Molecule ◽  
No Production ◽  
Sprague Dawley ◽  
Nephrotoxic Nephritis ◽  
Glomerular Damage

Nitric oxide (NO), generated by inducible NO synthase (iNOS) in migrating macrophages, is increased in glomerulonephritis. This study investigates the effect of NO inhibition on rat nephrotoxic nephritis (NTN) to clarify the role of NO production in glomerular damage. NTN was induced in Sprague Dawley rats by an injection of an anti-glomerular basement membrane (GBM) antibody. Urinary nitrite excretion and nitrite release from kidney slices (5.47 +/- 1.19 versus 2.15 +/- 0.73 nmol/mg protein, NTN versus Control, P < 0.05) were increased in NTN on day 2. Glomerular macrophage infiltration and intercellular adhesion molecule (ICAM)-1 expression increased from day 2. iNOS expression was increased in interstitial macrophages. Glomerular endothelial cell NOS (ecNOS) expression evaluated by counting immunogold particles along GBM was suppressed (0.06 +/- 0.02 versus 0.35 +/- 0.04 gold/micron GBM, P < 0.0001). Glomerular damage developed progressively. NG-nitro-L-arginine methyl ester (L-NAME), which inhibits both iNOS and ecNOS and aminoguanidine (AG), a relatively selective inhibitor for iNOS, equally suppressed nitrite in urine and renal tissue. Glomerular ICAM-1 expression and macrophage infiltration were reduced by L-NAME, but not by AG. Expression of ecNOS was significantly increased by L-NAME (0.91 +/- 0.08, P < 0.0001 versus NTN), but slightly by AG (0.18 +/- 0.04). AG significantly and L-NAME slightly attenuated the glomerular damage at day 4. In conclusion, suppression of iNOS prevents glomerular damage in the early stage of NTN. Treatment by L-NAME reduces macrophage infiltration by suppression of ICAM-1 expression, which may be explained by an increase in ecNOS expression.

scholarly journals Participation of nitric oxide in different models of experimental hypertension

2008 ◽  
pp. 813-825
Author(s):  
J Török
Keyword(s):  
Nitric Oxide ◽  
Blood Pressure ◽  
Nervous Activity ◽  
Sympathetic Nervous Activity ◽  
Experimental Hypertension ◽  
No Production ◽  
Common Denominator ◽  
Blood Pressure Elevation ◽  
Functional Changes ◽  
Wide Range

This review concerns the role of nitric oxide (NO) in the pathogenesis of different models of experimental hypertension (NO-deficient, genetic, salt-dependent), which are characterized by a wide range of etiology. Although the contribution of NO may vary between different models of hypertension, a unifying characteristic of these models is the presence of oxidative stress that participates in the maintenance of elevated arterial pressure and seems to be a common denominator underlying endothelial dysfunction in various forms of experimental hypertension. Besides the imbalance between the endothelial production of vasorelaxing and vasoconstricting compounds as well as the relative insufficiency of vasodilator systems to compensate augmented vasoconstrictor systems, there were found numerous structural and functional abnormalities in blood vessels and heart of hypertensive animals. The administration of antihypertensive drugs, antioxidants and NO donors is capable to attenuate blood pressure elevation and to improve morphological and functional changes of cardiovascular system in some but not all hypertensive models. The failure to correct spontaneous hypertension by NO donor administration reflects the fact that sympathetic overactivity plays a key role in this form of hypertension, while NO production in spontaneously hypertensive rats might be enhanced to compensate increased blood pressure. A special attention should be paid to the modulation of sympathetic nervous activity in central and peripheral nervous system. These results extend our knowledge on the control of the balance between NO and reactive oxygen species production and are likely to be a basis for the development of new approaches to the therapy of diseases associated with NO deficiency.

scholarly journals Periodic Assessment of Antenatal and Post Natal Serum Endothelin-1 (ET-1) and Nitric Oxide (NO) Levels in Hypertensive Disorders of Pregnancy (HDP)

2020 ◽  
Vol 18 (2) ◽  
Author(s):  
Hidayah I ◽  
Tariq A.R. ◽  
N.A. Jamani ◽  
Maizura M.Z.
Keyword(s):  
Nitric Oxide ◽  
Endothelial Dysfunction ◽  
Pregnant Women ◽  
Disease Risk ◽  
Chronic Hypertension ◽  
Hypertensive Disorders Of Pregnancy ◽  
Sample Collection ◽  
Endothelin 1 ◽  
Hypertensive Disorders ◽  
Potent Vasoconstrictor

Hypertensive Disorders of Pregnancy (HDP) is an independent risk factor of cardiovascular (CVS) disease with endothelial dysfunction postulated to be the pathophysiology. Endothelin-1 (ET-1), a potent vasoconstrictor, has been identified as a pivotal mediator in HDP. Disturbances in nitric oxide (NO) bioavailability found in endothelial dysfunction may increase susceptibility to cardiovascular diseases such as hypertension. The study aims to determine serial ET-1 and NO levels in patients with HDP and its role in persistent endothelial dysfunction. Thirty-six pregnant women from the following categories (i) normal pregnant women (Control) (ii) chronic hypertension during pregnancy (CH) and (iii) pregnancy induced hypertension (PIH) participated in this study. Blood pressure indices measurements and sample collection were done at antepartum (32 weeks) and postpartum (8 weeks and 12 weeks). ET-1 and serum NO were measured using the Human ET-1 (Endothelin-1) ELISA Kit and Nitric Oxide (total) detection kit respectively. Results: Serum ET-1 was significantly higher in patients with CH (55.3 pg/ml) and PIH (35.6 pg/ml) compared to Control (11.8 pg/ml) during antenatal until 3 months postpartum (CH 38.3 pg/ml, PIH 29.5 pg/ml, Control 1.9 pg/ml). This was accompanied by significantly lower levels of serum NO in HDP patients. Persistently higher than normal levels of ET-1 and lower than normal levels of NO up to 3 months postpartum in patients with history of HDP indicate presence of persistent endothelial dysfunction despite BP normalisation in PIH patients. Long term NO/ET-1 imbalance may account for the increased CVS disease risk.

scholarly journals Nitric oxide and l-arginine metabolism in a devascularized porcine model of acute liver failure

2012 ◽  
Vol 303 (3) ◽  
pp. G435-G441 ◽  
Author(s):  
Vikram Sharma ◽  
Gabriella A. M. Ten Have ◽  
Lars Ytrebo ◽  
Sambit Sen ◽  
Christopher F. Rose ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Liver Failure ◽  
Acute Liver Failure ◽  
Early Phase ◽  
Porcine Model ◽  
De Novo ◽  
Whole Body ◽  
No Production ◽  
Arginine Deficiency ◽  
Plasma Arginine

In acute liver failure (ALF), the hyperdynamic circulation is believed to be the result of overproduction of nitric oxide (NO) in the splanchnic circulation. However, it has been suggested that arginine concentrations (the substrate for NO) are believed to be decreased, limiting substrate availability for NO production. To characterize the metabolic fate of arginine in early-phase ALF, we systematically assessed its interorgan transport and metabolism and measured the endogenous NO synthase inhibitor asymmetric dimethylarginine (ADMA) in a porcine model of ALF. Female adult pigs (23–30 kg) were randomized to sham ( N = 8) or hepatic devascularization ALF ( N = 8) procedure for 6 h. We measured plasma arginine, citrulline, ornithine levels; arginase activity, NO, and ADMA. Whole body metabolic rates and interorgan flux measurements were calculated using stable isotope-labeled amino acids. Plasma arginine decreased >85% of the basal level at t = 6 h ( P < 0.001), whereas citrulline and ornithine progressively increased in ALF ( P < 0.001 and P < 0.001, vs. sham respectively). No difference was found between the groups in the whole body rate of appearance of arginine or NO. However, ALF showed a significant increase in de novo arginine synthesis ( P < 0.05). Interorgan data showed citrulline net intestinal production and renal consumption that was related to net renal production of arginine and ornithine. Both plasma arginase activity and plasma ADMA levels significantly increased in ALF ( P < 0.001). In this model of early-phase ALF, arginine deficiency or higher ADMA levels do not limit whole body NO production. Arginine deficiency is caused by arginase-related arginine clearance in which arginine production is stimulated de novo.

The % Tetrahydrobiopterin (BH4) and Serine 1177 Phosphorylation Is Reduced in Sickle Transgenic Mice.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3398-3398
Author(s):  
Qiuying Chen ◽  
Ashley Hale ◽  
Nicholas J. Alp ◽  
Keith M. Channon ◽  
Mary E. Fabry
Keyword(s):  
Nitric Oxide ◽  
Transgenic Mice ◽  
Vascular Function ◽  
Simple Relation ◽  
Superoxide Production ◽  
No Production ◽  
Red Cell ◽  
Air Plasma ◽  
Intracellular Ca ◽  
Plasma Arginine

Abstract Tetrahydrobiopterin (BH4) is an essential co-factor of nitric oxide synthase (NOS), the enzyme that generates nitric oxide (NO) from arginine and oxygen. NO plays an essential role in maintaining vascular tone and endothelial function, reducing levels of adhesion molecules and platelet aggregation, and reducing inflammation; all of which are critical in sickle cell disease (SCD). In addition to BH4, arginine, calmodulin, intracellular Ca++ levels, hsp90, phosphorylation at serine 1177 and threonine 495, and monomer/dimer equilibrium have all been shown to modulate NO and superoxide production by eNOS. Arginine levels are decreased in plasma in SCD. We have demonstrated that plasma arginine is reduced in sickle transgenic mice and that arginine supplementation partially restores both red cell and vascular function. Channon et al have demonstrated that, in atherosclerosis and diabetes, enhanced superoxide production is associated with BH4 depletion; superoxide can interfere with both NO production and, by reacting with NO, with bioavailability. We hypothesized that a similar depletion of BH4 occurs in SCD and that treatment protective of tissue BH4 levels may interrupt the cycle of polymerization, vaso-occlusion and inflammation that is the origin of pathology in SCD. We report here depletion of BH4 in tissue and plasma of several lines of sickle transgenic mice and the effect of hypoxia on % BH4 and serine 1177 phosphorylation in NY1DD mice, a mild sickle transgenic mouse that becomes more severe when exposed to hypoxia. Only BH4 is active as a NOS cofactor, the oxidized forms BH2 and biopterin (B) are inactive. Results are presented as %BH4 (BH4/(BH4+BH2+B)). We find that %BH4 is the same in C57BL and NY1DD mice under room air in plasma and brain. After exposure to 4 days of hypoxia (8% O2), % BH4 is reduced from 75.7%±3.8% to 53.7%±3.8% in plasma, p<0.004 and from 82.0%±3.7% to 68.7%±3.7% in brain, p<0.006. At the same time total biopterin (BT= BH4+BH2+B) increased in plasma, but remained constant in brain. We also measured eNOS phosphorylated at serine 1177 in brain in NY1DD mice. We find that the % phosphorylation decreases from 45.0%±7.9% to 28.3%±7.3%, p<0.007 after 4 days of hypoxia, but that at the same time total eNOS and total nNOS nearly doubled. BERK mice express exclusively HbS and, under normoxia, we found decreased %BH4 in brain in BERK mice (58%±3.3% vs 76.7%±3.0% for C57, p<0.003) with constant BT. In red cells of BERK mice, the %BH4 is about the same as C57BL (81.7% vs 76.7%, respectively), but BT doubled from 124 to 257, p>0.01. In conclusion, increased total expression of eNOS and nNOS and decreased %BH4 with decreased % phosphorylation at serine 1177 of eNOS suggest that NO production in brain in NY1DD mice after hypoxia may be severely compromised. Percent BH4 is also reduced in brain of BERK mice under normoxia, which suggests that BH4 is reduced in more severe mice under room air. Plasma and red cell %BH4 and BT do not have a simple relation to tissue levels, but do respond to pathology and may be the only readily measurable variable in human studies. The multiple pathways for disregulation of NOS in SCD involve not only NO scavenging by plasma free Hb and arginine deficiency, but also reduced bioavailability of BH4.

scholarly journals Intrinsic nitric oxide and superoxide production regulates descending vasa recta contraction

2010 ◽  
Vol 299 (5) ◽  
pp. F1056-F1064 ◽  
Author(s):  
Chunhua Cao ◽  
Aurélie Edwards ◽  
Mauricio Sendeski ◽  
Whaseon Lee-kwon ◽  
Lan Cui ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Renal Medulla ◽  
Ros Generation ◽  
No Production ◽  
Oxygen Species ◽  
Direct Effects ◽  
Vasa Recta ◽  
Luminal Perfusion ◽  
Oxide Synthase ◽  
Hydrophilic Solutes

Descending vasa recta (DVR) are 12- to 15-μm microvessels that supply the renal medulla with blood flow. We examined the ability of intrinsic nitric oxide (NO) and reactive oxygen species (ROS) generation to regulate their vasoactivity. Nitric oxide synthase (NOS) inhibition with Nω-nitro-l-arginine methyl ester (l-NAME; 100 μmol/l), or asymmetric NG, NG-dimethyl-l-arginine (ADMA; 100 μmol/l), constricted isolated microperfused DVR by 48.82 ± 4.34 and 27.91 ± 2.91%, respectively. Restoring NO with sodium nitroprusside (SNP; 1 mmol/l) or application of 8-Br-cGMP (100 μmol/l) reversed DVR vasoconstriction by l-NAME. The superoxide dismutase mimetic Tempol (1 mmol/l) and the NAD(P)H inhibitor apocynin (100, 1,000 μmol/l) also blunted ADMA- or l-NAME-induced vasoconstriction, implicating a role for concomitant generation of ROS. A role for ROS generation was also supported by an l-NAME-associated rise in oxidation of dihydroethidium that was prevented by Tempol or apocynin. To test whether H2O2 might play a role, we examined its direct effects. From 1 to 100 μmol/l, H2O2 contracted DVR whereas at 1 mmol/l it was vasodilatory. The H2O2 scavenger polyethylene glycol-catalase reversed H2O2 (10 μmol/l)-induced vasoconstriction; however, it did not affect l-NAME-induced contraction. Finally, the previously known rise in DVR permeability to 22Na and [3H]raffinose that occurs with luminal perfusion was not prevented by NOS blockade. We conclude that intrinsic production of NO and ROS can modulate DVR vasoactivity and that l-NAME-induced vasoconstriction occurs, in part, by modulating superoxide concentration and not through H2O2 generation. Intrinsic NO production does not affect DVR permeability to hydrophilic solutes.

Chronic hypertension impairs flow-induced vasodilation and augments the myogenic response in fetal lung

2002 ◽  
Vol 282 (1) ◽  
pp. L56-L66 ◽  
Author(s):  
Laurent Storme ◽  
Thomas A. Parker ◽  
John P. Kinsella ◽  
Robyn L. Rairigh ◽  
Steven H. Abman
Keyword(s):  
Nitric Oxide ◽  
Ductus Arteriosus ◽  
Fetal Lung ◽  
No Synthase ◽  
Chronic Hypertension ◽  
No Production ◽  
Myogenic Response ◽  
Hemodynamic Effects ◽  
No Signaling ◽  
Synthase Inhibitor

We hypothesized that altered vasoreactivity in perinatal pulmonary hypertension (PH) is characterized by abnormal responses to hemodynamic stress, including the loss of flow-induced vasodilation and an augmented myogenic response. Therefore, we studied the acute hemodynamic effects of brief compression of the ductus arteriosus (DA) in control fetal lambs and in lambs during exposure to chronic PH. In both groups, acute DA compression decreased pulmonary vascular resistance (PVR) by 20% at baseline ( day 0). After 2 days of hypertension, acute DA compression paradoxically increased PVR by 50% in PH lambs, whereas PVR decreased by 25% in controls. During the 8-day study period, PVR increased during acute DA compression in PH lambs, whereas acute DA compression continued to cause vasodilation in controls. Brief treatment with the nitric oxide (NO) synthase inhibitor nitro-l-arginine (l-NA) increased basal PVR in control but not PH lambs, suggesting decreased NO production in PH lambs. Chronic hypertension increased the myogenic response afterl-NA in PH lambs, whereas the myogenic response remained unchanged in controls. The myogenic response was inhibited by nifedipine in PH lambs, suggesting that the myogenic response is dependent upon the influx of extracellular calcium. We conclude that chronic PH impairs flow-induced vasodilation and increases the myogenic response in fetal lung. We speculate that decreased NO signaling and an augmented myogenic response contributes to abnormal vasoreactivity in PH.

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