Disruption of cGMP production in pulmonary arteries isolated from fetal lambs with pulmonary hypertension

1995 ◽  
Vol 268 (4) ◽  
pp. H1483-H1489 ◽  
Author(s):  
R. H. Steinhorn ◽  
J. A. Russell ◽  
F. C. Morin
Keyword(s):  
Pulmonary Hypertension ◽  
Soluble Guanylate Cyclase ◽  
Ductus Arteriosus ◽  
Pulmonary Veins ◽  
Pulmonary Arteries ◽  
Fourth Generation ◽  
Response Curves ◽  
Fetal Sheep ◽  
A 23187 ◽  
Arteries And Veins

Ligation of the ductus arteriosus of the fetal sheep produces severe pulmonary hypertension at birth. Standard tissue bath techniques were used to study third- and fourth-generation pulmonary arteries and veins isolated from fetal sheep with pulmonary hypertension created by ligation of the ductus arteriosus 11–12 days before birth as well as from age-matched control sheep. Vessels pretreated with indomethacin and propranolol were submaximally preconstricted with norepinephrine before exposure to A-23187 (10(-8) to 3 x 10(-7) M), sodium nitroprusside (SNP; 10(-9) to 10(-5) M), and nitric oxide (NO) gas (1-973 ppm). Pulmonary veins in both control and ligated animals relaxed similarly and completely to A-23187, SNP, and NO. Control pulmonary arteries relaxed by 16 +/- 2% to A-23187 and relaxed completely to SNP and NO, with concentration-response curves shifted rightward of those observed in pulmonary veins. Pulmonary arteries from ligated animals did not relax at all to A-23187. SNP relaxations in ligated arteries were shifted rightward of control. Ligated arteries relaxed by only 11 +/- 5% to the highest dose of NO. However, control and ligated pulmonary arteries relaxed similarly to 8-bromoguanosine 3',5'-cyclic monophosphate (8-bromo-cGMP; 10(-5) to 10(-3) M) and atrial natriuretic peptide (10(-9) to 10(-7) M). These data are most simply explained by decreased arterial vascular smooth muscle sensitivity to NO at the level of soluble guanylate cyclase.

Antenatal betamethasone therapy augments nitric oxide-mediated relaxation of preterm ovine pulmonary veins

1996 ◽  
Vol 80 (2) ◽  
pp. 390-396 ◽  
Author(s):  
H. Zhou ◽  
Y. Gao ◽  
J. U. Raj
Keyword(s):  
Nitric Oxide ◽  
Soluble Guanylate Cyclase ◽  
Pulmonary Veins ◽  
Pulmonary Arteries ◽  
Isometric Tension ◽  
Glucocorticoid Therapy ◽  
Fourth Generation ◽  
Cyclic Monophosphate ◽  
Significant Difference ◽  
Arteries And Veins

Antenatal glucocorticoid therapy improves pulmonary function in preterm newborns. We have determined the effect of antenatal glucocorticoid therapy on nitric oxide-mediated relaxation in pulmonary vessels of preterm lambs. Ovine fetuses (126 days gestation; full term = 150 days) were injected with betamethasone (0.5 mg/kg body wt) or saline. After 48 h, lambs were delivered, ventilated for 3 h, and killed. Isolated fourth-generation pulmonary arteries (2-3 mm diameter) and veins (1.5-2 mm diameter) were suspended in organ chambers filled with modified Krebs-Ringer solution (95% O2-5% CO2) at 37 degrees C, and their isometric tension was recorded. During contractions to endothelin-1 or U-46619 (in the presence of indomethacin), acetylcholine and bradykinin induced endothelium-dependent nitro-L-arginine-inhibitable relaxation in arteries and veins. The relaxation was greater in veins of betamethasone-treated than in those of control lambs. Veins from lambs without endothelium treated with betamethasone were more sensitive to sodium nitroprusside than veins from controls. For arteries, there was no significant difference in relaxation between different groups. Relaxation induced by 8-bromoguanosine 3′,5′-cyclic monophosphate was similar in arteries and veins of different groups. Radioimmunoassay showed that nitric oxide caused a greater increase in guanosine 3′,5′-cyclic monophosphate in betamethasone-treated veins than in controls. These data suggest that antenatal betamethasone therapy augments nitric oxide-mediated relaxation of pulmonary veins of preterm lambs, probably by increasing soluble guanylate cyclase activity of vascular smooth muscle.

Altered endothelium-dependent relaxations in lambs with high pulmonary blood flow and pulmonary hypertension

2001 ◽  
Vol 280 (1) ◽  
pp. H311-H317 ◽  
Author(s):  
Robin H. Steinhorn ◽  
James A. Russell ◽  
Satyan Lakshminrusimha ◽  
Sylvia F. Gugino ◽  
Stephen M. Black ◽  
...  
Keyword(s):  
Blood Flow ◽  
Pulmonary Hypertension ◽  
Vascular Graft ◽  
Pulmonary Blood Flow ◽  
Soluble Guanylate Cyclase ◽  
Pulmonary Veins ◽  
Pulmonary Arteries ◽  
No Synthase ◽  
A 23187 ◽  
Endothelium Dependent Relaxation

Congenital heart disease associated with increased pulmonary blood flow produces pulmonary hypertension. To characterize vascular alterations in the nitric oxide (NO)-cGMP cascade induced by increased pulmonary blood flow and pulmonary hypertension, 10 fetal lambs underwent in utero placement of an aortopulmonary vascular graft (shunt). When the lambs were 4–6 wk of age, we assessed responses of pulmonary arteries (PAs) and pulmonary veins (PVs) isolated from lungs of control and shunted lambs. PVs from control and shunted lambs relaxed similarly to exogenous NO ( S-nitrosyl-acetyl-penicillamine), to NO produced endogenously (zaprinast and A-23187), and to cGMP (atrial natriuretic peptide). In contrast, relaxations to A-23187 and zaprinast were blunted in PAs isolated from shunted lambs relative to controls. Inhibitors of NO synthase (NOS) and soluble guanylate cyclase constricted control but not shunt PAs, indicating reduced basal NOS activity in shunt PAs. Pretreatment of shunt PAs with the substratesl-arginine and sepiapterin, a precursor for tetrahydrobiopterin synthesis, did not augment A-23187 relaxations. However, pretreatment with superoxide dismutase and catalase significantly enhanced A-23187 relaxations in shunt PAs. We conclude that increased pulmonary blood flow induces an impairment of endothelium-dependent relaxation that is selective to PAs. The impaired relaxation may be mediated in part by excess superoxide production.

Heterogeneity in role of endothelium-derived NO in pulmonary arteries and veins of full-term fetal lambs

1995 ◽  
Vol 268 (4) ◽  
pp. H1586-H1592 ◽  
Author(s):  
Y. Gao ◽  
H. Zhou ◽  
J. U. Raj
Keyword(s):  
Nitric Oxide ◽  
Isometric Force ◽  
Pulmonary Veins ◽  
Pulmonary Arteries ◽  
Full Term ◽  
Fourth Generation ◽  
Cyclic Monophosphate ◽  
Arteries And Veins ◽  
Endothelium Dependent Relaxation

Endothelium-derived nitric oxide (EDNO) modulates fetal pulmonary vasoactivity. The role of EDNO in regulation of vasomotor tone in fetal pulmonary arteries vs. that in veins is not known. We have investigated the role of EDNO in the responses of pulmonary arteries and veins of full-term fetal lambs. Fourth-generation pulmonary arterial and venous rings were suspended in organ chambers filled with modified Krebs-Ringer bicarbonate solution (95% O2-5% CO2 at 37 degrees C), and their isometric force was measured. N omega-nitro-L-arginine had no effect on the resting tension of pulmonary arteries with endothelium but caused contraction of pulmonary veins with endothelium. The basal level of intracellular guanosine 3',5'-cyclic monophosphate (cGMP) of pulmonary veins with endothelium was higher than that of arteries with endothelium. In pulmonary arteries, bradykinin, but not acetylcholine, induced endothelium-dependent relaxation and an increase in cGMP content. In pulmonary veins, acetylcholine, but not bradykinin, induced endothelium-dependent relaxation and an increase in cGMP content. Agonist-induced maximal relaxation and increases in cGMP content were smaller in pulmonary arteries than in veins. All these endothelium-dependent responses were abolished by N omega-nitro-L-arginine. In tissues without endothelium, nitric oxide induced significantly less relaxation and less increase in cGMP content in pulmonary arteries than in pulmonary veins. All vessels relaxed similarly to 8-bromoguanosine 3',5'-cyclic monophosphate. Our data suggest that the role of EDNO in modulating tone differs between pulmonary arteries and veins in full-term fetal lambs.(ABSTRACT TRUNCATED AT 250 WORDS)

scholarly journals Cinaciguat, a soluble guanylate cyclase activator, augments cGMP after oxidative stress and causes pulmonary vasodilation in neonatal pulmonary hypertension

2011 ◽  
Vol 301 (5) ◽  
pp. L755-L764 ◽  
Author(s):  
Marc Chester ◽  
Gregory Seedorf ◽  
Pierre Tourneux ◽  
Jason Gien ◽  
Nancy Tseng ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Guanylate Cyclase ◽  
Soluble Guanylate Cyclase ◽  
Ductus Arteriosus ◽  
No Donor ◽  
Fetal Sheep ◽  
Cgmp Production ◽  
Pulmonary Vasodilation

Although inhaled NO (iNO) therapy is often effective in treating infants with persistent pulmonary hypertension of the newborn (PPHN), up to 40% of patients fail to respond, which may be partly due to abnormal expression and function of soluble guanylate cyclase (sGC). To determine whether altered sGC expression or activity due to oxidized sGC contributes to high pulmonary vascular resistance (PVR) and poor NO responsiveness, we studied the effects of cinaciguat (BAY 58-2667), an sGC activator, on pulmonary artery smooth muscle cells (PASMC) from normal fetal sheep and sheep exposed to chronic intrauterine pulmonary hypertension (i.e., PPHN). We found increased sGC α1- and β1-subunit protein expression but lower basal cGMP levels in PPHN PASMC compared with normal PASMC. To determine the effects of cinaciguat and NO after sGC oxidation in vitro, we measured cGMP production by normal and PPHN PASMC treated with cinaciguat and the NO donor, sodium nitroprusside (SNP), before and after exposure to 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ, an sGC oxidizer), hyperoxia (fraction of inspired oxygen 0.50), or hydrogen peroxide (H2O2). After treatment with ODQ, SNP-induced cGMP generation was markedly reduced but the effects of cinaciguat were increased by 14- and 64-fold in PPHN fetal PASMC, respectively ( P < 0.01 vs. controls). Hyperoxia or H2O2enhanced cGMP production by cinaciguat but not SNP in PASMC. To determine the hemodynamic effects of cinaciguat in vivo, we compared serial responses to cinaciguat and ACh in fetal lambs after ductus arteriosus ligation. In contrast with the impaired vasodilator response to ACh, cinaciguat-induced pulmonary vasodilation was significantly increased. After birth, cinaciguat caused a significantly greater fall in PVR than either 100% oxygen, iNO, or ACh. We conclude that cinaciguat causes more potent pulmonary vasodilation than iNO in experimental PPHN. We speculate that increased NO-insensitive sGC may contribute to the pathogenesis of PPHN, and cinaciguat may provide a novel treatment of severe pulmonary hypertension.

Prostaglandins E2 and I2 cause greater relaxations in pulmonary veins than in arteries of newborn lambs

1996 ◽  
Vol 81 (6) ◽  
pp. 2534-2539 ◽  
Author(s):  
Yuansheng Gao ◽  
Haiyan Zhou ◽  
Basil O. Ibe ◽  
J. Usha Raj
Keyword(s):  
Adenylate Cyclase ◽  
Isometric Force ◽  
Pulmonary Veins ◽  
Pulmonary Arteries ◽  
Calcium Ionophore ◽  
Fourth Generation ◽  
Breakdown Product ◽  
Cyclic Monophosphate ◽  
Vasoactive Mediators ◽  
Arteries And Veins

Gao, Yuansheng, Haiyan Zhou, Basil O. Ibe, and J. Usha Raj.Prostaglandins E2 and I2 cause greater relaxations in pulmonary veins than in arteries of newborn lambs. J. Appl. Physiol. 81(6): 2534–2539, 1996.—Prostaglandins E2(PGE2) and I2(PGI2) are important vasoactive mediators in pulmonary vessels. The present study was designed to determine whether the responses of pulmonary arteries to these prostanoids are different from those of veins in newborn lambs. Fourth-generation pulmonary arterial and venous rings without endothelium were suspended in organ chambers filled with modified Krebs-Ringer bicarbonate solution (95% O2-5% CO2, 37°C), and their isometric force was measured. During contraction with endothelin-1 or U-46619 (indomethacin was present to eliminate the possible involvement of endogenous cyclooxygenase products), PGE2, PGI2, and carbacyclin (a stable analogue of PGI2) induced greater relaxations in veins than in arteries. In both vessel types, relaxations induced by PGE2 were greater than those induced by PGI2or carbacyclin. Forskolin, an activator of adenylate cyclase, also induced greater relaxation of veins than of arteries. Relaxation induced by 8-bromoadenosine 3′,5′-cyclic monophosphate, an analogue of adenosine 3′,5′-cyclic monophosphate (cAMP), was comparable in both vessel types. Radioimmunoassay revealed that the basal and calcium ionophore A-23187-induced releases of PGE2 or 6-ketoprostaglandin F1α (the stable breakdown product of PGI2) were similar between arteries and veins. Measurement of cAMP (in the presence of isobutylmethylxanthine) showed that PGE2 and forskolin induced greater increase in cAMP in veins than in arteries. Our results demonstrate that PGE2 and PGI2 are more potent vasodilators in pulmonary veins than in arteries in newborn lambs. A difference in the activity of adenylate cyclase may contribute to the differential responses to PGE2 and PGI2 between pulmonary arteries and veins. Furthermore, PGE2appears play an more important role than does PGI2 in modulating pulmonary vascular tone of newborn lambs.

Endothelium-dependent relaxations to adenosine in juvenile rabbit pulmonary arteries and veins

1994 ◽  
Vol 266 (5) ◽  
pp. H2001-H2006 ◽  
Author(s):  
R. H. Steinhorn ◽  
F. C. Morin ◽  
D. G. Van Wylen ◽  
S. F. Gugino ◽  
E. C. Giese ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Nitric Oxide Synthase ◽  
Adenosine Receptor ◽  
Receptor Agonist ◽  
Pulmonary Veins ◽  
Pulmonary Arteries ◽  
Response Curves ◽  
Pulmonary Vessels ◽  
Oxide Synthase ◽  
Arteries And Veins

We studied the actions of adenosine and its analogues 5'-(N-ethylcarboxamido)-adenosine (NECA) and N6-cyclohexyladenosine (CHA) in pulmonary vessels isolated from juvenile rabbits. Pulmonary arteries relaxed in a concentration-dependent fashion to all three compounds. Pretreatment with the methylxanthine 8-p-sulfophenyltheophylline shifted the concentration-response curves to adenosine and NECA rightward, indicating that the vasodilator effects were mediated by the adenosine receptor. The order of potency of adenosine compounds was NECA > adenosine > CHA, indicating that the A2-receptor mediates relaxations to adenosine in rabbit pulmonary arteries. Endothelium rubbing attenuated relaxations to adenosine at concentrations of < or = 3 x 10(-7) M and to all NECA concentrations. Inhibition of nitric oxide synthase with NG-nitro-L-arginine (L-NNA) similarly attenuated relaxations at concentrations of < or = 3 x 10(-7) M for adenosine and < or = 3 x 10(-8) M for NECA. With the use of the same methods, a substantial endothelial contribution was additionally observed in pulmonary veins to the vasodilator effects of NECA. We conclude that adenosine, and the more specific A2-receptor agonist NECA, dilate pulmonary arteries and veins isolated from young rabbits via a mechanism that is partially dependent on endothelium-derived nitric oxide.

Newborn rat response to single vs. combined cGMP-dependent pulmonary vasodilators

2014 ◽  
Vol 306 (2) ◽  
pp. L207-L215 ◽  
Author(s):  
Masahiro Enomoto ◽  
Amish Jain ◽  
Jingyi Pan ◽  
Yulia Shifrin ◽  
Todd Van Vliet ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Synergistic Effect ◽  
Soluble Guanylate Cyclase ◽  
Pulmonary Arteries ◽  
Small Heat Shock Protein ◽  
No Donor ◽  
Clinical Exposure ◽  
Pulmonary Vasodilators ◽  
Pulmonary Vasodilator

Inhaled nitric oxide (NO) and other cGMP- or cAMP-dependent pulmonary vasodilators are often used in combination for the treatment of the persistent pulmonary hypertension of the newborn syndrome. There is in vitro evidence to indicate that NO downregulate the pulmonary vascular response to cGMP-dependent agonists raising concern as to whether a synergistic effect is observed when employing a combined strategy in newborns. Hypothesizing that a synergistic effect is absent, we evaluated newborn and juvenile rat pulmonary arteries to determine the individual and combined vasodilatory effect of cGMP- and cAMP-dependent agonists. In precontracted near-resistance pulmonary arteries, the addition of sildenafil reduced vasorelaxation response to NO donor S-nitroso- N-acetyl penicillamine (SNAP). A similar decrease in SNAP-induced vasodilation was observed in arteries pretreated with BAY 41–2272 (10−9 M), a soluble guanylate cyclase stimulator cGMP, and its downstream protein kinase activator. cGMP also reduced the vasorelaxant response to the cAMP-dependent forskolin. Inhibition of endogenous vascular NO generation enhanced SNAP-induced relaxation. The present data suggest that the mechanism involved in the cGMP desensitization to other relaxant agonists involves downregulation of the small heat shock protein HSP20 and is evident in rat pulmonary and systemic vascular smooth muscle cells. In newborn rats with chronic hypoxia-induced pulmonary hypertension, the combination of sildenafil and inhaled NO resulted in a lesser reduction in pulmonary vascular resistance compared with their individual effect. These data suggest that clinical exposure to one cGMP-dependent pulmonary vasodilator may affect the response to other cGMP- or cAMP-mediated agonists.

Vasoconstrictor Responses to Vasopressor Agents in Human Pulmonary and Radial Arteries

2014 ◽  
Vol 121 (5) ◽  
pp. 930-936 ◽  
Author(s):  
Dale A. Currigan ◽  
Richard J. A. Hughes ◽  
Christine E. Wright ◽  
James A. Angus ◽  
Paul F. Soeding
Keyword(s):  
Pulmonary Hypertension ◽  
Radial Artery ◽  
Vascular Tone ◽  
Pulmonary Arteries ◽  
Right Heart Failure ◽  
Response Curves ◽  
Vasopressor Agent ◽  
Vasopressor Agents ◽  
Vascular Beds ◽  
Potent Vasoconstrictor

Abstract Background: Vasopressor drugs, commonly used to treat systemic hypotension and maintain organ perfusion, may also induce regional vasoconstriction in specialized vascular beds such as the lung. An increase in pulmonary vascular tone may adversely affect patients with pulmonary hypertension or right heart failure. While sympathomimetics constrict pulmonary vessels, and vasopressin does not, a direct comparison between these drugs has not been made. This study investigated the effects of clinically used vasopressor agents on human isolated pulmonary and radial arteries. Methods: Isolated pulmonary and radial artery ring segments, mounted in organ baths, were used to study the contractile responses of each vasopressor agent. Concentration–response curves to norepinephrine, phenylephrine, metaraminol, and vasopressin were constructed. Results: The sympathomimetics norepinephrine, phenylephrine, and metaraminol caused concentration-dependent vasoconstriction in the radial (pEC50: 6.99 ± 0.06, 6.14 ± 0.09, and 5.56 ± 0.07, respectively, n = 4 to 5) and pulmonary arteries (pEC50: 6.86 ± 0.11, 5.94 ± 0.05 and 5.56 ± 0.09, respectively, n = 3 to 4). Vasopressin was a potent vasoconstrictor of the radial artery (pEC50 9.13 ± 0.20, n = 3), whereas in the pulmonary artery, it had no significant effect. Conclusions: Sympathomimetic-based vasopressor agents constrict both human radial and pulmonary arteries with similar potency in each. In contrast, vasopressin, although a potent vasoconstrictor of radial vessels, had no effect on pulmonary vascular tone. These findings provide some support for the use of vasopressin in patients with pulmonary hypertension.

scholarly journals The soluble guanylate cyclase stimulator riociguat is the first-line therapy for chronic thromboembolic pulmonary hypertension patients

Kardiologiia ◽  
2020 ◽  
Vol 60 (8) ◽  
pp. 115-123
Author(s):  
Z. S. Valieva ◽  
S. E. Gratsianskaya ◽  
T. V. Martynyuk
Keyword(s):  
Pulmonary Hypertension ◽  
Guanylate Cyclase ◽  
Soluble Guanylate Cyclase ◽  
Pulmonary Arteries ◽  
Chronic Thromboembolic Pulmonary Hypertension ◽  
First Line ◽  
Pulmonary Thromboendarterectomy ◽  
First Line Therapy ◽  
Thromboembolic Pulmonary Hypertension ◽  
Pulmonary Microcirculation

Chronic thromboembolic pulmonary hypertension (CTEPH) is a precapillary type of pulmonary hypertension with chronic obstruction of large and medium branches of pulmonary arteries along with secondary alterations in pulmonary microcirculation, which cause progressive increases in pulmonary vascular resistance and pulmonary arterial pressure and ensuing severe right heart dysfunction and heart failure. Pulmonary thromboendarterectomy (PTE) is the treatment of choice for CTEPH; however, this procedure is available not for all patients. Although the surgery performed in the conditions of centers with advanced experience generally shows good results, up to 40% of patients are technically inoperable or PTE is associated with a high risk of complications. At present, riociguat, the only officially approved drug from the class of soluble guanylate cyclase stimulators, is considered as a first-line treatment for inoperable and residual forms of STEPH. Introduction of riociguat to clinical practice can be called a real breakthrough in the treatment of patients with STEPH who cannot undergo PTE or those with relapse or persistent STEPH after the surgery.

Upregulation of ET-1 and its receptors and remodeling in small pulmonary veins under hypoxic conditions

2001 ◽  
Vol 280 (6) ◽  
pp. L1104-L1114 ◽  
Author(s):  
Hideki Takahashi ◽  
Sanae Soma ◽  
Masashi Muramatsu ◽  
Masahiko Oka ◽  
Yoshinosuke Fukuchi
Keyword(s):  
Pulmonary Hypertension ◽  
Smooth Muscle ◽  
Vascular Remodeling ◽  
Smooth Muscle Actin ◽  
Pulmonary Veins ◽  
Pulmonary Arteries ◽  
Immunohistochemical Method ◽  
Muscle Actin ◽  
Converting Enzyme ◽  
Hypoxic Conditions

Pulmonary veins show greater sensitivity to endothelin (ET)-1-induced vasoconstriction than pulmonary arteries, and remodeling was observed in pulmonary veins under hypoxic conditions. We examined, using an immunohistochemical method, the expression of Big ET-1, ET-converting enzyme (ECE), and ETA and ETB receptors in rat pulmonary veins under normoxic and hypoxic conditions. In control rats, Big ET-1 and ECE were coexpressed in the intima and media of the pulmonary veins, with an even distribution along the axial pathway. ETA and ETB receptors were expressed in the pulmonary veins, with a predominant distribution in the proximal segments. The expression of Big ET-1 was more abundant in the pulmonary veins than in the pulmonary arteries. After exposure to hypoxia for 7 or 14 days, the expression of Big ET-1, ECE, and ET receptors increased in small pulmonary veins. Increases in the medial thickness, wall thickness, and immunoreactivity for α-smooth muscle actin were also observed in the small pulmonary veins under hypoxic conditions. The upregulation of ET-1 and ET receptors in the small pulmonary veins is associated with vascular remodeling, which may lead to the development of hypoxic pulmonary hypertension.

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