Basal Pulmonary Vascular Resistance Research Articles

Effects of vagotomy on cardiovascular and heart rate variability alterations following chronic normobaric hypoxia in adult rabbits

Backgroundchronic hypoxia increases basal ventilation and pulmonary vascular resistance, with variable changes in arterial blood pressure and heart rate, but it’s impact on heart rate variability and autonomic regulation have been less well examined. We studied changes in arterial blood pressure, heart rate and heart rate variability (HRV) in rabbits subjected to chronic normobaric hypoxia (CNH; PB ~ 719 mmHg; FIO2 ~ 9.2%) for 14 days and assess the effect of autonomic control by acute bilateral vagal denervation.Resultsexposure to CNH stalled animal weight gain and increased the hematocrit, without affecting heart rate or arterial blood pressure. Nevertheless, Poincaré plots of the electrocardiographic R–R intervals showed a reduced distribution parallel to the line of identity, which interpreted as reduced long-term HRV. In the frequency domain, CNH reduced the very-low- (< 0.2 Hz) and high-frequency components (> 0.8 Hz) of the R–R spectrograms and produced a prominent component in the low-frequency component (0.2–0.5 Hz) of the power spectrum. In control and CNH exposed rabbits, bilateral vagotomy had no apparent effect on the short- and long-term HRV in the Poincaré plots. However, bilateral vagotomy differentially affected higher-frequency components (> 0.8 Hz); reducing it in control animals without modifying it in CNH-exposed rabbits.ConclusionsThese results suggest that CNH exposure shifts the autonomic balance of heart rate towards a sympathetic predominance without modifying resting heart rate or arterial blood pressure.

Pulmonary vascular resistance and proper timing of percutaneous balloon mitral valvotomy

It is frequent to see pulmonary hypertension (PH) in patients with mitral stenosis (MS) secondary to increased pulmonary vascular resistance (PVR), data about the effect of PVR on the results of percutaneous balloon mitral valvotomy (PBMV) are insufficient. To detect the role of PVR in predicting residual PH immediately after PBMV. This prospective study comprised 49 consecutive patients with moderate to severe MS who were investigated pre and within 48h post a successful PBMV for the first time. Echocardiography was used to assess the mitral valve area (MVA), mean transmitral pressure gradient (MPG), mitral valve resistance (MVR), right ventricular systolic pressure (RVSP) and PVR. Patients were classified into two groups according to the pre PVR (≥ 1.6 WU as group I and < 1.6 as group II). At baseline compared to group II (32 patients), Group I (17 patients) had higher MPG (13.6 ± 5.2 vs. 11.7 ± 3.7mmHg, P < 0.05), RVSP (45.6 vs. 37.9mmHg, P < 0.001) and PVR (2.2 ± 0.1 vs. 1.2 ± 0.1WU, P < 0.001) with no significant difference regarding age, gender, MVS, MVA and MVR. Patients of group I had comparatively lower improvement immediate post procedural of RVSP and PVR with no significant difference in immediate post procedural improvement in NYHA classification, MVA, MPG and MVR. Basal PVR > 1.8WU was proved to be a highly specific (91%), a good predictor (AUC 0.78) of persistent elevation of RVSP > 50mmHg post PMV. Pathological rise of PVR that associates MS had provided a strong and an independent predictor of persistent pulmonary hypertension post PBMV and by this aspect it could be used as a valuable tool as MVA and MPG to send patients earlier for PBMV even with less severe MS. PVR > 1.81 WU could be used as a noninvasive parameter for predicting regression of PH immediately after PBMV.

Differential Effects of Chronic Hypoxia on Basal and Agonist‐Induced NO‐Dependent Pulmonary Vasodilation in Neonatal Rats

Endothelial dysfunction contributes to chronic hypoxia (CH)‐induced pulmonary hypertension (PH) in neonates. However, whether basal and stimulated endothelium‐derived nitric oxide (EDNO)‐dependent pulmonary vasodilation are similarly impaired in neonatal PH is unclear. We hypothesized that CH attenuates EDNO‐dependent pulmonary vasodilation both basally and in response to receptor activation in a neonatal rat model of PH. To test this hypothesis, we assessed effects of the NO synthase inhibitor Nω‐nitro‐L‐arginine (L‐NNA; 300 μM) on baseline pulmonary vascular resistance (PVR) in salt‐perfused lungs (in situ) from 2‐wk‐old control and CH (2 wk at 0.5 atm) rats. The contribution of active tone to PVR was assessed by examining responses to exogenous NO (spermine NONOate, 100 μM). Lungs from CH rats showed greater baseline PVR compared to controls (p&lt;0.05) in the absence of L‐NNA. This response to CH reflected active tone, whereas no basal tone was observed in control lungs. Consistent with our hypothesis, L‐NNA modestly increased PVR in the control group (p&lt;0.05 vs. vehicle), but had no effect in lungs from CH neonates. We next examined EDNO‐dependent vasodilatory responses to arginine vasopressin (AVP, 25 nM) in U‐46619‐constricted lungs. Surprisingly, lungs from CH rats showed augmented responses to AVP compared to controls (p&lt;0.05). L‐NNA abolished AVP responses in both groups (p&lt;0.05 vs vehicle). We conclude that CH 1) increases basal PVR in part through vasoconstriction, and 2) impairs EDNO‐dependent pulmonary vasodilation under basal conditions, but paradoxically augments AVP‐induced EDNO‐dependent vasodilation in a neonatal rat model of PH.

Pulmonary vascular effects of serotonin and selective serotonin reuptake inhibitors in the late-gestation ovine fetus.

Maternal use of selective serotonin (5-HT) reuptake inhibitors (SSRIs) is associated with an increased risk for persistent pulmonary hypertension of the newborn (PPHN), but little is known about 5-HT signaling in the developing lung. We hypothesize that 5-HT plays a key role in maintaining high pulmonary vascular resistance (PVR) in the fetus and that fetal exposure to SSRIs increases 5-HT activity and causes pulmonary hypertension. We studied the hemodynamic effects of 5-HT, 5-HT receptor antagonists, and SSRIs in chronically prepared fetal sheep. Brief infusions of 5-HT (3-20 μg) increased PVR in a dose-related fashion. Ketanserin, a 5-HT 2A receptor antagonist, caused pulmonary vasodilation and inhibited 5-HT-induced pulmonary vasoconstriction. In contrast, intrapulmonary infusions of GR127945 and SB206553, 5-HT 1B and 5-HT 2B receptor antagonists, respectively, had no effect on basal PVR or 5-HT-induced vasoconstriction. Pretreatment with fasudil, a Rho kinase inhibitor, blunted the effects of 5-HT infusion. Brief infusions of the SSRIs, sertraline and fluoxetine, caused potent and sustained elevations of PVR, which was sustained for over 60 min after the infusion. SSRI-induced pulmonary vasoconstriction was reversed by infusion of ketanserin and did not affect the acute vasodilator effects of acetylcholine. We conclude that 5-HT causes pulmonary vasoconstriction, contributes to maintenance of high PVR in the normal fetus through stimulation of 5-HT 2A receptors and Rho kinase activation, and mediates the hypertensive effects of SSRIs. We speculate that prolonged exposure to SSRIs can induce PPHN through direct effects on the fetal pulmonary circulation.

Decline in arterial partial pressure of oxygen after exercise: a surrogate marker of pulmonary vascular obstructive disease in patients with atrial septal defect and severe pulmonary hypertension

To examine the utility of decline in arterial partial pressure of oxygen after exercise as a marker of pulmonary vascular obstructive disease in patients with atrial septal defect and pulmonary hypertension. Treadmill exercise was performed in 18 patients with atrial septal defect and pulmonary hypertension. Arterial blood gas samples were obtained before and after peak exercise. A decline in the arterial pressure of oxygen of more than 10 millimetres of mercury after exercise was considered significant based on preliminary tests conducted on the controls. Cardiac catheterisation was performed in all patients and haemodynamic data sets were obtained on room air, oxygen, and a mixture of oxygen and nitric oxide (30-40 parts per million). There were 10 patients who had more than a 10 millimetres of mercury drop in arterial partial pressure of oxygen after exercise and who had a basal pulmonary vascular resistance index of more than 7 Wood units per square metre. Out of eight patients who had less than a 10 millimetres of mercury drop in arterial partial pressure of oxygen after exercise, seven had a basal pulmonary vascular resistance index of less than 7 Wood units per square metre, p equals 0.0001. A decline in arterial partial pressure of oxygen of more than 10 millimetres of mercury predicted a basal pulmonary vascular resistance index of more than 7 Wood units per square metre with a specificity of 100% and a sensitivity of 90%. A decline in arterial partial pressure of oxygen following exercise appears to predict a high pulmonary vascular resistance index in patients with atrial septal defect and pulmonary hypertension. This test is a useful non-invasive marker of pulmonary vascular obstructive disease in this subset.

Transcatheter Closure of Adult Patent Ductus Arteriosus with Severe Pulmonary Hypertension

The purpose of this study was to investigate the application of trial balloon occlusion for permanent closure of patent ductus arteriosus (PDA) with severe pulmonary hypertension (PH) in adults, and to assess its immediate and short-term results. From September 1999 to September 2005, a total of ten adults (two males, ages ranging from 20 to 54 years) with PDA who met the criterion for severe PH (basal pulmonary vascular resistance >8 Wood units) received trial balloon occlusion via an embolectomy balloon catheter. Post-occlusion hemodynamics, along with an overall clinical and hemodynamic assessment, was used to consider the indication of closure of PDA. Nine of the patients underwent successful transcatheter closure of PDA and subsequently used Amplatzer occluder devices. Chest X-ray, cardiography and echocardiography were used for follow-up evaluation of the treatment within 6 months after successful closure of PDA. No patient had a detectable residual shunt by color flow mapping or any other complications (device migration, hemolysis, endocarditis, etc.) at follow-up. In conclusion, trial balloon occlusion helps to determine anticipated hemodynamics after closure of PDA, so it is conducive to indicating permanent closure of adult PDA with reversible but severe PH. Furthermore, satisfactory immediate and short-term outcomes have proven this method to be safe and valid. (Hypertens Res 2008; 31: 1997-2002).

Role of Sildenafil in Acute Posttransplant Right Ventricular Dysfunction: Successful Experience in 13 Consecutive Patients

Background Superimposed acute right ventricular dysfunction in the setting of preexisting pulmonary hypertension is a nearly fatal complication after heart transplantation. The optimal treatment modality remains a matter of debate. Recently, sildenafil citrate, a nonselective pulmonary vasodilator, has gained popularity in the treatment of pulmonary hypertension in transplant candidates. Methods Herein we have presented a series of 13 patients in whom sildenafil was used to treat right ventricular dysfunction and pulmonary hypertension as detected by transesophageal echocardiography and Swan-Ganz right heart catheterization after heart transplant. Their characteristics were mean age 49 ± 11.4 years; 38.4% with previous cardiac procedures, 30.8% status I, basal pulmonary vascular resistance index 10.4 ± 4.6 WoodU, mean transpulmonary gradient 18.7 ± 5.4 mmHg. In addition to conventional inodilator support, we administered 1 to 3 mg per kilogram of sildenafil. Complete hemodynamic measurements were obtained before and after the institution of the therapy and at 1-month follow-up. Results Within the first 72 hours, acute right ventricular dysfunction resolved in all cases without untoward side effects or significant systemic impact. Sildenafil significantly decreased the transpulmonary gradient and pulmonary vascular resistance index relative to baseline values; 5.6 ± 1.82 versus 10.4 ± 4.6 WU, ( P < .05), 13.5 ± 3.4 mm Hg versus 18.7 ± 5.4 mm Hg ( P < .05), respectively. Improved indices of right ventricular function were observed on echocardiographic monitoring. After 1 month, sildenafil treatment was discontinued. Conclusion Management of acute right ventricular dysfunction in heart transplant recipients with pulmonary hypertension using sildenafil proved safe and effective.

Effects of Phosphodiesterase 5 Inhibitor on Pulmonary Vascular Reactivity in the Fetal Lamb

Nitric oxide released by pulmonary vascular endothelium is a potent vasodilator related to increased cyclic guanosine monophosphate (cGMP) content. Hydrolysis of cGMP is achieved predominately by cGMP-specific phosphodiesterases. Sildenafil is a selective phosphodiesterase-5 (PDE5) inhibitor. The purpose of the study is to assess the effects of sildenafil on pulmonary vascular circulation during the perinatal period. Thirty-two pregnant ewes were operated on at the end of gestation, and fetal lambs were prepared with catheters placed into the aorta, vena cava, pulmonary artery, and left atrium. An ultrasonic flow transducer and an inflatable vascular occluder were placed respectively around the left pulmonary artery and the ductus arteriosus. Fetal lambs were randomly divided into two groups: (1) sildenafil group, infused continuously with sildenafil for 24 hours at a rate of 1 mg/h; or (2) control group, infused with saline for 24 hours. After 24 hours of infusion, we compared basal pulmonary vascular resistance and the pulmonary vascular responses to increase in fetal PaO2 and to acute ductus arteriosus compression causing "shear stress." Sildenafil infusion did not change mean aortic and pulmonary artery pressures, increased mean left pulmonary blood flow by 160%, and decreased pulmonary vascular resistance by 60% (p < 0.05). However, both mean flow (Q) and pulmonary vascular resistance returned to baseline values after 2 hours of sildenafil infusion. Despite similar baseline values, pulmonary vascular resistance during maternal O2 inhalation was lower in the sildenafil group than in the control group (0.21 +/- 0.03 versus 0.33 +/- 0.03 mm Hg.mL(-1).min(-1), respectively; p < 0.01). Furthermore, drop in pulmonary vascular resistance during acute ductus arteriosus compression was greater in the sildenafil group (from 0.56 +/- 0.06 to 0.26 +/- 0.04 mm Hg.mL(-1).min(-1)) than in the control group (from 0.55 +/- 0.05 to 0.39 +/- 0.03 mm Hg.mL(-1).min(-1); p < 0.01). Although sildenafil induces a transient pulmonary vasodilation, it mediates a sustained change in vascular reactivity, especially to birth-related stimuli in the ovine fetal lung. These data suggest that PDE5 is involved in the regulation of pulmonary vascular reactivity during the perinatal period and may potentiate birth-related pulmonary vasodilator stimuli.

Inhibition of 20-HETE abolishes the myogenic response during NOS antagonism in the ovine fetal pulmonary circulation

Mechanisms that maintain high pulmonary vascular resistance (PVR) and oppose vasodilation in the fetal lung are poorly understood. In fetal lambs, increased pulmonary artery pressure evokes a potent vasoconstriction, suggesting that a myogenic response contributes to high PVR in the fetus. In adult systemic circulations, the arachidonic acid metabolite 20-hydroxyeicosatetraenoic acid (20-HETE) has been shown to modulate the myogenic response, but its role in the fetal lung is unknown. We hypothesized that acute increases in pulmonary artery pressure release 20-HETE, which causes vasoconstriction, or a myogenic response, in the fetal lung. To address this hypothesis, we studied the hemodynamic effects of N-methylsufonyl-12,12-dibromododec-11-enamide (DDMS), a specific inhibitor of 20-HETE production, on the pulmonary vasoconstriction caused by acute compression of the ductus arteriosus (DA) in chronically prepared fetal sheep. An inflatable vascular occluder around the DA was used to increase pulmonary artery pressure under three study conditions: control, after pretreatment with nitro-L-arginine (L-NA; to inhibit shear-stress vasodilation), and after combined treatment with both L-NA and a specific 20-HETE inhibitor, DDMS. We found that DA compression after L-NA treatment increased PVR by 44 +/- 12%. Although intrapulmonary DDMS infusion did not affect basal PVR, DDMS completely abolished the vasoconstrictor response to DA compression in the presence of L-NA (44 +/- 12% vs. 2 +/- 4% change in PVR, L-NA vs. L-NA + DDMS, P < 0.05). We conclude that 20-HETE mediates the myogenic response in the fetal pulmonary circulation and speculate that pharmacological inhibition of 20-HETE might have a therapeutic role in neonatal conditions characterized by pulmonary hypertension.

Heme oxygenase does not contribute to control of basal vascular tone in isolated blood-perfused rat lung

Background Vasoconstriction in pulmonary ischemia–reperfusion injury may involve dysfunction of the physiologic vasodilation of pulmonary arteries. Little is known of the relative importance of heme oxygenase (HO)/carbon monoxide (CO)-dependent vs nitric oxide synthase (NOS)/nitric oxide (NO)-dependent vasodilation of the pulmonary vasculature. We evaluated the significance of HO function on basal pulmonary vascular resistance (PVR) and compared it with the function of NOS. Methods Using an isolated blood-perfusion model, lungs of Lewis rats were assigned to 3 groups ( n = 6/group). After stabilization, either an inhibitor of HO (tin-protoporphyrin-9 [SnPP-9]) or an inhibitor of NOS (NG-nitro- l-arginine methylester [ l-NAME]) was added to the perfusate (50 μmol/liter and 1 mmol/liter as the final concentration, respectively). Lungs receiving saline served as controls. Gas exchange, hemodynamic and respiratory functions and the levels of cyclic 3′,5′-guanosine monophosphate (cGMP) in the perfusate were measured. Results Inhibition of NOS by l-NAME resulted in a significant ( p < 0.01) increase in PVR (ΔPVR: 0.110 ± 0.012 cm H 2O/ml · min) within 5 minutes. In contrast, PVR was minimally affected by SnPP-9 (ΔPVR: 0.005 ± 0.005 cm H 2O/ml · min), which was comparable to control lungs (ΔPVR: 0.012 ± 0.005 cm H 2O/ml · min). The level of cGMP in the perfusate 5 minutes after drug application was markedly, but not significantly, lower in the l-NAME group (1.67 ± 0.74 nmol/liter) when compared with controls (2.69 ± 0.89 nmol/liter) and SnPP-9-treated lungs (2.65 ± 0.66 nmol/liter). Conclusions NOS but not HO contributes to the control of basal vascular tone in the rat lung.

Basal pulmonary vascular resistance and its response to exogenous nitric oxide late after fontan operation

Basal pulmonary vascular resistance and its response to exogenous nitric oxide late after fontan operation

Reversal of Pulmonary Hypertension Associated with Plexiform Lesions in Congenital Heart Disease: A Case Report

We describe a 2-year-old child with severe pulmonary hypertension due to a patent ductus arteriosus (PDA) with plexiform lesions on lung biopsy. Despite high basal pulmonary vascular resistance with minimal responsiveness to inhaled nitric oxide and other vasodilators, and advanced plexogenic arteriopathy on lung biopsy, her pulmonary hypertension completely resolved after PDA ligation and during 8 years of follow-up.

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

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

Role of Inducible Nitric Oxide Synthase in the Pulmonary Vascular Response to Birth-Related Stimuli in the Ovine Fetus

To determine whether type II nitric oxide synthase (NOS II) contributes to the NO-mediated fall in pulmonary vascular resistance (PVR) at birth, we studied the effects of selective NOS II antagonists N-(3-aminomethyl) benzylacetamidine dihydrochloride (1400W) and aminoguanidine (AG) and a nonselective NOS antagonist, nitro-L-arginine (L-NA), during mechanical ventilation with low FIO(2) (<10%), high FIO(2) (100%), and inhaled NO (20 ppm) in 23 near-term fetal lambs. Intrapulmonary infusions of AG, 1400W, and L-NA increased basal PVR before delivery (P<0.05). In control animals, ventilation with low and high FIO(2) decreased PVR by 62% and 85%, respectively. Treatment with AG and 1400W attenuated the fall in PVR by 50% during ventilation with low and high FIO(2) (control versus treatment, P<0.05 for each intervention). L-NA treatment attenuated the fall in PVR during ventilation with low and high FIO(2) to a similar degree as the NOS II antagonists. To test the selectivity of the NOS II antagonists, we studied the effects of acetylcholine and inhaled NO in each study group. Acetylcholine-induced pulmonary vasodilation remained intact after treatment with selective NOS II antagonists but not after treatment with nonselective NOS blockade with L-NA. In contrast, the response to inhaled NO was similar between treatment groups. We conclude that selective NOS II inhibition is as effective as nonselective NOS blockade in attenuating pulmonary vasodilation at birth and speculate that NOS II activity contributes to NO-mediated pulmonary vasodilation at birth. We additionally speculate that stimulation of the airway epithelium by rhythmic distension and increased FIO(2) may activate NOS II release at birth.

Role of neuronal nitric oxide synthase in regulation of vascular and ductus arteriosus tone in the ovine fetus.

Nitric oxide (NO) is produced by NO synthase (NOS) and contributes to the regulation of vascular tone in the perinatal lung. Although the neuronal or type I NOS (NOS I) isoform has been identified in the fetal lung, it is not known whether NO produced by the NOS I isoform plays a role in fetal pulmonary vasoregulation. To study the potential contribution of NOS I in the regulation of basal fetal pulmonary vascular resistance (PVR), we studied the hemodynamic effects of a selective NOS I antagonist, 7-nitroindazole (7-NINA), and a nonselective NOS antagonist, N-nitro-L-arginine (L-NNA), in chronically prepared fetal lambs (mean age 128 +/- 3 days, term 147 days). Brief intrapulmonary infusions of 7-NINA (1 mg) increased basal PVR by 37% (P < 0.05). The maximum increase in PVR occurred within 20 min after infusion, and PVR remained elevated for up to 60 min. Treatment with 7-NINA also increased the pressure gradient between the pulmonary artery and aorta, suggesting constriction of the ductus arteriosus (DA). To test whether 7-NINA treatment selectively inhibits the NOS I isoform, we studied the effects of 7-NINA and L-NNA on acetylcholine-induced pulmonary vasodilation. The vasodilator response to acetylcholine remained intact after treatment with 7-NINA but was completely inhibited after L-NNA, suggesting minimal effects on endothelial or type III NOS after 7-NINA infusion. Western blot analysis detected NOS I protein in the fetal lung and great vessels including the DA. NOS I protein was detected in intact and endothelium-denuded vessels, suggesting that NOS I is present in the medial or adventitial layer. We conclude that 7-NINA, a selective NOS I antagonist, increases basal PVR, systemic arterial pressure, and DA tone in the late-gestation fetus and that NOS I protein is present in the fetal lung and great vessels. We speculate that NOS I may contribute to NO production in the regulation of basal vascular tone in the pulmonary and systemic circulations and the DA.

K+-channel blockade inhibits shear stress-induced pulmonary vasodilation in the ovine fetus.

To determine whether K+-channel activation mediates shear stress-induced pulmonary vasodilation in the fetus, we studied the hemodynamic effects of K+-channel blockers on basal pulmonary vascular resistance and on the pulmonary vascular response to partial compression of the ductus arteriosus (DA) in chronically prepared late-gestation fetal lambs (128-132 days gestation). Study drugs included tetraethylammonium (TEA; Ca2+-dependent K+-channel blocker), glibenclamide (Glib; ATP-dependent K+-channel blocker), charybdotoxin (CTX; preferential high-conductance Ca2+-dependent K+-channel blocker), apamin (Apa; low-conductance Ca2+-dependent K+-channel blocker), and 4-aminopyridine (4-AP; voltage-dependent K+-channel blocker). Catheters were inserted in the left pulmonary artery (LPA) for selective drug infusion and in the main pulmonary artery, aorta, and left atrium to measure pressure. An inflatable vascular occluder was placed around the DA. LPA flow was measured with an ultrasonic flow transducer. Animals were treated with saline, high- or low-dose TEA, Glib, Apa, CTX, CTX plus Apa, or 4-AP injected into the LPA. DA compression caused a time-related decrease in pulmonary vascular resistance in the control, Glib, Apa, CTX, CTX plus Apa, and low-dose TEA groups but not in the high-dose TEA and 4-AP groups. These data suggest that pharmacological blockade of Ca2+- and voltage-dependent K+-channel activity but not of low-conductance Ca2+- and ATP-dependent K+-channel activity attenuates shear stress-induced fetal pulmonary vasodilation.

Endothelin A receptor blockade decreases pulmonary vascular resistance in premature lambs with hyaline membrane disease.

Endothelin (ET)-1 is a potent vasoconstrictor peptide that modulates basal pulmonary vascular resistance (PVR) in the normal ovine fetus and contributes to high PVR after chronic intrauterine pulmonary hypertension. Although high PVR is present in premature lambs with severe hyaline membrane disease (HMD), whether ET-1 plays a role in the pathophysiology of experimental HMD is unknown. To test the hypothesis that ET-1 activity contributes to high PVR in the premature lamb with HMD, we studied the hemodynamic effects of a selective ET(A) receptor antagonist, BQ 123, in 10 animals (gestational age 125 d; 147 d=term). After baseline measurements, animals were intubated, treated with surfactant (Infasurf), and mechanically ventilated with a fraction of inspired oxygen of 1.00 for 8 h. Animals were treated with continuous infusions of either BQ 123 (1 mg/h; treatment group, n=5) or 1% DMSO (control; n=5). Plasma ET-1 levels progressively increased during prolonged ventilation with hyperoxia (0.8+/-0.1 pg/mL, baseline to 6.8+/-2.5 pg/mL, 8 h, p < 0.05). In comparison with control lambs, BQ 123 treatment caused a sustained reduction in pulmonary vascular resistance (0.55+/-0.04 mm Hg mL-(-1) min(-1), control versus 0.18+/-0.04 mm Hg mL(-1) min(-1), BQ 123, p < 0.05), increased left pulmonary artery blood flow (70+/-12 mL/min, control versus 194+/-28 mL/min, BQ 123, p < 0.05), and increased arterial PaO2 (53+/-14 mm Hg, control versus 174+/-71 mm Hg, BQ 123, p < 0.05) 8 h after the onset of ventilation. We conclude that circulating levels of ET-1 increase after delivery of premature lambs with severe HMD, and that selective ET(A) receptor blockade causes sustained improvement in hemodynamics in severe experimental HMD. These studies suggest that ET-1 contributes to the hemodynamic abnormalities in this model of pulmonary hypertension and severe HMD.

Role of inducible nitric oxide synthase in regulation of pulmonary vascular tone in the late gestation ovine fetus.

Nitric oxide (NO) produced by NO synthase (NOS) modulates fetal pulmonary vascular tone and contributes to the fall in pulmonary vascular resistance (PVR) at birth. Although the inducible (type II) NOS isoform is present in human and rat fetal lungs, it is uncertain whether type II NOS activity contributes to vascular NO production in the fetal lung. To determine whether type II NOS is present in the ovine fetal lung and to study the potential contribution of type II NOS on the regulation of basal PVR in the fetus, we measured the hemodynamic effects of three selective type II NOS antagonists: aminoguanidine (AG), 2-amino-5,6-dihydro-6-methyl-4H-1,3 thiazine (AMT), and S-ethylisothiourea (EIT). Studies were performed after at least 72 h of recovery from surgery in 19 chronically prepared fetal lambs (133+/-3 d; 147 d, term). Brief intrapulmonary infusions of AG (140 mg), AMT (0.12 mg), and EIT (0.12 mg) increased basal PVR by 82, 69, and 77%, respectively (P < 0.05). The maximum increase in PVR occurred within 20 min, but often persisted up to 80 min. These agents also increased mean aortic pressure but did not alter the pressure gradient between the pulmonary artery and aorta, suggesting little effect on tone of the ductus arteriosus. Acetylcholine-induced pulmonary vasodilation remained intact after treatment with selective type II NOS antagonists, but not after treatment with the nonselective NOS blocker, nitro-L-arginine. Using Northern blot analysis with poly(A)+ RNA, we demonstrated the presence of two mRNA transcripts for type II NOS (4.1 and 2.6 kb) in the fetal lung. We conclude that the type II NOS isoform is present in the ovine fetal lung, and that selective type II NOS antagonists increase PVR and systemic arterial pressure in the late-gestation fetus. We speculate that type II NOS may play a physiological role in the modulation of vascular tone in the developing fetal lung.

Endothelin A Receptor Blockade Decreases Pulmonary Vascular Resistance in Severe Experimental Hyaline Membrane Disease † 112

Endothelin-1 (ET-1) is a potent vasoconstrictor peptide which modulates basal pulmonary vascular resistance (PVR) in the normal ovine fetus and contributes to high PVR after chronic intrauterine pulmonary hypertension. Pulmonary hypertension complicates the course of the premature lamb with severe hyaline membrane disease (HMD); however, whether ET-1 plays a role in the pathophysiology of HMD is unknown. To test the hypothesis that ET-1 activity contributes to high PVR in the premature fetal lung with severe HMD, we studied the hemodynamic effects of a selective ET A receptor antagonist, BQ 123, in 7 fetal lambs (gestational age 125 days; 147 days = term). We placed catheters in the main pulmonary artery (PAP), aorta (AoP), and left atrium(LAP) to measure pressure and an ultrasonic flow transducer on the left pulmonary artery (LPA) to measure blood flow. After baseline measurements, animals were intubated, treated with surfactant (Infasurf), and mechanically ventilated (FiO2, 1.00). Animals were treated with either BQ 123 (1 mg/hour, n= 4) or saline (control; n = 3) in the MPA. One animal in the control group died at 4 hours. In comparison with controls, BQ 123 treated animals had lower PVR and improved LPA flow at 8 hours. (* = p<0.05 between groups)Table We conclude that selective ET A receptor blockade lowers PVR in experimental HMD. We speculate that ET-1 contributes to pulmonary hypertension in an ovine model of severe HMD.

Hemodynamic and gas exchange responses to inhalation of nitric oxide in patients with the acute respiratory distress syndrome and in hypoxemic patients with chronic obstructive pulmonary disease

Inhalation of nitric oxide (NO) can improve oxygenation and decrease mean pulmonary artery pressure (MPAP) in patients with the acute respiratory distress syndrome (ARDS). It is not known whether inhaled NO exerts a similar effect in hypoxemic patients with chronic obstructive pulmonary disease (COPD). Prospective clinical study. General intensive care unit in Sabadell, Spain. Nine mechanically ventilated COPD patients (mean age 72 +/- 2 years; forced expiratory volume in 1 s 0.91 +/- 0.11 l) and nine ARDS patients (mean age 57 +/- 6 years; mean lung injury score 2.8 +/- 0.1). We measured hemodynamic and gas exchange parameters before NO inhalation (basal 1), during inhalation of 10 ppm NO (NO-10), and 20 min after NO was discontinued (in basal 2) in the ARDS group. In the COPD group, these parameters were measured before NO inhalation (basal 1), during different doses of inhaled NO (10, 20, and 30 ppm), and 20 min after NO was discontinued (basal 2). A positive response to NO was defined as a 20% increment in basal arterial partial pressure of oxygen (PaO2). MPAP and pulmonary vascular resistance (PVR) decreased significantly, while other hemodynamic parameters remained unchanged after NO-10 in both groups. Basal oxygenation was higher in the COPD group (PaO2/FIO2 (fractional inspired oxygen) 190 +/- 18 mmHg) than in the ARDS group (PaO2/FIO2 98 +/- 12 mmHg), (p < 0.01). After NO-10, PaO2/FIO2 increased (to 141 +/- 17 mmHg, p < 0.01) and Qva/Qt decreased (39 +/- 3 to 34 +/- 3%, p < 0.01) in the ARDS group. There were no changes in PaO2/FIO2 and Qva/Qt when the NO concentration was increased to 30 ppm in the COPD group. In both groups, a correlation was found between basal MPAP and basal PVR, and between the NO-induced decrease in MPAP and in PVR. The NO-induced increase in PaO2/FIO2 was not correlated with basal PaO2/FIO2. In the ARDS group, six of the nine patients (66%) responded to NO and in the COPD group, two of nine (22%) (p = 0.05). NO inhalation had similar effects on hemodynamics but not on gas exchange in ARDS and COPD patients, and this response probably depends on the underlying disease.