Role of ATP-sensitive potassium channels in ovine fetal pulmonary vascular tone

1992 ◽  
Vol 263 (5) ◽  
pp. H1363-H1368 ◽  
Author(s):  
D. N. Cornfield ◽  
J. A. McQueston ◽  
I. F. McMurtry ◽  
D. M. Rodman ◽  
S. H. Abman
Keyword(s):  
Blood Flow ◽  
Pulmonary Circulation ◽  
Pulmonary Blood Flow ◽  
Vascular Tone ◽  
Left Pulmonary Artery ◽  
Late Gestation ◽  
Flow Transducer ◽  
Pulmonary Vasodilation ◽  
Relaxing Factor

To study the potential role of ATP-sensitive K+ (K+ATP) channels in fetal pulmonary vasoregulation, we studied the effect of a K+ATP channel agonist, lemakalim, and antagonist, glibenclamide, on the fetal pulmonary circulation in nine chronically instrumented late-gestation fetal lambs. Left pulmonary artery (LPA) blood flow was measured with an electromagnetic flow transducer. Brief (10 min) infusions of lemakalim at 3, 10, and 30 micrograms/min into the LPA produced dose-dependent increases in flow from 68 +/- 7 to 96 +/- 11, 160 +/- 15, and 204 +/- 34 ml/min, respectively. The duration of pulmonary vasodilation after the 10-min infusions of lemakalim at 3, 10, and 30 micrograms/min was 20 +/- 3, 47 +/- 10, and 55 +/- 15 min, respectively. Pulmonary blood pressure and flow did not change with intrapulmonary infusion of glibenclamide (10 mg), a K+ATP channel antagonist. Lemakalim-induced pulmonary vasodilation was not affected by nitro-L-arginine (10 mg), a competitive inhibitor of endothelium-dependent relaxing factor, but was blocked by glibenclamide. Prolonged (2 h) intrapulmonary infusions of lemakalim (2-6 micrograms/min) increased pulmonary blood flow by 137%. The increase in pulmonary blood flow was sustained throughout the infusion. Systemic and pulmonary arterial pressures decreased during prolonged infusion. We conclude that K+ATP channels are present in the fetal pulmonary circulation, but do not participate in the regulation of basal pulmonary vascular tone. K+ATP channel activation produces sustained vasodilation that is not mediated by endothelium-derived relaxing factor. We speculate that birth-related stimuli activate K+ATP channels to enhance the pulmonary vasodilation that occurs at birth.

scholarly journals Role of endothelium-derived relaxing factor during transition of pulmonary circulation at birth

1990 ◽  
Vol 259 (6) ◽  
pp. H1921-H1927 ◽  
Author(s):  
S. H. Abman ◽  
B. A. Chatfield ◽  
S. L. Hall ◽  
I. F. McMurtry
Keyword(s):  
Blood Flow ◽  
Pulmonary Artery ◽  
Pulmonary Circulation ◽  
Atrial Natriuretic Factor ◽  
Pulmonary Blood Flow ◽  
Relaxing Factor ◽  
Natriuretic Factor ◽  
Endothelium Derived Relaxing Factor ◽  
Atrial Natriuretic

To examine the potential role of endothelium-derived relaxing factor (EDRF) in regulation of the perinatal pulmonary circulation, we studied the hemodynamic effects of a selective inhibitor of EDRF production, nitro-L-arginine (L-NA), on pulmonary vascular tone and dilator reactivity in the late-gestation ovine fetus and on the pulmonary vasodilation that normally occurs at birth. L-NA infusion decreased pulmonary blood flow from 78 +/- 8 to 65 +/- 6 ml/min (P less than 0.01) and increased pulmonary artery pressure from 48 +/- 2 to 54 +/- 3 mmHg (P less than 0.002, n = 8 animals). To study the selectivity of L-NA on vasodilator responses to endothelium-dependent (acetylcholine) and -independent (atrial natriuretic factor) stimuli, we measured responses to brief infusions of each dilator before and after L-NA treatment. Acetylcholine increased pulmonary blood flow during the control period but not after L-NA treatment. In contrast, L-NA had little effect on the vasodilator response to atrial natriuretic factor. To study the role of EDRF in the transition of the pulmonary circulation from fetal to neonatal conditions, we infused L-NA into the left pulmonary artery immediately before cesarean-section delivery. In comparison with control animals, the rise in pulmonary blood flow at 1 h after delivery was reduced in the L-NA-treated animals (331 +/- 28 in control vs. 185 +/- 16 ml/min in treated, P less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of oxygen and exogenous L-arginine on EDRF activity in fetal pulmonary circulation

1993 ◽  
Vol 264 (3) ◽  
pp. H865-H871 ◽  
Author(s):  
J. A. McQueston ◽  
D. N. Cornfield ◽  
I. F. McMurtry ◽  
S. H. Abman
Keyword(s):  
Blood Flow ◽  
Pulmonary Artery ◽  
Pulmonary Circulation ◽  
Fetal Lung ◽  
Left Pulmonary Artery ◽  
Late Gestation ◽  
Arginine Infusion ◽  
Pulmonary Vasodilation ◽  
Pulmonary Vasodilator ◽  
Vasodilator Activity

To determine whether L-arginine, the precursor of endothelium-derived relaxing factor (EDRF), increases vasodilator activity in the fetal pulmonary circulation, we studied its effects on basal pulmonary vascular tone and on pulmonary vasodilation stimulated by oxygen and acetylcholine (ACh) in chronically prepared late-gestation fetal lambs. L-Arginine infusion (30–300 mg over 10 min) into the left pulmonary artery (LPA) increased blood flow (18–57%) without changing pulmonary artery pressure. To determine whether O2-induced vasodilation involves EDRF and is augmented by L-arginine treatment, we infused L-arginine or NG-nitro-L-arginine (L-NNA), an inhibitor of EDRF synthesis, while increasing fetal PO2 6 Torr by delivering 100% O2 to the ewe for 120 min. In controls, LPA blood flow progressively increased from 106 +/- 13 ml/min (baseline) to 257 +/- 34 ml/min (peak) at 40 min of increased PO2 (P < 0.05, baseline vs. peak) but steadily returned toward baseline during the next hour. Treatment with L-NNA markedly attenuated O2-induced pulmonary vasodilation (P < 0.05 vs. control). L-Arginine infusion did not augment or sustain the O2-induced vasodilator response. We also examined whether L-arginine could sustain pulmonary vasodilation to ACh, another EDRF-dependent stimulus, and found that the EDRF substrate neither potentiated nor sustained the ACh response. We conclude that: in the fetal lung 1) exogenous L-arginine is a fetal pulmonary vasodilator, 2) increased PO2 augments EDRF activity in the fetal lung, and 3) supplemental L-arginine does not sustain either O2- or ACh-induced vasodilation.(ABSTRACT TRUNCATED AT 250 WORDS)

Bradykinin produces pulmonary vasodilation in fetal lambs: role of prostaglandin production

1989 ◽  
Vol 67 (4) ◽  
pp. 1512-1517 ◽  
Author(s):  
E. Frantz ◽  
S. J. Soifer ◽  
R. I. Clyman ◽  
M. A. Heymann
Keyword(s):  
Blood Flow ◽  
Pulmonary Vascular Resistance ◽  
Vascular Resistance ◽  
Pulmonary Blood Flow ◽  
The Other ◽  
Prostaglandin I2 ◽  
Pulmonary Vasodilation ◽  
Relaxing Factor ◽  
Pulmonary Vasodilators

Bradykinin produces pulmonary vasodilation and also stimulates production of other pulmonary vasodilators, including prostaglandin I2 (PGI2) and endothelial-derived relaxing factor. In 12 chronically instrumented fetal lambs, we therefore investigated potential mediation of the bradykinin response by PGI2 or other cyclooxygenase products. A 15-min infusion of bradykinin (approximately 1 microgram/kg estimated fetal wt/min) increased fetal pulmonary blood flow by 522% (P less than 0.05) and decreased pulmonary vascular resistance by 86% (P less than 0.05); plasma 6-ketoprostaglandin F1 alpha (6-keto-PGF1 alpha) concentration also increased (P less than 0.05). After cyclooxygenase inhibition by indomethacin (3 mg), bradykinin increased pulmonary blood flow by only 350% (P less than 0.05) and decreased pulmonary vascular resistance by 83% (P less than 0.05); plasma 6-keto-PGF1 alpha concentrations did not increase. The increase in pulmonary blood flow produced by bradykinin was greater before administration of indomethacin than after (P less than 0.05). These studies demonstrate that bradykinin produces fetal pulmonary vasodilation by at least two mechanisms, one dependent on and the other independent of PGI2 production, the latter mechanism predominating.

scholarly journals Cinaciguat, a soluble guanylate cyclase activator, causes potent and sustained pulmonary vasodilation in the ovine fetus

2009 ◽  
Vol 297 (2) ◽  
pp. L318-L325 ◽  
Author(s):  
Marc Chester ◽  
Pierre Tourneux ◽  
Greg Seedorf ◽  
Theresa R. Grover ◽  
Jason Gien ◽  
...  
Keyword(s):  
Blood Flow ◽  
Pulmonary Hypertension ◽  
Pulmonary Artery ◽  
Pulmonary Vascular Resistance ◽  
Vascular Resistance ◽  
Guanylate Cyclase ◽  
Soluble Guanylate Cyclase ◽  
Left Pulmonary Artery ◽  
Flow Transducer ◽  
Pulmonary Vasodilation

Impaired nitric oxide-cGMP signaling contributes to severe pulmonary hypertension after birth, which may in part be due to decreased soluble guanylate cyclase (sGC) activity. Cinaciguat (BAY 58-2667) is a novel sGC activator that causes vasodilation, even in the presence of oxidized heme or heme-free sGC, but its hemodynamic effects have not been studied in the perinatal lung. We performed surgery on eight fetal (126 ± 2 days gestation) lambs (full term = 147 days) and placed catheters in the main pulmonary artery, aorta, and left atrium to measure pressures. An ultrasonic flow transducer was placed on the left pulmonary artery to measure blood flow, and a catheter was placed in the left pulmonary artery for drug infusion. Cinaciguat (0.1–100 μg over 10 min) caused dose-related increases in pulmonary blood flow greater than fourfold above baseline and reduced pulmonary vascular resistance by 80%. Treatment with 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), an sGC-oxidizing inhibitor, enhanced cinaciguat-induced pulmonary vasodilation by >120%. The pulmonary vasodilator effect of cinaciguat was prolonged, decreasing pulmonary vascular resistance for >1.5 h after brief infusion. In vitro stimulation of ovine fetal pulmonary artery smooth muscle cells with cinaciguat after ODQ treatment resulted in a 14-fold increase in cGMP compared with non-ODQ-treated cells. We conclude that cinaciguat causes potent and sustained fetal pulmonary vasodilation that is augmented in the presence of oxidized sGC and speculate that cinaciguat may have therapeutic potential for severe neonatal pulmonary hypertension.

scholarly journals Inhaled carbon monoxide does not cause pulmonary vasodilation in the late-gestation fetal lamb

2000 ◽  
Vol 278 (4) ◽  
pp. L779-L784 ◽  
Author(s):  
Theresa R. Grover ◽  
Robyn L. Rairigh ◽  
Jeanne P. Zenge ◽  
Steven H. Abman ◽  
John P. Kinsella
Keyword(s):  
Carbon Monoxide ◽  
Blood Flow ◽  
Pulmonary Artery ◽  
Vascular Tone ◽  
Ductus Arteriosus ◽  
Protoporphyrin Ix ◽  
Left Lung ◽  
Late Gestation ◽  
Zinc Protoporphyrin ◽  
Pulmonary Vasodilation

As observed with nitric oxide (NO), carbon monoxide (CO) binds and may activate soluble guanylate cyclase and increase cGMP levels in smooth muscle cells in vitro. Because inhaled NO (INO) causes potent and sustained pulmonary vasodilation, we hypothesized that inhaled CO (ICO) may have similar effects on the perinatal lung. To determine whether ICOcan lower pulmonary vascular resistance (PVR) during the perinatal period, we studied the effects of ICOon late-gestation fetal lambs. Catheters were placed in the main pulmonary artery, left pulmonary artery (LPA), aorta, and left atrium to measure pressure. An ultrasonic flow transducer was placed on the LPA to measure blood flow to the left lung. After baseline measurements, fetal lambs were mechanically ventilated with a hypoxic gas mixture (inspired O2fraction < 0.10) to maintain a constant fetal arterial [Formula: see text]. After 60 min (baseline), the lambs were treated with ICO[5–2,500 parts/million (ppm)]. Comparisons were made with INO(5 and 20 ppm) and combined INO(5 ppm) and ICO(100 and 2,500 ppm). We found that ICOdid not alter left lung blood flow or PVR at any of the study doses. In contrast, low-dose INOdecreased PVR by 47% ( P < 0.005). The combination of INOand ICOdid not enhance the vasodilator response to INO. To determine whether endogenous CO contributes to vascular tone in the fetal lung, zinc protoporphyrin IX, an inhibitor of heme oxygenase, was infused into the LPA in three lambs. Zinc protoporphyrin IX had no effect on baseline PVR, aortic pressure, or the pressure gradient across the ductus arteriosus. We conclude that ICOdoes not cause vasodilation in the near-term ovine transitional circulation, and endogenous CO does not contribute significantly to baseline pulmonary vascular tone or ductus arteriosus tone in the late-gestation ovine fetus.

Increasing oxygen tension dilates fetal pulmonary circulation via endothelium-derived relaxing factor

1993 ◽  
Vol 265 (1) ◽  
pp. H376-H380 ◽  
Author(s):  
M. H. Tiktinsky ◽  
F. C. Morin
Keyword(s):  
Blood Flow ◽  
Oxygen Tension ◽  
Hyperbaric Oxygen ◽  
Pulmonary Circulation ◽  
Left Atrial ◽  
Pulmonary Blood Flow ◽  
Absolute Pressure ◽  
Relaxing Factor ◽  
Pulmonary Arterial ◽  
Endothelium Derived Relaxing Factor

We examined the role of endothelium-derived relaxing factor (EDRF) in the increase in pulmonary blood flow caused by increasing oxygen tension in the lungs of the fetus. Fetal lambs at 133 days of gestation were instrumented for intrauterine measurement of pulmonary arterial, left atrial, and amniotic fluid pressure and pulmonary blood flow. Three days later oxygen tension in the pulmonary arterial blood of the fetus was doubled by having the ewe breathe 100% oxygen at 3 atm absolute pressure. In the control fetuses (n = 5), hyperbaric oxygenation increased pulmonary blood flow eightfold. Blocking EDRF production by infusing 45 mg of NG-monomethyl-L-arginine into the superior vena cava of the fetus over 5 min starting 30 min after the beginning of hyperbaric oxygen reversed the increase in pulmonary blood flow (n = 5). Blocking EDRF production by infusing NG-nitro-L-arginine at 1 mg/min for 60 min starting 30 min before hyperbaric oxygen blunted the initial increase in pulmonary blood flow and eliminated it by the end of the experiment (n = 5). As hyperbaric oxygen did not significantly alter pulmonary arterial or left atrial pressure, changes in pulmonary vascular conductance paralleled those in pulmonary blood flow. We conclude that the majority of the vasodilation of the fetal pulmonary circulation caused by increasing oxygen tension is mediated by EDRF. We speculate that EDRF is involved in maintaining low vascular tone at the relatively high oxygen tension of the postnatal lung.

EDRF inhibition attenuates the increase in pulmonary blood flow due to oxygen ventilation in fetal lambs

1992 ◽  
Vol 73 (5) ◽  
pp. 2151-2157 ◽  
Author(s):  
P. Moore ◽  
H. Velvis ◽  
J. R. Fineman ◽  
S. J. Soifer ◽  
M. A. Heymann
Keyword(s):  
Blood Flow ◽  
Pulmonary Vascular Resistance ◽  
Vascular Resistance ◽  
Pulmonary Blood Flow ◽  
Vascular Tone ◽  
Competitive Inhibitor ◽  
In Utero ◽  
Prostaglandin Synthesis ◽  
Arginine Infusion ◽  
Pulmonary Vasodilation

At birth, pulmonary vasodilation occurs during rhythmic distension of the lungs and oxygenation. Inhibition of prostaglandin synthesis prevents pulmonary vasodilation during rhythmic distension of the lungs but not during oxygenation. Because endothelium-derived relaxing factor (EDRF) modulates pulmonary vascular tone at birth, at rest, and during hypoxia in older animals, we hypothesized that EDRF may modulate pulmonary vascular tone during oxygenation in fetal lambs. We studied the responses to N omega-nitro-L-arginine, a competitive inhibitor of EDRF synthesis, in nine near-term fetal lambs and to drug vehicle in six of these lambs and the subsequent responses to in utero ventilation with 95% O2 in these fetal lambs. In all fetal lambs, prostaglandin synthesis was prevented by meclofenamate. N omega-nitro-L-arginine increased pulmonary and systemic arterial pressures by 28% (P < 0.05) and 31% (P < 0.05), respectively, and decreased pulmonary blood flow by 83% (P < 0.05). In the controls, ventilation with 95% O2 increased pulmonary blood flow by 1,050% (P = 0.05) without changing pressures, thereby decreasing pulmonary vascular resistance by 88% (P = 0.05). During N omega-nitro-L-arginine infusion, ventilation with 95% O2 increased pulmonary blood flow by 162% (P = 0.05) and decreased pulmonary vascular resistance by 74% (P = 0.05). This suggests that EDRF may play an important role in modulating resting pulmonary vascular tone in fetal lambs and in the vasodilatory response to ventilation with O2 in utero.

scholarly journals Nitric Oxide: Considerations for the Treatment of Ischemic Stroke

2012 ◽  
Vol 32 (7) ◽  
pp. 1332-1346 ◽  
Author(s):  
Nicole A Terpolilli ◽  
Michael A Moskowitz ◽  
Nikolaus Plesnila
Keyword(s):  
Nitric Oxide ◽  
Blood Flow ◽  
Vascular Tone ◽  
Human Biology ◽  
Common Cause ◽  
Physiological Functions ◽  
Relaxing Factor ◽  
Current Review ◽  
Endothelium Derived Relaxing Factor

Some 40 years ago it was recognized by Furchgott and colleagues that the endothelium releases a vasodilator, endothelium-derived relaxing factor (EDRF). Later on, several groups identified EDRF to be a gas, nitric oxide (NO). Since then, NO was identified as one of the most versatile and unique molecules in animal and human biology. Nitric oxide mediates a plethora of physiological functions, for example, maintenance of vascular tone and inflammation. Apart from these physiological functions, NO is also involved in the pathophysiology of various disorders, specifically those in which regulation of blood flow and inflammation has a key role. The aim of the current review is to summarize the role of NO in cerebral ischemia, the most common cause of stroke.

Effects of BAY 41–2272, a soluble guanylate cyclase activator, on pulmonary vascular reactivity in the ovine fetus

2005 ◽  
Vol 288 (4) ◽  
pp. L727-L733 ◽  
Author(s):  
Philippe Deruelle ◽  
Theresa R. Grover ◽  
Laurent Storme ◽  
Steven H. Abman
Keyword(s):  
Blood Flow ◽  
Pulmonary Artery ◽  
Guanylate Cyclase ◽  
Pulmonary Circulation ◽  
Soluble Guanylate Cyclase ◽  
Critical Role ◽  
No Production ◽  
Flow Transducer ◽  
Pulmonary Vasodilation ◽  
Pulmonary Vasodilator

Nitric oxide (NO)-cGMP signaling plays a critical role during the transition of the pulmonary circulation at birth. BAY 41–2272 is a novel NO-independent direct stimulator of soluble guanylate cyclase that causes vasodilation in systemic and local circulations. However, the hemodynamic effects of BAY 41–2272 have not been studied in the perinatal pulmonary circulation. We hypothesized that BAY 41–2272 causes potent and sustained fetal pulmonary vasodilation. We performed surgery on 14 fetal lambs (125–130 days gestation; term = 147 days) and placed catheters in the main pulmonary artery, aorta, and left atrium to measure pressures. An ultrasonic flow transducer was placed on the left pulmonary artery (LPA) to measure blood flow, and a catheter was placed in the LPA for drug infusion. Pulmonary vascular resistance (PVR) was calculated as pulmonary artery pressure minus left atrial pressure divided by LPA blood flow. BAY 41–2272 caused dose-related increases in pulmonary blood flow up to threefold above baseline and reduced PVR by 75% ( P < 0.01). Prolonged infusion of BAY 41–2272 caused sustained pulmonary vasodilation throughout the 120-min infusion period. The pulmonary vasodilator effect of BAY 41–2272 was not attenuated by Nω-nitro-l-arginine, a NO synthase inhibitor. In addition, compared with sildenafil, a phosphodiesterase 5 inhibitor, the pulmonary vasodilator response to BAY 41–2272 was more prolonged. We conclude that BAY 41–2272 causes potent and sustained fetal pulmonary vasodilation independent of NO release. We speculate that BAY 41–2272 may have therapeutic potential for pulmonary hypertension associated with failure to circulatory adaptation at birth, especially in the setting of impaired NO production.

Effects of catecholamines on the pulmonary circulation in the ovine fetus

2001 ◽  
Vol 281 (2) ◽  
pp. R607-R614 ◽  
Author(s):  
S. Jaillard ◽  
V. Houfflin-Debarge ◽  
Y. Riou ◽  
T. Rakza ◽  
S. Klosowski ◽  
...  
Keyword(s):  
Pulmonary Artery ◽  
Pulmonary Circulation ◽  
Vascular Tone ◽  
Left Pulmonary Artery ◽  
Late Gestation ◽  
Dopamine Infusion ◽  
Pulmonary Vasodilator ◽  
Norepinephrine Infusion ◽  
Ovine Fetus ◽  
Oxide Synthase

High levels of circulating catecholamines are found in the fetus, and fetal stress and birth induce a marked surge in catecholamine secretion. Little is known about the role of catecholamines on the fetal pulmonary circulation. To determine the effects of catecholamines on the pulmonary vascular tone, we tested the hemodynamic response to norepinephrine and dopamine infusion in chronically prepared late-gestation fetal lambs. We found that norepinephrine infusion (0.5 μg · kg−1· min−1) increased pulmonary artery pressure (PAP) by 10 ± 1% ( P < 0.01), left pulmonary artery blood flow by 73 ± 14% ( P < 0.01), and decreased pulmonary vascular resistance (PVR) by 33 ± 6% ( P < 0.01). The pulmonary vasodilator effect of norepinephrine was abolished after nitric oxide synthase inhibition. Dopamine infusion at 5 μg · kg−1· min−1did not significantly change PVR. Conversely, dopamine infusion at 10 μg · kg−1· min−1increased PAP ( P < 0.01) and progressively increased PVR by 30 ± 14% ( P < 0.01). These results indicate that catecholamines may modulate basal pulmonary vascular tone in the ovine fetus. We speculate that catecholamines may play a significant role in the maintenance of the fetal pulmonary circulation and in mediating changes in the transitional pulmonary circulation.

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