Thromboxane synthase inhibition and perinatal pulmonary response to arachidonic acid

1985 ◽  
Vol 58 (3) ◽  
pp. 710-716 ◽  
Author(s):  
M. L. Tod ◽  
S. Cassin
Keyword(s):  
Arachidonic Acid ◽  
Pulmonary Vascular Resistance ◽  
Vascular Resistance ◽  
Pressor Response ◽  
Specific Inhibitor ◽  
Left Lobe ◽  
Pulmonary Response ◽  
Pulmonary Vasoconstriction ◽  
Lower Left Lobe

Arachidonic acid causes dose-dependent increases in pulmonary vascular resistance in perinatal lambs. The specific metabolites that produce this effect are not known; however, a role for thromboxanes (TX's), potent constrictors of vascular smooth muscle, has been proposed. The effects of a specific inhibitor of TX synthase, OKY-1581, were tested in newborn and ventilated fetal lambs using an in situ pump-perfused lower left lobe preparation. Pulmonary and systemic responses of newborns and ventilated fetuses to infusions of arachidonic acid were evaluated in the presence and absence of OKY-1581. Increases in pulmonary vascular resistance caused by arachidonic acid were diminished by TX synthase inhibition. The degree of systemic hypotension observed with arachidonic acid infusions was significantly greater in animals receiving OKY-1581 than in animals without the inhibitor. The effect of OKY-1581 on periods of hypoxia was also evaluated in newborn lambs. There were no significant differences in the hypoxic pressor response in lambs with and without TX synthase inhibition. These results suggest that OKY-1581 can reduce most of the pulmonary vasoconstriction produced by arachidonic acid in perinatal lambs.

Reversal of reflex pulmonary vasoconstriction induced by main pulmonary arterial distension

1985 ◽  
Vol 58 (4) ◽  
pp. 1107-1114 ◽  
Author(s):  
C. E. Juratsch ◽  
R. F. Grover ◽  
C. E. Rose ◽  
J. T. Reeves ◽  
W. F. Walby ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Arachidonic Acid ◽  
Pulmonary Vascular Resistance ◽  
Vascular Resistance ◽  
Bolus Injection ◽  
Main Pulmonary Artery ◽  
Pulmonary Vasoconstriction ◽  
Pulmonary Vasodilator ◽  
Anesthetized Dogs ◽  
The Right

Distension of the main pulmonary artery (MPA) induces pulmonary hypertension, most probably by neurogenic reflex pulmonary vasoconstriction, although constriction of the pulmonary vessels has not actually been demonstrated. In previous studies in dogs with increased pulmonary vascular resistance produced by airway hypoxia, exogenous arachidonic acid has led to the production of pulmonary vasodilator prostaglandins. Hence, in the present study, we investigated the effect of arachidonic acid in seven intact anesthetized dogs after pulmonary vascular resistance was increased by MPA distention. After steady-state pulmonary hypertension was established, arachidonic acid (1.0 mg/min) was infused into the right ventricle for 16 min; 15–20 min later a 16-mg bolus of arachidonic acid was injected. MPA distension was maintained throughout the study. Although the infusion of arachidonic acid significantly lowered the elevated pulmonary vascular resistance induced by MPA distension, the pulmonary vascular resistance returned to control levels only after the bolus injection of arachidonic acid. Notably, the bolus injection caused a biphasic response which first increased the pulmonary vascular resistance transiently before lowering it to control levels. In dogs with resting levels of pulmonary vascular resistance, administration of arachidonic acid in the same manner did not alter the pulmonary vascular resistance. It is concluded that MPA distension does indeed cause reflex pulmonary vasoconstriction which can be reversed by vasodilator metabolites of arachidonic acid. Even though this reflex may help maintain high pulmonary vascular resistance in the fetus, its function in the adult is obscure.

Prostaglandin D2 inhibits hypoxic pulmonary vasoconstriction in neonatal lambs

1983 ◽  
Vol 54 (6) ◽  
pp. 1585-1589 ◽  
Author(s):  
J. B. Philips ◽  
R. K. Lyrene ◽  
M. McDevitt ◽  
W. Perlis ◽  
C. Satterwhite ◽  
...  
Keyword(s):  
Arterial Pressure ◽  
Pulmonary Vascular Resistance ◽  
Vascular Resistance ◽  
Inferior Vena ◽  
Hypoxic Pulmonary Vasoconstriction ◽  
Vena Cava ◽  
Systemic Arterial Pressure ◽  
Prostaglandin D2 ◽  
Pulmonary Vasoconstriction ◽  
Neonatal Lambs

Intrapulmonary injections of prostaglandin D2 (PGD2) reduce pulmonary arterial pressure and resistance in fetal and hypoxic neonatal lambs without affecting systemic arterial pressure. This apparently specific pulmonary effect of PGD2 could be explained by inactivation of the agent during passage through the pulmonary capillary bed. We therefore studied the effects of both pulmonary and systemic infusions of PGD2 on the acute vascular response to a 1-min episode of hypoxia in newborn lambs. Since PGD2 has been reported to be a pulmonary vasoconstrictor in normoxic lambs, we also evaluated its effects during normoxemia. Pulmonary vascular pressures were not affected by either 1- or 10-micrograms . kg-1 . min-1 infusions into the left atrium or inferior vena cava during normoxia. Infusion of 1 microgram . kg-1 . min-1 PGD2 into the inferior vena cava decreased pulmonary vascular resistance and increased systemic arterial pressure. These two parameters were unchanged with the other three infusion regimens. Mean pulmonary vascular resistance rose 83% with hypoxia and no PGD2. PGD2 prevented any change in pulmonary vascular resistance with hypoxia, while systemic arterial pressure increased (1-microgram . kg-1 . min-1 doses) or was unchanged. Thus PGD2 specifically prevents hypoxic pulmonary vasoconstriction while maintaining systemic pressures, regardless of infusion site. PGD2 may be indicated in treatment of persistent pulmonary hypertension of the newborn and other pulmonary hypertensive disorders.

Inhaled nitric oxide partially reverses hypoxic pulmonary vasoconstriction in the dog

1994 ◽  
Vol 76 (3) ◽  
pp. 1350-1355 ◽  
Author(s):  
J. A. Romand ◽  
M. R. Pinsky ◽  
L. Firestone ◽  
H. A. Zar ◽  
J. R. Lancaster
Keyword(s):  
Nitric Oxide ◽  
Arterial Pressure ◽  
Pulmonary Vascular Resistance ◽  
Vascular Resistance ◽  
Hypoxic Pulmonary Vasoconstriction ◽  
Canine Model ◽  
Systemic Arterial Pressure ◽  
Vasomotor Tone ◽  
Pulmonary Vasoconstriction ◽  
Pulmonary Arterial

Nitric oxide (NO) inhaled during a hypoxia-induced increase in pulmonary vasomotor tone decreases pulmonary arterial pressure (Ppa). We conducted this study to better characterize the hemodynamic effects induced by NO inhalation during hypoxic pulmonary vasoconstriction in 11 anesthetized ventilated dogs. Arterial and venous systemic and pulmonary pressures and aortic flow probe-derived cardiac output were recorded, and nitrosylhemoglobin (NO-Hb) and methemoglobin (MetHb) were measured. The effects of 5 min of NO inhalation at 0, 17, 28, 47, and 0 ppm during hyperoxia (inspiratory fraction of O2 = 0.5) and hypoxia (inspiratory fraction of O2 = 0.16) were observed. NO inhalation has no measurable effects during hyperoxia. Hypoxia induced an increase in Ppa that reached plateau levels after 5 min. Exposure to 28 and 47 ppm NO induced an immediate (< 30 s) decrease in Ppa and calculated pulmonary vascular resistance (P < 0.05 each) but did not return either to baseline hyperoxic values. Increasing the concentration of NO to 74 and 145 ppm in two dogs during hypoxia did not induce any further decreases in Ppa. Reversing hypoxia while NO remained at 47 ppm further decreased Ppa and pulmonary vascular resistance to baseline values. NO inhalation did not induce decreases in systemic arterial pressure. MetHb remained low, and NO-Hb was unmeasurable. We concluded that NO inhalation only partially reversed hypoxia-induced increases in pulmonary vasomotor tone in this canine model. These effects are immediate and selective to the pulmonary circulation.

Dependency of hypoxic pulmonary vasoconstriction on temperature

1977 ◽  
Vol 42 (1) ◽  
pp. 56-58 ◽  
Author(s):  
J. L. Benumof ◽  
E. A. Wahrenbrock
Keyword(s):  
Blood Flow ◽  
Pulmonary Vascular Resistance ◽  
Temperature Change ◽  
Vascular Resistance ◽  
Hypoxic Pulmonary Vasoconstriction ◽  
Lower Lobe ◽  
Effect Of Temperature ◽  
Hypoxic Response ◽  
Pulmonary Vasoconstriction ◽  
Mechanism Of Inhibition

We studied the effect of temperature change on hypoxic pulmonary vasoconstriction. Selective hypoxia on the left lower lobe of the lung in open-chested dogs at 37 degrees C caused the electromagnetically measured blood flow to the lobe to decrease 51 +/- 5 (SE)% and its vascular resistance to increase 155 +/- 25%. Testing hypoxic response. The hypoxic response at 31.1 +/- 0.4 degrees C was only a 26 +/- 6% decrease in lobar blood flow compared to the hypoxic response at 40.0 +/- 0.5 degrees C which was a 60 +/- 5% decrease in lobar blood flow. Hypothermia itself was associated with a significant increase in pulmonary vascular resistance. We conclude that hypothermia inhibits and hyperthermia enhances hypoxic pulmonary vasoconstriction. The mechanism of inhibition may involve prehypoxic vasoconstriction.

Perinatal pulmonary prostaglandin production

1981 ◽  
Vol 241 (5) ◽  
pp. H756-H759 ◽  
Author(s):  
C. W. Leffler ◽  
J. R. Hessler
Keyword(s):  
Pulmonary Vascular Resistance ◽  
Vascular Resistance ◽  
Electron Capture Detection ◽  
Pulmonary Resistance ◽  
Pulmonary Vasodilation ◽  
Resistance Vessels ◽  
Before And After ◽  
Fetal Lungs ◽  
Resistance Decrease

Products of reactions catalyzed by prostaglandin cyclo-oxygenase [prostaglandins (PG), thromboxanes] were analyzed by gas chromatography with electron-capture detection in the venous effluents of in situ Krebs-perfused lungs of exteriorized fetal goats and sheep before and after ventilation with air. The major products were 6-keto-PGF1 alpha and 6,15-diketo[13,14-dihydro] PGI2 without blood components. After ventilation, which decreased pulmonary vascular resistance to 63% of the before-ventilation value, lung production of 6-keto-PGF1 alpha and metabolite increased 50 and 230%, respectively. These data, in addition to earlier findings of inhibition of ventilation-induced pulmonary vasodilation by indomethacin and increased net production of PG-like material after ventilation of blood-perfused fetal lungs, support the hypothesis that ventilation of fetal lungs with air at birth increases synthesis of PGI2 by or near pulmonary resistance vessels, resulting in high local concentrations of PGI2 near its site of production. PGI2 appears to be important in the pulmonary vascular resistance decrease that is necessary for successful perinatal transition.

Pulmonary vasodilation by acetazolamide during hypoxia is unrelated to carbonic anhydrase inhibition

2007 ◽  
Vol 292 (1) ◽  
pp. L178-L184 ◽  
Author(s):  
Claudia Höhne ◽  
Philipp A. Pickerodt ◽  
Roland C. Francis ◽  
Willehad Boemke ◽  
Erik R. Swenson
Keyword(s):  
Carbonic Anhydrase ◽  
Pulmonary Artery ◽  
Pulmonary Vascular Resistance ◽  
Pulmonary Artery Pressure ◽  
Vascular Resistance ◽  
Low Dose ◽  
Hypoxic Pulmonary Vasoconstriction ◽  
Artery Pressure ◽  
Pulmonary Vasoconstriction ◽  
Mean Pulmonary Artery Pressure

Acute hypoxic pulmonary vasoconstriction can be inhibited by high doses of the carbonic anhydrase inhibitor acetazolamide. This study aimed to determine whether acetazolamide is effective at dosing relevant to human use at high altitude and to investigate whether its efficacy against hypoxic pulmonary vasoconstriction is dependent on carbonic anhydrase inhibition by testing other potent heterocyclic sulfonamide carbonic anhydrase inhibitors. Six conscious dogs were studied in five protocols: 1) controls, 2) low-dose intravenous acetazolamide (2 mg·kg−1·h−1), 3) oral acetazolamide (5 mg/kg), 4) benzolamide, a membrane-impermeant inhibitor, and 5) ethoxzolamide, a membrane-permeant inhibitor. In all protocols, unanesthetized dogs breathed spontaneously during the first hour (normoxia) and then breathed 9–10% O2 for the next 2 h. Arterial oxygen tension ranged between 35 and 39 mmHg during hypoxia in all protocols. In controls, mean pulmonary artery pressure increased by 8 mmHg and pulmonary vascular resistance by 200 dyn·s·cm−5 ( P <0.05). With intravenous acetazolamide, mean pulmonary artery pressure and pulmonary vascular resistance remained unchanged during hypoxia. With oral acetazolamide, mean pulmonary artery pressure increased by 5 mmHg ( P < 0.05), but pulmonary vascular resistance did not change during hypoxia. With benzolamide and ethoxzolamide, mean pulmonary artery pressure increased by 6–7 mmHg and pulmonary vascular resistance by 150–200 dyn·s·cm−5 during hypoxia ( P < 0.05). Low-dose acetazolamide is effective against acute hypoxic pulmonary vasoconstriction in vivo. The lack of effect with two other potent carbonic anhydrase inhibitors suggests that carbonic anhydrase is not involved in the mediation of hypoxic pulmonary vasoconstriction and that acetazolamide acts on a different receptor or channel.

Pulmonary vascular resistance in adult rats exposed to hypoxia in the neonatal period

1990 ◽  
Vol 68 (3) ◽  
pp. 419-424 ◽  
Author(s):  
T. S. Hakim ◽  
J. P. Mortola
Keyword(s):  
Pulmonary Vascular Resistance ◽  
Vascular Resistance ◽  
Flow Rate ◽  
Vascular Reactivity ◽  
Neonatal Period ◽  
Pressor Response ◽  
Autologous Blood ◽  
Venous Pressure ◽  
Pulmonary Vasculature ◽  
Adult Rats

Newborn rats were exposed to hypoxia (10% O2 + N2) from 24 h to day 6 of neonatal life and then returned to room air until 45 days of age (experimental). The rats were anaesthetized, heparinized, and exsanguinated. The chest was opened and the lungs were perfused with diluted autologous blood at a constant flow rate (Q). The pulmonary arterial pressure (Pa) and venous pressure (Pv) were monitored. The properties of the pulmonary vasculature were assessed by measuring baseline vascular resistance, PVR = (Pa−Pv)/Q, segmental pressure gradients (double occlusion technique), pressure–flow relationship, hypoxic pressor response (HPR, 3% O2), and the response to 0.5 μg bolus of angiotensin II (AII). These were compared with similar measurements on age-matched control animals never exposed to hypoxia. The perfusate hematocrit and gases were not significantly different between the two groups. The PVR normalized to body weight was 30% higher in the experimental groups (p < 0.005). The double occlusion results (obtained at a flow rate of 13 mL/min) revealed that this increase in resistance was primarily due to the increase in the postcapillary resistance. HPR was primarily in the upstream segment in both groups but was larger in the experimental group. In contrast, the response to AII occurred in both the upstream as well as in the downstream vascular segments and did not differ between the two groups. We conclude that adult rats exposed to hypoxia in the neonatal period have elevated pulmonary vascular resistance and increased vascular reactivity to hypoxia.Key words: resistance, angiotensin, lung development, pulmonary hypertension.

Pulmonary vasoconstriction during histotoxic hypoxia

1965 ◽  
Vol 20 (3) ◽  
pp. 488-490 ◽  
Author(s):  
Thomas C. Lloyd
Keyword(s):  
Pulmonary Vascular Resistance ◽  
Oxygen Concentration ◽  
Technical Assistance ◽  
Pressor Response ◽  
Vascular Effect ◽  
Pulmonary Vasoconstriction ◽  
Vascular Bed ◽  
Arteries And Veins ◽  
Histotoxic Hypoxia ◽  
Lung Lobes

Increases in pulmonary vascular resistance could be produced in excised perfused ventilated dog lung lobes by lowering the alveolar Po2. When dinitrophenol was added to the perfusate a similar change in the vascular bed occurred that could be reversed by ventilating with supernormal oxygen concentrations. The similarity of the responses to dinitrophenol and lowered alveolar Po2 was demonstrated using normally and retrogradely perfused lobes. The hypoxic pressor response was shown to be independent of the Po2 of blood contained in the arteries and veins. Note: (With the Technical Assistance of Emily McCartney) dinitrophenol; cyanide; vascular effect of intravascular oxygen concentration Submitted on August 13, 1964

Effect of protein kinase C inhibition on hypoxic pulmonary vasoconstriction

2001 ◽  
Vol 280 (5) ◽  
pp. L888-L895 ◽  
Author(s):  
Scott A. Barman
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
Pulmonary Vascular Resistance ◽  
Vascular Resistance ◽  
Pressor Response ◽  
Hypoxic Pulmonary Vasoconstriction ◽  
Pulmonary Vasculature ◽  
Kinase C ◽  
Vasoconstrictor Response ◽  
Voltage Dependent

The current study was done to test the hypothesis that protein kinase C (PKC) inhibitors prevent the increase in pulmonary vascular resistance and compliance that occurs in isolated, blood-perfused dog lungs during hypoxia. Pulmonary vascular resistances and compliances were measured with vascular occlusion techniques. Hypoxia significantly increased pulmonary arterial resistance, pulmonary venous resistance, and pulmonary capillary pressure and decreased total vascular compliance by decreasing both microvascular and large-vessel compliances. The nonspecific PKC inhibitor staurosporine (10−7 M), the specific PKC blocker calphostin C (10−7 M), and the specific PKC isozyme blocker Gö-6976 (10−7 M) inhibited the effect of hypoxia on pulmonary vascular resistance and compliance. In addition, the PKC activator thymeleatoxin (THX; 10−7 M) increased pulmonary vascular resistance and compliance in a manner similar to that in hypoxia, and the L-type voltage-dependent Ca2+channel blocker nifedipine (10−6 M) inhibited the response to both THX and hypoxia. These results suggest that PKC inhibition blocks the hypoxic pressor response and that the pharmacological activation of PKC by THX mimics the hypoxic pulmonary vasoconstrictor response. In addition, L-type voltage-dependent Ca2+channel blockade may prevent the onset of the hypoxia- and PKC-induced vasoconstrictor response in the canine pulmonary vasculature.

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