© 1995 American Heart Association, Inc.
Articles |
Endothelium-Derived Nitric Oxide Plays a Larger Role in Pulmonary Veins Than in Arteries of Newborn Lambs
From the Department of Pediatrics, Harbor-UCLA Medical Center, University of California, Los Angeles, School of Medicine, Torrance, Calif.
Correspondence to Yuansheng Gao, MD, PhD, Harbor-UCLA Medical Center, Research and Education Institute, 1124 W Carson St, RB-1, Torrance, CA 90502.
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Abstract |
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Abstract In perinatal lungs, veins contribute substantially to total pulmonary vascular resistance. The present study was designed to determine the role of endothelium-derived nitric oxide (EDNO) in modulating the responsiveness of pulmonary veins and arteries in newborn lambs. Fourth-order pulmonary arterial and venous rings of newborn lambs were suspended in organ chambers filled with modified Krebs-Ringer bicarbonate solution (95% O2/5% CO2, 37°C), and their isometric force was measured. Nitro-L-arginine had no effect on the resting tension of pulmonary arteries but caused an endothelium-dependent contraction of pulmonary veins. During contraction to endothelin-1 or U46619, acetylcholine, bradykinin, and calcium ionophore A23187 induced larger endothelium-dependent relaxation in pulmonary veins than in arteries. The endothelium-dependent relaxation of pulmonary vessels was abolished by nitro-L-arginine. In vessels without endothelium, nitric oxide induced significantly greater relaxation in pulmonary veins than in arteries. All vessels relaxed similarly to 8-bromo-cGMP. Radioimmunoassay showed that the basal level of intracellular cGMP of pulmonary veins with endothelium was higher than that of arteries with endothelium. Acetylcholine, bradykinin, and calcium ionophore A23187 induced a significantly larger endothelium-dependent increase in the intracellular content of cGMP in pulmonary veins than in arteries. In vessels without endothelium, nitric oxide induced a larger increase in cGMP content in pulmonary veins than in arteries. The present study suggests that EDNO may play a larger role in modulation of pulmonary venous than arterial reactivity, which may be mainly due to a difference in the activity of soluble guanylate cyclase in vascular smooth muscle.
Key Words: endothelium • acetylcholine • bradykinin • cGMP • neonatal pulmonary circulation
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Vascular endothelium-derived nitric oxide or nitric oxide–like substance (from here on referred to as EDNO) is synthesized from L-arginine both under basal conditions and in response to a variety of stimuli.1 2 It is believed that by activating soluble guanylate cyclase, EDNO increases the intracellular content of cGMP and thus causes smooth muscle to relax.1 3
EDNO plays an important role in modulating pulmonary vascular tone in the fetus and newborn.4 5 6 7 8 9 10 11 12 13 In in vivo studies, nitro-L-arginine, an inhibitor of nitric oxide synthase,14 increases pulmonary arterial pressure of fetal and newborn lambs. Pretreatment with nitro-L-arginine attenuated pulmonary vasodilation induced by oxygen ventilation and by endothelium-dependent vasodilators such as acetylcholine and ATP.5 6 8 Studies in vitro show that EDNO modulates the responses of pulmonary arteries of fetal and newborn sheep, pigs, and guinea pigs.4 7 9 10 11 12 13
In the fetus and newborn, pulmonary veins exhibit considerable vasoactivity in response to a variety of stimuli. Veins also contribute substantially to total pulmonary vascular resistance.15 16 17 18 19 20 21 22 23 24 25 26 However, the regulation of pulmonary venous activity by EDNO is not well understood. Recent studies with pulmonary vessels of newborn and juvenile sheep indicate that venous but not arterial tone is modulated by the basal release of EDNO.10 Also, in pulmonary vessels of newborn sheep, acetylcholine induces the release of EDNO from veins but not from arteries.10
In the present study, we have compared the responses of pulmonary arteries and veins of newborn lambs in response to agents that activate different steps of the nitric oxide pathway. We also measured changes in the intracellular content of cGMP induced by different agonists. Our data show that EDNO plays a larger role in modulating the responsiveness of pulmonary veins than that of arteries and that this may be due to a difference in the activity of soluble guanylate cyclase in vascular smooth muscle.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Lungs of 17 newborn lambs (6 to 11 days old, either sex; Nebeker Ranch, Lancaster, Calif) were used. Each lamb was anesthetized with ketamine hydrochloride (30 mg/kg IM) and killed with an overdose of pentobarbital (100 mg/kg IV).12
Preparation of Tissue
Fourth-order pulmonary arteries and veins were dissected from
the lungs and cut into rings (length, 3 mm; outside diameter, 2.0 to
3.0 mm for arteries and 1.5 to 2.0 mm for veins). In some rings, the
endothelium was removed by gently rubbing the luminal surface with the
tips of a watchmaker's forceps. Removal of the endothelium was
confirmed by lack of relaxation to acetylcholine (3x10-6
to 3x10-5 mol/L).
Organ Chamber Study
Rings of fourth-order pulmonary arteries and veins were
suspended in organ chambers filled with 10 mL modified Krebs-Ringer
bicarbonate solution containing (mmol/L) NaCl 118.3, KCl 4.7,
CaCl2 2.5, MgSO4 1.2,
KH2PO4 1.2, NaHCO3 25.0, and
glucose 11.1, which was maintained at 37±0.5°C and aerated with 95%
O2/5% CO2 (pH 7.4). Each ring was
suspended by two stirrups passed through the lumen. One stirrup was
anchored to the bottom of the organ chamber; the other one was
connected to a force-displacement transducer (model FT03C, Grass
Instrument Co) for the measurement of isometric
force.27
At the beginning of each experiment, vessel rings were brought to their optimal tension by stretching the tissues progressively until the contractile responses to 100 mmol/L KCl were maximal. The optimal resting tension was 0.25±0.04 and 0.35±0.07 g/mg tissue for pulmonary arteries with and without endothelium, respectively (n=11 to 13, P>.05) and 0.21±0.04 and 0.29±0.07 g/mg tissue for pulmonary veins with and without endothelium, respectively (n=14, P>.05). One hour of equilibration was allowed after tissues were brought to their optimal tension.
Relaxation of pulmonary arteries to different agents was determined during contraction to endothelin-1; relaxation of veins was determined during contraction to U46619, a thromboxane A2 analogue.21 Preliminary studies showed that endothelin-1 evoked a stable contraction and did not induce endothelium-dependent responses of pulmonary arteries of newborn lambs. Since endothelin caused endothelium-dependent relaxation of pulmonary veins, we did not use this peptide to contract veins (data not shown). Preliminary studies also showed that U46619 evoked a stable contraction and did not induce endothelium-dependent responses in ovine pulmonary veins. U46619 is not a good constrictor of pulmonary arteries, since this thromboxane analogue, at concentrations of up to 10-5 mol/L, only induced a very small contraction of pulmonary arteries of newborn lambs (data not shown).
Measurements of cGMP
The vessel rings were incubated in modified Krebs-Ringer
bicarbonate solution (95% O2/5%
CO2, 37°C) containing indomethacin
(10-5 mol/L) and isobutyl methylxanthine (IBMX,
10-4 mol/L); these inhibitors were used to prevent the
involvement of cyclooxygenase products and to prevent the degradation
of cGMP by phosphodiesterase, respectively.3 28 In some
experiments, nitro-L-arginine (10-4 mol/L) was
present to determine the role of endogenous nitric oxide in the
production of cGMP.
After 45 minutes of equilibration, acetylcholine, bradykinin, calcium ionophore A23187, or nitric oxide was added. The preparations were freeze-clamped rapidly at different time points after administration of the agonist and were later thawed in trichloroacetic acid (6%). Vessel rings were later homogenized in glass with a motor-driven polytetrafluoroethylene pestle, sonicated for 5 seconds, and centrifuged (13 000g for 15 minutes). The supernatant was extracted with four vol water-saturated diethyl ether and lyophilized; the pellets were weighed. The lyophilized samples were resuspended in 0.5 mL sodium acetate buffer (0.05 mol/L, pH 6.2), and the content of cGMP was determined by using a cGMP kit (Biomedical Technologies Inc). The content of cyclic nucleotide is expressed as picomoles per milligram tissue.29
Preparation of Nitric Oxide
A gas bulb sealed with a silicone rubber injection septum was
filled with nitric oxide from a cylinder (Union Carbide). An
appropriate volume (0.25 or 2.5 mL) was removed with a syringe and
injected into another gas bulb filled with 250 mL distilled water,
which had been gassed with helium for >3 hours, giving stock solutions
of nitric oxide of 4.2x10-5 and 4.2x10-4
mol/L.29
Drugs
The following drugs were used (unless otherwise specified,
all were obtained from Sigma Chemical Co): acetylcholine chloride,
bradykinin, 8-bromo-cGMP, calcium ionophore A23187, endothelin-1
(Peptides International), indomethacin, IBMX, methylene blue,
nitro-L-arginine (Aldrich Chemical Co, Inc), and U46619
(9,11-dideoxy-11
,9-epoxymethanoprostaglandin
F2).
Calcium ionophore A23187 was dissolved in dimethylsulfoxide (DMSO; highest final concentration in organ chamber, 0.1%). IBMX was dissolved in ethanol (final concentration in organ chamber, 0.1%). Preliminary experiments indicated that DMSO and ethanol at the concentrations used did not significantly affect contraction of the tissues to endothelin-1 and U46619 or the endothelium-dependent relaxation to acetylcholine and bradykinin (data not shown). Indomethacin (10-5 mol/L) was prepared in equal molar Na2CO3. This concentration of Na2CO3 did not significantly affect the pH of the solution in the organ chamber. The other drugs were prepared with distilled water. All inhibitors and antagonists were administered at least 45 minutes before experimentation to test their effects.
Data Analyses
Contractions are expressed in grams per milligram tissue.
Relaxations are expressed as percentage of contraction of tissues to
endothelin-1 or U46619. Data are shown as mean±SEM. When mean values
of two groups of the same vessel type were compared, Student's
t test for unpaired observations was used. When the mean
values of the same group before and after stimulation were compared,
Student's t test for paired observations was used.
Comparison of mean values of more than two groups from same vessel type
was performed by one-way ANOVA, with the Student-Newman-Keuls test used
for post hoc testing of multiple comparison. For comparison of mean
values of groups of different vessel types (pulmonary arteries and
veins), two-way ANOVA was used. All these analyses were performed by
use of a commercially available statistics package
(SIGMASTAT, Jandel Scientific). Statistical significance
was accepted at (two-tailed) P<.05. In all experiments, n
represents the number of lambs.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Organ Chamber Studies
To exclude the involvement of endogenous cyclooxygenase products,10 28 experiments were performed in the presence of indomethacin (10-5 mol/L) unless otherwise stated. This inhibitor of cyclooxygenase did not significantly affect the resting tension of pulmonary arteries but raised the resting tension of veins, with and without endothelium, by 0.15±0.05 and 0.34±0.06 g/mg tissue (n=13 to 14), respectively. The increase in tension induced by indomethacin in veins with endothelium was significantly smaller than that in veins without endothelium (P<.05).
Nitro-L-arginine (10-4 mol/L), an inhibitor of nitric oxide synthase,14 had no effect on the resting tension of pulmonary arteries with and without endothelium and veins without endothelium (n=9 for each group). Nitro-L-arginine raised the resting tension of veins with endothelium by 0.56±0.21 g/mg tissue (n=9, P<.05).
Relaxation of pulmonary vessels to different agents was determined after their tension was raised by constrictors to a level similar to that evoked by 100 mmol/L KCl. Pulmonary arteries were contracted with endothelin-1 (10-8 to 3x10-8 mol/L). The increases in tension were 1.12±0.23 and 1.23±0.17 g/mg tissue for arteries with and without endothelium, respectively (n=13, P>.05). Pulmonary veins were contracted with U46619 (3x10-7 to 10-6 mol/L). The increases in tension were 1.90±0.29 and 1.62±0.19 g/mg tissue for veins with and without endothelium, respectively (n=14, P>.05).
During contraction, acetylcholine caused
endothelium-dependent relaxation of pulmonary arteries
and veins. The relaxation of veins was significantly greater than that
of arteries (Fig 1
). The
endothelium-dependent relaxation induced by
acetylcholine was not significantly affected by indomethacin
(10-5 mol/L, Table). In vessels treated with
nitro-L-arginine (10-4 mol/L) and vessels
without endothelium, acetylcholine had no significant effect on
pulmonary arteries but evoked contraction of the veins (Fig 1).
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Bradykinin and calcium ionophore A23187 induced
endothelium-dependent relaxation in pulmonary vessels,
which was inhibited by nitro-L-arginine. The
endothelium-dependent relaxation induced by bradykinin
from 10-9 to 10-6 mol/L (Fig 2) and that induced by the calcium ionophore from
3x10-8 to 10-6 mol/L (Fig 3)
were significantly greater in pulmonary veins than in arteries
(P<.05).
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In vessels without endothelium, nitric oxide induced
concentration-dependent relaxation. The relaxation of pulmonary veins
was significantly greater than that of arteries (P<.05). In
both arteries and veins, nitric oxide–induced relaxation was not
significantly affected by nitro-L-arginine
(10-4 mol/L) but was abolished or significantly attenuated
by methylene blue (10-5 mol/L), an inhibitor of soluble
guanylate cyclase30 (Fig 4).
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When stimulated with 8-bromo-cGMP, a cell membrane–permeable analogue
of cGMP,31 pulmonary arteries and veins (without
endothelium) relaxed to a similar extent (Fig 5).
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Measurements of cGMP
Under basal conditions, the intracellular content of cGMP of
pulmonary veins with endothelium (3.59±0.46 pmol/mg tissue, n=7) was
significantly higher than that of arteries with endothelium (1.84±0.53
pmol/mg tissue, n=7). In both arteries and veins, the intracellular
content of cGMP of vessels with endothelium was significantly higher
than that of vessels without endothelium. These differences were
abolished by nitro-L-arginine (10-4 mol/L)
(Fig 6). Acetylcholine (3x10-6 mol/L),
bradykinin (10-6 mol/L), and calcium ionophore A23187
(10-6 mol/L) induced an
endothelium-dependent
nitro-L-arginine–sensitive increase in the intracellular
content of cGMP (Figs 6 and 7). The increase in cGMP
content was significantly higher in veins than in arteries (Figs 6 and 7).
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In vessels without endothelium, nitric oxide (1.6x10-7
mol/L) induced a significantly larger increase in cGMP content in
pulmonary veins than in arteries. The increases in cGMP content induced
by nitric oxide were abolished by methylene blue (Fig 8).
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Discussion |
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In blood vessels, EDNO is synthesized from L-arginine by the endothelium under basal conditions and after stimulation.1 2 Nitric oxide is lipophilic. When released, it can readily diffuse into the underlying smooth muscle cells and activate soluble guanylate cyclase.1 3 This results in an increase in the synthesis of cGMP, which then causes vascular smooth muscle to relax.1 3 31 32 In the present study, nitro-L-arginine, an inhibitor of nitric oxide synthase,14 had no effect on the resting tension of pulmonary arteries but caused contraction of veins. Furthermore, the intracellular content of cGMP of pulmonary veins with endothelium was higher than that of arteries with endothelium. Such a difference was abolished by nitro-L-arginine. These results suggest that EDNO released at basal conditions plays a larger role in modulating pulmonary venous tone compared with arterial tone. A more active role for EDNO at basal conditions in pulmonary veins compared with arteries has also been implicated in sheep <36 hours old and 5 to 6 weeks old.10 In the present study, indomethacin, an inhibitor of cyclooxygenase, also increased resting tension in veins but not in arteries. Such a phenomenon was more pronounced in veins without endothelium than in veins with endothelium. These observations imply that a vasodilator, prostaglandin, is a more important modulator of veins than arteries. It is known that a variety of cyclooxygenase products are generated in the lung and that they may modulate pulmonary vasoactivity.10 28
In the present study, acetylcholine, bradykinin, and calcium ionophore A23187 induced a larger endothelium-dependent relaxation in veins than in arteries. Since the relaxation was abolished by nitro-L-arginine, this suggests that it was mediated by EDNO.1 32 The difference in relaxation between arteries and veins is unlikely to be due to the fact that the two types of vessels were precontracted with different constrictors, since in the absence of constrictors, acetylcholine, bradykinin, and calcium ionophore A23187 caused a larger endothelium-dependent, nitro-L-arginine–sensitive increase in cGMP in veins than in arteries. In the present study, experiments were performed in the presence of indomethacin, an inhibitor of cyclooxygenase.28 Since indomethacin selectively increased resting tension of veins, its action may contribute to the difference in relaxation between arteries and veins. However, the possibility seems to be unlikely, since our results showed that indomethacin did not significantly affect the endothelium-dependent relaxations of both pulmonary arteries and veins induced by acetylcholine.
A larger relaxation was observed in pulmonary veins compared with arteries not only in response to acetylcholine, bradykinin, and calcium ionophore A23187 but also in response to exogenous nitric oxide. Since the response to nitric oxide was obtained in vessels without endothelium and was not affected by nitro-L-arginine, the difference in EDNO-dependent responses between the two types of vessels appears not to be due to a difference in the release of EDNO.1 2
Nitrovasodilators including nitric oxide cause relaxation of smooth muscle mainly by activating soluble guanylate cyclase.3 13 31 On activation, guanylate cyclase catalyzes the formation of cGMP from GTP. Consequently, cGMP activates cGMP-dependent protein kinase and thus causes relaxation of smooth muscle.1 3 31 In the present study, 8-bromo-cGMP, a cell membrane–permeable analogue of cGMP,31 induced a similar degree of relaxation in pulmonary arteries and veins. This suggests that the sensitivity of both types of vessels to cGMP is comparable. Since nitric oxide induced a smaller increase in cGMP content in pulmonary arteries than in veins, a lower production of cGMP may be responsible for the difference in nitrovasodilator-induced relaxation between these two vessel types.1 2 3 31
Superoxide anions are generated from mammalian cells, and they inactivate nitric oxide.33 34 Therefore, a lower production of cGMP in arteries in response to nitric oxide may be due to the fact that more superoxide anions are generated by pulmonary arteries than by veins. In fetal sheep, pulmonary veins relax more to nitric oxide than do arteries, and both types of vessels relax similarly to 8-bromo-cGMP. The relaxation of both pulmonary arteries and veins induced by nitric oxide is augmented by superoxide dismutase, which scavenges superoxide anions.33 34 However, the difference in response to nitric oxide between arteries and veins is not significantly affected by superoxide dismutase (Y. Gao, H. Zhou, J.U. Raj, unpublished results, 1994). Therefore, superoxide anions may not contribute significantly to the difference in the responses of nitrovasodilators between arteries and veins. cGMP formed in cells is subjected to degradation by phosphodiesterase.3 31 A higher activity of phosphodiesterase in arterial smooth muscle cells may also result in a lower cGMP content in response to nitric oxide and thus result in a smaller relaxation. Since we measured cGMP after the vessels were treated with IBMX, an inhibitor of phosphodiesterase,31 such a possibility seems unlikely. Finally, if the activity of soluble guanylate cyclase in pulmonary arteries is lower than in veins, nitrovasodilators will cause a smaller increase in cGMP in arteries than in veins. This possibility warrants further investigation.
In our previous micropuncture studies, under basal conditions,
pulmonary veins of newborn lambs contribute 
36% and arteries
contribute 32% to total pulmonary vascular
resistance.18 During hypoxia and in response to
thromboxane, platelet-activating factor, and endothelin, pulmonary
veins constrict equally or more than arteries in
lambs.19 21 24 In the micropuncture study, the resistance
of pulmonary arteries or veins is calculated by dividing the
differential pressure between main pulmonary artery or vein and 20- to
80-µm arterioles or venules by flow. Thus, the arterial and venous
resistance obtained reflects that of vessel segments from the main
branch to 20- to 80-µm microvessels.18 19 21 24 In the
present organ chamber study, we observed that midsized veins relax
more to both endothelium-dependent and -independent
vasodilators than midsized arteries. These results provide support for
an active role of midsized veins in the pulmonary circulation. However,
the role of pulmonary vessels of different sizes, especially arterioles
and venules, in the regulation of the pulmonary circulation remains to
be determined.
Pulmonary veins have long been seen primarily as conduit vessels that have little vasoactivity. Substantial evidence indicates that pulmonary veins of many species, including sheep, exhibit significant vasoactivity under a variety of physiological and pathological conditions.16 17 20 22 23 26 In rats and ferrets, pulmonary veins constrict as vigorously as or more than arteries during hypoxia.20 26 In rats, dogs, and pigs, platelet-activating factor mainly causes pulmonary veins to constrict.15 17 23 In ferrets, thromboxane and endothelin predominantly cause pulmonary veins to constrict.22 These data, combined with those from our present study, would suggest that pulmonary veins are the major site of action of a number of constrictors and vasodilators. Pulmonary vessels undergo complicated remodeling both structurally and functionally under pathological conditions.35 36 37 Thus, whether EDNO can act as an important means of protection of the lungs from increased venous resistance, high microvascular pressure, and pulmonary edema under a variety of pathological conditions remains to be determined.
In conclusion, our data demonstrate that in the lungs of normal newborn lambs, EDNO plays a larger role in modulating the vasoactivity of veins than arteries. Such a difference is likely to be mainly due to a difference in the activity of soluble guanylate cyclase of smooth muscle.1 3 31 Since pulmonary veins are the major site of action of a number of vasoconstrictors, a larger role for EDNO in the regulation of venous tone may be important for normal microcirculatory hemodynamics.
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Acknowledgments |
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This study was supported by National Heart, Lung, and Blood Institute grants HL-38438 and HL-47804 and National Institute of Child Health and Human Development grant HD-29713. We thank Dr Nancy G. Berman for help in statistical analysis, Jean Anderson for technical assistance, and Nancy Feldman for secretarial assistance.
Received May 19, 1994; accepted December 6, 1994.
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Y. Gao and J. U. Raj Parathyroid hormone-related protein-mediated responses in pulmonary arteries and veins of newborn lambs Am J Physiol Lung Cell Mol Physiol, July 1, 2005; 289(1): L60 - L66. [Abstract] [Full Text] [PDF]
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Y. Gao and J. U. Raj Role of veins in regulation of pulmonary circulation Am J Physiol Lung Cell Mol Physiol, February 1, 2005; 288(2): L213 - L226. [Abstract] [Full Text] [PDF]
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X. Ding and P. A. Murray Regulation of pulmonary venous tone in response to muscarinic receptor activation Am J Physiol Lung Cell Mol Physiol, January 1, 2005; 288(1): L131 - L140. [Abstract] [Full Text] [PDF]
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Y. Gao, S. Dhanakoti, E. M. Trevino, X. Wang, F. C. Sander, A. D. Portugal, and J. U. Raj Role of cGMP-dependent protein kinase in development of tolerance to nitric oxide in pulmonary veins of newborn lambs Am J Physiol Lung Cell Mol Physiol, April 1, 2004; 286(4): L786 - L792. [Abstract] [Full Text] [PDF]
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Y. Gao, S. Dhanakoti, E. M. Trevino, F. C. Sander, A. M. Portugal, and J. U. Raj Effect of oxygen on cyclic GMP-dependent protein kinase-mediated relaxation in ovine fetal pulmonary arteries and veins Am J Physiol Lung Cell Mol Physiol, September 1, 2003; 285(3): L611 - L618. [Abstract] [Full Text] [PDF]
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U. Raj and L. Shimoda Oxygen-dependent signaling in pulmonary vascular smooth muscle Am J Physiol Lung Cell Mol Physiol, October 1, 2002; 283(4): L671 - L677. [Abstract] [Full Text] [PDF]
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J. L. Aschner, T. K. Smith, N. Kovacs, J. M. B. Pinheiro, and M. Fuloria Mechanisms of bradykinin-mediated dilation in newborn piglet pulmonary conducting and resistance vessels Am J Physiol Lung Cell Mol Physiol, August 1, 2002; 283(2): L373 - L382. [Abstract] [Full Text] [PDF]
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 B. Thebaud, T. Petit, P. de Lagausie, J. Dall'Ava-Santucci, J.-C. Mercier, and A. T. Dinh-Xuan Altered Guanylyl-Cyclase Activity In Vitro of Pulmonary Arteries from Fetal Lambs with Congenital Diaphragmatic Hernia Am. J. Respir. Cell Mol. Biol., July 1, 2002; 27(1): 42 - 47. [Abstract] [Full Text] [PDF]
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 J.-F. Tolsa, Y. Gao, F. C. Sander, A.-C. Souici, A. Moessinger, and J. U. Raj Differential responses of newborn pulmonary arteries and veins to atrial and C-type natriuretic peptides Am J Physiol Heart Circ Physiol, January 1, 2002; 282(1): H273 - H280. [Abstract] [Full Text] [PDF]
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 S. N. Dhanakoti, Y. Gao, M. Q. Nguyen, and J. U. Raj Involvement of cGMP-dependent protein kinase in the relaxation of ovine pulmonary arteries to cGMP and cAMP J Appl Physiol, May 1, 2000; 88(5): 1637 - 1642. [Abstract] [Full Text] [PDF]
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 L. WALCH, X. NOREL, J.-P. GASCARD, and C. BRINK Functional Studies of Leukotriene Receptors in Vascular Tissues Am. J. Respir. Crit. Care Med., February 1, 2000; 161(2): S107 - 111. [Full Text] [PDF]
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J.-F. Tolsa, Y. Gao, and J. U. Raj Developmental change in magnesium sulfate-induced relaxation of rabbit pulmonary arteries J Appl Physiol, November 1, 1999; 87(5): 1589 - 1594. [Abstract] [Full Text] [PDF]
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F. I. Arrigoni, A. A. Hislop, S. G. Haworth, and J. A. Mitchell Newborn intrapulmonary veins are more reactive than arteries in normal and hypertensive piglets Am J Physiol Lung Cell Mol Physiol, November 1, 1999; 277(5): L887 - L892. [Abstract] [Full Text] [PDF]
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Y. Gao, S. Dhanakoti, J.-F. Tolsa, and J. U. Raj Role of protein kinase G in nitric oxide- and cGMP-induced relaxation of newborn ovine pulmonary veins J Appl Physiol, September 1, 1999; 87(3): 993 - 998. [Abstract] [Full Text] [PDF]
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A. H. Stephenson, R. S. Sprague, and A. J. Lonigro 5,6-Epoxyeicosatrienoic acid reduces increases in pulmonary vascular resistance in the dog Am J Physiol Heart Circ Physiol, July 1, 1998; 275(1): H100 - H109. [Abstract] [Full Text] [PDF]
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Y. Gao, J.-F. Tolsa, M. Botello, and J. U. Raj Developmental change in isoproterenol-mediated relaxation of pulmonary veins of fetal and newborn lambs J Appl Physiol, May 1, 1998; 84(5): 1535 - 1539. [Abstract] [Full Text] [PDF]
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Y. Gao, J.-F. Tolsa, H. Shen, and J. U. Raj Effect of selective phosphodiesterase inhibitors on response of ovine pulmonary arteries to prostaglandin E2 J Appl Physiol, January 1, 1998; 84(1): 13 - 18. [Abstract] [Full Text] [PDF]
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W. Shi, D. H. Eidelman, and R. P. Michel Differential relaxant responses of pulmonary arteries and veins in lung explants of guinea pigs J Appl Physiol, November 1, 1997; 83(5): 1476 - 1481. [Abstract] [Full Text] [PDF]
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Y. Gao, H. Zhou, B. O. Ibe, and J. U. Raj Prostaglandins E2 and I2 cause greater relaxations in pulmonary veins than in arteries of newborn lambs J Appl Physiol, December 1, 1996; 81(6): 2534 - 2539. [Abstract] [Full Text] [PDF]
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C. D. Fike and M. R. Kaplowitz Chronic hypoxia alters nitric oxide-dependent pulmonary vascular responses in lungs of newborn pigs J Appl Physiol, November 1, 1996; 81(5): 2078 - 2087. [Abstract] [Full Text] [PDF]
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 J.-S. Jin and L. G. D'Alecy Stimulation of Endogenous Nitric Oxide Pathway by L-Arginine Reduces Declamp Mortality and Attenuates Hypertension Associated With Aortic Cross-Clamp–Induced Hindlimb Ischemia in Rats Hypertension, September 1, 1995; 26(3): 406 - 412. [Abstract] [Full Text]
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