Baseline Pulmonary Vascular Resistance Research Articles

Pharmacological testing of the reversibility of increased pulmonary vascular resistance before heart transplantation with prostaglandin I2 (prostacyclin)

An increased pulmonary vascular resistance (PVR) or an increased transpulmonary gradient (TPG) is a risk factor for increased 3-day and 3-month mortality after heart transplantation (HTx). The reversibility of increased PVR or TPG under pharmacologic testing is supposed to indicate a decreased probability of right ventricular failure/death after transplantation. We tested the response of an increased PVR (> 2.5 Wood units, WU) and/or of an increased TPG (> 15 mm Hg) in 29 right heart catheterizations (thermodilution catheter) of 23 patients (54 +/- 8 years, mean NYHA-class 3.1 +/- 0.6, ischemic n = 8, dilated cardiomyopathy n = 15). Increasing doses of prostaglandin I2 (PGI2, mean maximum dose 13.5 +/- 6.4 ng/kg/min) were applied stepwise over at least 10 min at the maximum dose level. We analyzed any dependence of the reversibility of PVR and TPG under prostaglandin I2 on hemodynamic values, echocardiographic parameters, demographic data, and laboratory findings. A decrease of PVR to a range usually accepted as no contraindication for HTx (< or = 4 WU) was found in each patient without symptomatic systemic hypotension during application of PGI2 (baseline value: 4.7 +/- 1.3 WU, during PGI2: 2.3 +/- 0.6 WU). An unresponsive, fixed increased PVR or TPG was not observed using PGI2. In 62% of investigations, both PVR and TPG decreased below 2.5 WU and 15 mmHg, respectively. The extent of reversibility of PVR and TPG was individually different and did not depend on the mean pulmonary artery pressure, mean capillary wedge pressure, cardiac output, mean systemic artery pressure or echocardiographic parameters (EDD, FS, ES-distance), sodium, urea or bilirubin levels, medication, age of the patients or the duration of the disease. The baseline PVR correlated inversely with its percentile value during PGI2 (r = -0.76, p < 0.05). In advanced heart failure, PGI2 decreases PVR in ranges of lower risk concerning orthotopic HTx, without causing an intolerable systemic hypotension. The individual extent of reversibility of PVR and TPG under PGI2 is not influenced by basic hemodynamic parameters or the patient's demographic profile.

Continuous Inhalation of Nitric Oxide From Birth Preserves the Pulmonary Vasoconstrictor Response to Hypoxia in Chronically Ventilated Preterm Lambs• 1614

Chronic lung injury from prolonged mechanical ventilation of preterm lambs inhibits the normal postnatal decrease in pulmonary vascular resistance (PVR) and blunts the vasoconstrictor response to hypoxia (Bland et al, Pediatr Res 39:327A, 1996). These abnormalities of lung vascular tone and reactivity may contribute to impaired respiratory gas exchange that often exists in infants with chronic lung disease (CLD). We previously reported that nitric oxide (NO) inhalation for 1 h reduced PVR in preterm lambs with evolving CLD. To see if continuous NO inhalation from birth might inhibit the pulmonary vascular dysfunction that occurs in this model of CLD, we studied 4 preterm lambs (124± 3 d gestation; term = 147 d) that were mechanically ventilated for 3-4 wks at a respirator rate of 20 breaths/min, tidal volume 10-15 ml/kg, with 5-15 ppm NO and sufficient O2 to keep the PaO2 ≅ 50-90 mmHg. All lambs received surfactant at birth and had surgery for ductus arteriosus ligation and catheter placement to allow weekly assessment of PVR from measurements of pulmonary arterial and left atrial pressures and pulmonary blood flow before and during steady-state hypoxia. Results of these studies were compared with those of similar studies done with 10 lambs of the same gestation that were mechanically ventilated the same way but without NO. After 3 wks of mechanical ventilation, baseline PVR was not significantly different in the 4 lambs that received NO compared with the 10 lambs that did not receive NO (PVR = 44.8 ± 5.4 vs 53.9 ± 21.2 mmHg/(L/sec)/kg, respectively). However, in response to hypoxia (baseline FiO2.28±.09, PaO2 73 ± 3; hypoxia FiO2.17 ±.03, PaO2 35 ± 1), PVR consistently increased from 48.3 ± 2.3 to 74.0 ± 20.0 mmHg/(L/sec)/kg at the end of wk 3 in lambs that received NO from birth, whereas PVR did not increase significantly at the end of wk 3 in chronically ventilated lambs that did not receive NO. When inhaled NO was discontinued for 2-4 h after 3 wks of mechanical ventilation in the 4 NO-treated lambs, PVR increased on average from 50.5 ± 11.7 to 64.5± 18.7 mmHg/(L/sec)/kg. Subsequent hypoxia (FiO2.17 ±.03, PaO2 35 ± 4 mmHg), without inhaled NO, further increased PVR to 87.8 ± 27.2 mmHg/(L/sec)/kg. Thus, continuous nitric oxide inhalation from birth may help to preserve the normal pulmonary vasoconstrictor response to hypoxia and thereby facilitate ventilation-perfusion matching and respiratory gas exchange in chronically ventilated preterm lambs.

Intravascular Ultrasonic Characteristics and Vasoreactivity of the Pulmonary Vasculature in Children With Pulmonary Hypertension

We sought to describe the morphologic characteristics of pulmonary arteries by intravascular ultrasound (IVUS) in children with and without pulmonary hypertension to compare these anatomic findings with those of pulmonary wedge angiography, and to determine the relation between these structural findings and functional reactivity to pulmonary vasodilators. Direct evaluation of pulmonary vascular structure in children with pulmonary hypertension with current imaging techniques has been limited and little is known about the relation between structural and functional characteristics of the pulmonary vasculature. In 23 children undergoing cardiac catheterization (15 with pulmonary hypertension and 8 controls) we performed IVUS and pulmonary wedge angiography of the distal pulmonary arteries in the same lobe. IVUS was performed in 44 pulmonary arteries measuring 2.5 to 5.0 mm internal diameter with a 3.5Fr 30-MHz IVUS catheter. We assessed vasoreactivity to inhaled nitric oxide (NO) and oxygen in 13 of 15 children with pulmonary hypertension. Baseline pulmonary vascular resistance (PVR) was greater in the 15 children with pulmonary hypertension than in the 8 controls (9.5 ± 1.9 vs 1.5 ± 0.3 U × m 2, p <0.05). NO lowered PVR in patients with pulmonary hypertension (p <0.05). IVUS studies in patients with pulmonary hypertension showed a thicker middle layer, wall thickness ratio, and diminished pulsatility than did those in controls (p <0.05). The inner layer was not visualized by IVUS in any control patient, but was seen in 9 of 15 patients with pulmonary hypertension. Pulmonary artery wedge angiography correlated with baseline mean pulmonary artery pressure and PVR as well as with IVUS findings of wall thickness ratio and inner layer thickness. The inner layer was not visualized by IVUS in any patient with grade 1 wedge angiograms or in 86% of patients with grade 2 wedge angiograms. All patients with grade 4 and 80% of patients with grade 3 wedge angiograms had a visible inner layer. Vasoreactivity to NO and oxygen did not correlate with structural assessment of the pulmonary vasculature by IVUS. Structural changes in the pulmonary arteries in children with pulmonary hypertension can be directly visualized by IVUS, but are not predictive of NO-induced pulmonary vasodilation. IVUS examination of pulmonary arteries may complement current techniques utilized in the evaluation of children with pulmonary hypertension.

Changes in pulmonary vascular resistance in response to partial liquid ventilation

Background/Purpose: Partial liquid ventilation (PLV) with perfluorocarbons decreases pulmonary vascular resistance (PVR) in injured piglet lungs without supplemental oxygen. These PVR changes may result either from direct mechanical effects or improved arterial oxygenation. In an uninjured hypoxic model of elevated PVR the authors asked the following questions: (1) Does prophylactic or therapeutic PLV ameliorate the PVR response to hypoxia? (2) Do prophylactic and therapeutic PLV have different PVR effects? (3) Does supplemental oxygen modify PVR response to PLV? Methods: Piglet (3 to 4 kg) lungs were isolated in situ without ischemia, hypoxia, or reperfusion injury. Pulmonary artery (PA) and left atrial (LA) cannulae were attached to a bloodprimed extracorporeal membrane oxygenation (ECMO) perfusion circuit with a flow (Q PA) of 80 mL/kg/min. Pressure-limited, volume-cycled ventilation (PIP < 25 mm Hg, T v = 15 mL/kg) was initiated. PLV with perfluorodecalin (15 mL/kg) was administered endotracheally. Continuously monitored blood gas parameters allowed airway and extracorporeal adjustment of Fio 2 to produce a Po 2 appropriate to the experimental phase. PVR was calculated as ( P PA−P LA Q PA ). After a stable 30-minute normoxic baseline, animals were assigned randomly to three groups. In group I, control (n = 7), PVR was measured for 150 minutes in hypoxic lungs ( Fio 2 = 0.07, P PAo 2 = 40 mm Hg, S PAo 2 = 70%). In group II, prophylactic (n = 8), PLV was administered, followed by 90 minutes of hypoxia, and 60 minutes of oxygen recovery ( Fio 2 = 0.21 – 0.30, P PAo 2 > 100 mm Hg, S PAo 2 = 100%). In group III, therapeutic (n = 8), after 30 hypoxic minutes, PLV was administered and maintained for 90 minutes, followed by a 60-minute oxygen recovery phase. Results were expressed as mean ± SEM. Statistical analysis of groups was performed by repeated measures of analysis of variance (ANOVA) and Tukey correction. Results: In group I normoxic gas-ventilated PVR was 174 ± 12 mm Hg/L/kg/min. After 90 hypoxic minutes PVR was 318 ± 37 ( P < .01 v baseline). In group II baseline PVR was 183 ± 14. PVR after 30 normoxic minutes of PLV was 199 ± 14 ( P = ns v baseline). After 90 hypoxic minutes, PVR was 350 ± 31 ( P < .01 v baseline, and PLV alone) followed by a decrease to 192 ± 19 after 60 minutes of oxygen recovery ( P = ns v baseline or PLV alone). In group III baseline PVR was 160 ± 17 and 325 ± 29 after 30 hypoxic minutes. After 90 hypoxic minutes of PLV, PVR was 366 ± 22 ( P = ns v hypoxia control, P < .01 v normoxic baseline). PVR recovered to 189 ± 19 after 60 minutes of oxygen recovery ( P = ns v baseline). Conclusions: Prophylactic/therapeutic PLV had no effect on hypoxia-induced increases in PVR and did not differ from each other. Although PLV alone decreases PVR in the injured lung without supplemental oxygen, elevated PVR associated with hypoxia was ameliorated only by supplemental oxygen in the liquid ventilated lung.

Inhaled nitric oxide (40 ppm) during one-lung ventilation, in the lateral decubitus position, does not decrease pulmonary vascular resistance or improve oxygenation in normal patients

Objectives: To determine the effects of inhaled nitric oxide (NO) on venous admixture (Qs/Qt), mean pulmonary artery pressure (MPAP), and pulmonary vascular resistance (PVR) in patients undergoing one-lung ventilation (1LV) in the lateral decubitus position. Design: Prospective, blinded, crossover. Setting: University hospital. Participants: Six adult patients scheduled for thoracotomy. Interventions: Patients were anesthetized with thoracic epidural lidocaine, intravenous fentanyl, and inhaled isoflurane and were monitored with a systemic and pulmonary artery catheter (PAC). In the lateral decubitus position, the dependent lung was ventilated with 70% oxygen (O 2) and 30% nitrogen (N 2) for the control 1LV condition. For the experimental 1LV condition, the dependent lung was ventilated with the same gas concentration + NO at 40 ppm. Patients were alternated between the control and the experimental NO (40 ppm) conditions every 15 minutes for as long as the case would allow. Measurements and Main Results: During all conditions, oxygenation, Qs/Qt, and pulmonary and systemic hemodynamics were measured in a double-blinded fashion. The mean PVR during 1LV was 128 ± 39 (SD) dyne · s · cm −5. Inhaled NO at 40 ppm did not affect MPAP, PVR, or Qs/Qt. Conclusions: Inhaled NO at 40 ppm, during 1LV in the lateral decubitus position, did not significantly decrease MPAP in patients with normal baseline PVR. Oxygenation and Qs/Qt did not change in this setting because MPAP was not altered. At present, interventions other than administration of inhaled NO should be applied to patients with normal PVR who experience hypoxia during one-lung ventilation.

Partial liquid ventilation (PLV) and lung injury: Is PLV able to modify pulmonary vascular resistance?

Introduction: Partial liquid ventilation (PLV) with perfluorocarbons can be advantageous in treating lung injury. We studied this phenomenon in isolated piglet lungs devoid of systemic detractors by studying the changes in pulmonary vascular resistance (PVR) after lung injury with and without PLV. The following questions were asked. (1) Does PLV alone affect PVR in the uninjured lung? (2) Does PLV prevent the increase in PVR associated with oleic acid-induced lung injury? (3) Does PLV modify the increase in PVR associated with oleic acid lung injury? (4) Are the prophylactic and therapeutic effects of PLV on the increased PVR associated with oleic acid-induced lung injury different? Methods: Neonatal piglet (3 to 4 kg) lungs were prepared without pulmonary ischemia, hypoxia, or reperfusion injury for in situ study. Before pulmonary vascular isolation (eg, aortic and ductus arteriosus ligation) the pulmonary artery (PA) and left atrium (LA) were cannulated and attached to a blood-primed perfusion circuit (flow, 80 mL/kg/min). Pressure-limited volume-cycled ventilation (F IO 2, 0.21; TV, 15 mL/kg; PIP, 25 cm H 2O) was accomplished via occlusive tracheostomy. Blood gas parameters were monitored continuously and maintained within normal range (SpaO 2, 75%; pH, 7.35 to 7.45; pCO 2, 35 to 45 torr). Pulmonary artery pressure (P pa), left atrial pressure (P ia) and pulmonary blood flow (Q pa) were recorded and PVR calculated ( PVR = P pa − P ia Q pa ). After achieving a stable baseline with gas ventilation only, the animal preparations were assigned to one of the following four groups. In group 1 (n = 7) PLV was given alone, using endotracheally administered perfluorodecalin (15 mL/kg). In group 2 (Prophylactic, n = 7) PLV was given prophylactically 60 minutes before lung injury induced by injecting oleic acid (OA) at 0.08 mL/kg into the pulmonary artery. In group 3 (Therapeutic, n = 8) PLV was given 60 minutes after OA-induced lung injury. P PA, P LA, and Q PA were measured and PVR was calculated. In group 4 (n = 7) OA was given alone. Significance of differences between groups was obtained by repeated measures analysis of variance (ANOVA). Results were expressed as mean ± SEM (mm Hg/L/Kg). Results: Group I showed baseline PVR of the normoxic gas ventilated animals was 127 ± 19 mm Hg/L/kg. PVR 180 minutes after PLV administration was 160 ± 15 mm Hg/L/kg ( P = ns v baseline). In group 2 after OA infusion, PVR increased from 109 ± 13 to 281 ± 26 mm Hg/L/kg ( P < .01 v baseline), and 60 minutes later, PVR decreased to 193 ± 22 mm Hg/L/kg ( P < .05 v OA). In group 3 PVR on gas ventilation, before lung injury, was 137 ± 28 mm Hg/L/kg. Sixty minutes after OA infusion, PVR increased to 314 ± 23 mm Hg/L/kg ( P < .01 v baseline). After 60 additional minutes of PLV, PVR decreased to 201 ± 31 mm Hg/L/kg, ( P < .05 v maximum). In group 4 baseline PVR was 96 ± 16 mm Hg/L/kg. After 120 minutes of OA injection, PVR increased to 414 ± 20 mm Hg/L/kg ( P < .01 v baseline). Endpoint analysis of PVR at the conclusion of the recording interval showed no difference between group 2 and group 3 (P = not significant [ns]). Conclusions: (1) PLV does not significantly alter PVR in the uninjured lung when given for 2 hours; (2) prophylactic administration of PLV prevents the sustained increase in PVR known to be induced by OA injury; (3) PLV abates OA-induced elevation in PVR when given therapeutically after injury; and (4) Prophylactic and therapeutic PLV have similar effects on PVR in the OA-injured lung.

The Effects of Dependent Ventilated Lung Nitric Oxide in Patients with Normal Baseline Pulmonary Vascular Resistance

The Effects of Dependent Ventilated Lung Nitric Oxide in Patients with Normal Baseline Pulmonary Vascular Resistance

Sustained pulmonary vasodilation after inhaled nitric oxide for hypoxic pulmonary hypertension in swine

It has been shown that pulmonary vasodilation is sustained after discontinuation of inhaled nitric oxide (INO) during moderate hypoxic pulmonary hypertension (HPH) in swine. The present investigations demonstrated how INO dose, hypoxia duration, and endogenous NO production influence this important phenomenon. Fifteen adolescent Yorkshire swine were randomly assigned to three groups (n = 5 each) and underwent the following phasic experimental protocol: (I) Baseline ventilation (F io 2 = .3); (II) Initiating HPH (F io 2 = .16 to .18, Pa o 2 = 45 to 55 mm Hg); (III) INO at 10 ppm; (IV) Posttreatment observation; (V) INO of 80 ppm; and (VI) Posttreatment observation. Phase II (pretreatment hypoxia) lasted 30 minutes in group A (short hypoxia) and 120 minutes in group B (long hypoxia). N-nitro- l-arginine methyl ester (NAME) was used to inhibit nitric oxide synthase (NOS) throughout the experiment in group C (short hypoxia + NAME). Hemodynamics and blood gases were monitored by systemic and pulmonary artery catheters placed by femoral cutdown. Analysis of variance with post-hoc adjustment was used to compare groups at each phase, and the paired t test was used for comparisons within a group. With respect to baseline mean pulmonary artery pressure (MPAP) and pulmonary vascular resistance (PVR), there were no significant differences among the three groups. MPAP and PVR were significantly higher in group C than in group A during phase II, (MPAP, 76% ± 8% v 33% ± 2%; PVR, 197% ± 19% v 78% ± 10%; P < .05). There were no significant differences in MPAP or PVR during phases III through VI. When MPAP was expressed as percent dilation, 80 ppm caused significantly more dilation than did 10 ppm in all three groups. Groups A and C had significantly higher sustained pulmonary artery dilation after 80 ppm than after 10 ppm (A, 82% ± 31% v 17% ± 11%; C, 68% ± 10% v 42% ± 12%; both P < .05), but group B did not (43% ± 15% v 30% ± 9%; P = .25). High dose results in stronger vasodilation than low dose during and after INO for moderate HPH of short duration. Long hypoxia blunts this high-dose advantage. Endogenous NO inhibition augments HPH but does not decrease pulmonary vasodilation during or after INO.

Acute hypoxic pulmonary vasoconstriction in man is attenuated by type I angiotensin II receptor blockade

We examined the hypothesis that angiotensin II (ANG II) is a modulator of acute hypoxic pulmonary vasoconstriction (HPV) by looking at the effect of losartan, a selective type 1 ANG II receptor antagonist, on acute HPV in man. Ten normal volunteers were studied on two separate days. They either received pre-treatment with losartan 25, 50, 100, 100 mg respectively on four consecutive days or matched placebo. They were then rendered hypoxaemic, by breathing an N2/O2 mixture for 20 min to achieve an SaO2 of 85-90% adjusted for a further 20 min to achieve an SaO2 of 75-80%. Pulsed wave Doppler echocardiography was used to measure mean pulmonary artery pressure (MPAP), cardiac output and hence pulmonary vascular resistance (PVR). Baseline MPAP and PVR (during normoxaemia) were unaffected by losartan pre-treatment compared with placebo. However, losartan significantly reduced MPAP at both levels of hypoxaemia compared with placebo: 14.7 +/- 0.7 vs 19.0 +/- 0.7 mmHg at an SaO2 85-90% (P < 0.01) and 20.0 +/- 0.7 vs 25.7 +/- 0.8 mmHg at an SaO2 75-80% (P < 0.05) respectively. Similarly losartan significantly reduced PVR compared to placebo: 191 +/- 9 vs 246 +/- 10 dyne.s.cm-5 at an SaO2 85-90% (P < 0.005) and 233 +/- 12 vs 293 +/- 18 dyne.s.cm-5 at an SaO2 75-80% (P < 0.05), respectively. Pre-treatment with losartan, however, had no significant effect on systemic vascular resistance although losartan compared to placebo resulted in a significant (P < 0.05) reduction in mean arterial pressure at an SaO2 75-80%: 78 +/- 2 vs 87 +/- 2 mmHg. Losartan had no effect on baseline pulmonary haemodynamics but significantly attenuated acute hypoxic pulmonary vasoconstriction, suggesting that angiotensin II plays a role in modulating this response in man via its effects on the type 1 angiotensin II receptor.

Effects of hypoxia and vascular tone on endothelium-dependent and -independent responses in developing lungs

Both increases and decreases in endothelium-derived nitric oxide (EDNO) activity have been described in the developing pulmonary vasculature. We hypothesized that differences in baseline vasomotor tone and/or oxygen tension may contribute to this variability. Pulmonary arterial dose responses to endothelium-dependent and -independent vasodilators acetylcholine (ACh) and sodium nitroprusside (SNP), respectively, were measured in indomethacin-treated lungs of 1- to 2-day-old (2D) and 1-mo-old (1M) lambs. During 4% O2 ventilation, baseline pulmonary vascular resistance (PVR) and the dilator response to both ACh and SNP were greater in 2D lungs. However, when baseline PVR values were matched at both ages during either hypoxia or infusion of a thromboxane mimetic under normoxic conditions, developmental differences in ACh-induced vasodilation were minimal. Furthermore, hypoxia itself did not alter the responses to ACh in 2D lungs. In contrast, SNP caused greater vasodilation in 2D than in 1M lungs regardless of baseline PVR. These data and studies suggest that whereas high PVR enhances EDNO synthesis, responsiveness to ENDO decreases as synthesis of ENDO increases in developing lungs studied under basal conditions.

Regulation of pulmonary vascular resistance by endogenous and exogenous nitric oxide

Inhaled nitric oxide (NO) causes selective pulmonary vasodilatation under conditions of hypoxia or pulmonary vascular dysfunction. We have observed that NO affects canine pulmonary vascular resistance minimally under normal conditions. We hypothesized that endogenous NO is partly responsible for pulmonary vasomotor regulation in normoxic and hypoxic states. Dogs were studied before and after pulmonary endothelial injury with monocrotaline and N-omega-nitro- l-arginine (LNNA). Systemic vascular resistance was unaffected by NO. Under normal conditions, exogenous NO had little effect on pulmonary vascular resistance. After monocrotaline administration, baseline pulmonary vascular resistance was unchanged but decreased further in response to NO. After LNNA administration, pulmonary vascular resistance increased and there was an exaggerated increase with hypoxia that was reduced by NO. The effect of monocrotaline on in vitro endothelial function was evaluated with isolated pulmonary arteries, which showed a decreased relaxation response to bradykinin (an endothelial-dependent vasodilator) and a normal response to nitroprusside (an endothelial-independent vasodilator). These results support the hypothesis that endogenous NO is an important regulator of pulmonary vasomotor tone and is of even greater importance during hypoxia.

Pulmonary Hydraulic Impedance Response to Cromakalim (BRL 34915) in Newborn Pigs

Cromakalim (BRL 34915), a novel vasodilator, is used clinically to manage systemic hypertension. Its effects on the intact newborn pulmonary circulation remain unclear. The purpose of this study was to determine the response of both the mean and pulsatile pulmonary hemodynamic parameters to intravenous infusion of BRL 34915 (0.1 mg/kg/min for 10 min) in 48-hr-old open-chest Yorkshire pigs. Animals were divided into two groups: Group I pigs had a high mean baseline pulmonary artery pressure (PAP) (>17 mm Hg), while Group II pigs had a low to normal baseline mean PAP (<17 mm Hg). Following instrumentation for high-fidelity recordings of PAP and flow, baseline data were acquired. Employing Fourier analysis, characteristic impedance (Zo), input mean impedance (Zm), impedance harmonic moduli (units in dyn sec cm-5), and phase angles (radians) were determined. Pulmonary vascular resistance (PVR) was calculated and aortic pressure (AP, mm Hg) was also measured. All values = mean ± SEM. Group I animals ("high tone") underwent a decrease in PAP (17.9 ± 1.6 mm Hg vs 13.6 ± 1.9 mm Hg, P = 0.008) and PVR (4310 ± 816 dyn sec cm-5 vs 3713 ± 687 dyn sec cm-5, P = 0.04). Group II animals ("low tone") responded with an increase in PAP (11.5 ± 0.4 mm Hg vs 16.6 ± 1.8 mm Hg, P = 0.029). AP decreased in Group I (40 ± 3.8 mm Hg vs 21.5 ± 2.8 mm Hg, P = 0.008) and Group II (51.2 ± 10.8 mm Hg vs 31.2 ± 10.9 mm Hg, P = 0.05). BRL 34915 caused Group I impedance moduli to decrease at the lower frequencies. Group II impedance modulus and phase angle were not altered with BRL 34915. Zo was not changed in either group. These data indicate that in animals manifesting an elevated baseline pulmonary arteriolar tone, BRL 34915 caused pulmonary arteriolar dilatation and reduced wave reflections, thereby reducing the total hydraulic input energy by up to 40%. In contrast, animals with a lower baseline PAP and PVR responded with an increase in pressure. A tone-dependent response to K+ channel activators in an intact newborn animal has not previously been reported.

Direct effects of intravenous anesthetics on pulmonary vascular resistance in the isolated rat lung.

We determined the direct effects of thiopental, ketamine, midazolam, etomidate, and propofol on pulmonary vascular resistance (PVR), the relationship of the direct effects to the baseline PVR, and the possible interaction with functional endothelium. The intravenous anesthetics were injected randomly into 1) endothelium-intact isolated rat lungs which were either unconstricted or constricted with angiotensin II (n = 10), and 2) lungs with endothelial injury produced by electrolysis (n = 10). In endothelium-intact lungs thiopental (0.5 and 5.0 mg/kg) and etomidate (3.0 mg/kg) significantly (P < 0.05) increased PVR by 3% +/- 1%, 30% +/- 7%, and 29% +/- 5%, respectively. Ketamine (3.0 and 100 mg/kg) and propofol (20 mg/kg) significantly (P < 0.05) decreased the PVR by 6% +/- 1%, 15% +/- 1%, and 8% +/- 1%, respectively. Midazolam (0.3 and 3.0 mg/kg) and smaller doses of etomidate (0.3 mg/kg) and propofol (2.0 mg/kg) did not affect PVR. These responses did not vary with the baseline PVR over a twofold range. The effects of thiopental, ketamine, etomidate, and midazolam were not altered by endothelial injury. In contrast to the vasodilation produced by propofol in normal lungs, propofol (20 mg/kg) significantly (P < 0.05) increased the PVR by 8% +/- 2% after endothelial injury. In conclusion, this study demonstrates that thiopental and etomidate are direct pulmonary vasoconstrictors, ketamine and propofol are direct pulmonary vasodilators, and midazolam has no direct effects in the isolated rat lung. Further, these effects on pulmonary vasculature do not vary with baseline PVR, and only propofol appears to have endothelium-dependent effects.

Inhaled Nitric Oxide

Inhaled nitric oxide (NO), an endothelium-derived relaxing factor, is a selective pulmonary vasodilator. The authors investigated whether the pulmonary vasodilation resulting from 20 ppm inhaled NO is related to the degree of pulmonary hypertension or affected by cardiopulmonary bypass (CPB) or the presence of intravenous nitrates. In patients undergoing cardiac surgery (n = 20) or in whom the circulation was supported with a ventricular assist device (VAD; n = 5), the lungs were ventilated with 80% O2 and 20% N2 followed by the same gas concentrations containing 20 ppm NO for 6 min. Inhaled NO decreased (P < 0.05) the pulmonary artery pressure from 36 +/- 3 to 29 +/- 2 mmHg and 32 +/- 2 to 27 +/- 1 mmHg, before and after CPB, respectively, and from 68 +/- 12 to 55 +/- 9 mmHg in patients with a VAD. Similarly, the pulmonary vascular resistance (PVR) decreased (P < 0.05) from 387 +/- 44 to 253 +/- 26 dyne.cm.s-5 and 260 +/- 27 to 182 +/- 18 dyne.cm.s-5, before and after CPB, respectively, and from 1,085 +/- 229 to 752 +/- 130 dyne.cm.s-5 in patients with a VAD. Central venous pressure, cardiac output, systemic hemodynamics, and blood gases did not change after inhalation of NO before or after CPB, whereas arterial oxygen tension, mixed venous hemoglobin saturation, and mean arterial pressure increased (P < 0.05) in patients supported with a VAD. All hemodynamic and laboratory data returned to control 6 min after discontinuation of NO. The decrease in PVR was proportional to baseline PVR (delta PVR = -0.45 PVRb + 39.9) before CPB. The pre- and post-CPB slopes were identical despite possible damage to the endothelium resulting from CPB and the post-CPB presence of intravenous nitroglycerin (17 of 20 patients). This study demonstrates that 20 ppm inhaled NO is a selective pulmonary vasodilator in cardiac surgical patients before and after CPB and in patients in whom the circulation is supported with a VAD. Furthermore, NO-induced pulmonary vasodilation is proportional to PVRb and does not appear to be altered by CPB, the presence of a VAD, or infusion of nitrates.

Role of adenosine triphosphate and adenosine in oxygen-induced pulmonary vasodilation in fetal lambs.

We investigated the hypothesis that purine nucleotides, ATP and adenosine, mediate the pulmonary vasodilation that occurs at birth in response to an increase in arterial O2 pressure (PaO2). We studied 20 fetal lambs 1 to 3 d after placement of intravascular catheters and a flow transducer around left pulmonary artery. In 16 lambs, we investigated the effects of 1) an increase in fetal PaO2 on ATP levels in pulmonary circulation and 2) 8-phenyl-theophylline (8-PT) and cibacron blue, antagonists of receptors for adenosine and ATP, on pulmonary vasodilation caused by increased PaO2. In four other lambs, we investigated the specificity of 8-PT and cibacron blue for purine receptors by investigating their effects on pulmonary vasodilation caused by acetylcholine, bradykinin, and nitroprusside. The fetal PaO2 increased by 7 +/- 2 during administration of 100% O2 to the pregnant ewe, resulting in a 3-fold decrease in PVR and increase in pulmonary blood flow. Blood and plasma concentrations of ATP in fetal pulmonary artery and left atrium increased significantly during the increase in fetal PaO2. 8-PT and cibacron blue caused increases in baseline pulmonary and systemic vascular pressures and pulmonary vascular resistance and inhibited the pulmonary vasodilation caused by O2. 8-PT and cibacron blue did not alter the pulmonary vascular effects of acetylcholine, bradykinin, and nitroprusside. An increase in baseline pulmonary vascular resistance caused by infusion of U46619 (in four lambs) did not alter the pulmonary vasodilation caused by O2. In summary, O2-induced pulmonary vasodilation is accompanied by increased ATP levels in pulmonary circulation and is attenuated by antagonists of purine receptors.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine as a vasodilator in primary pulmonary hypertension.

The acute administration of vasodilator drugs to patients with primary pulmonary hypertension has been advocated to identify those with reversible pulmonary vasoconstriction. Unfortunately, the usefulness of the drugs currently available is limited by accompanying systemic hypotension. A vasodilator with effects confined to the pulmonary circulation would therefore be advantageous in such patients. The purine nucleoside adenosine was infused into the pulmonary artery in seven patients with primary pulmonary hypertension (baseline pulmonary vascular resistance [PVR], 442-1,295 dyne/cm/sec-5) to determine its effect on PVR. In all patients, there was a dose-dependent and significant reduction (mean maximal percent decrease from baseline, 38.9%; p less than 0.001) in PVR mediated through a decrease in pulmonary artery pressure and an increase in cardiac output. Systemic vascular resistance (SVR) also decreased, but the ratio of PVR to SVR decreased (maximal mean percent decrease from baseline) by 10.5% (p less than 0.025), indicating that adenosine has a preferential vasodilator effect on the pulmonary circulation when administered in this manner. Because of its pharmacokinetic and vasodilator properties, adenosine may have a specific role in the investigation of primary pulmonary hypertension.

Acute effects on pulmonary haemodynamics of nifedipine in adult patients with cystic fibrosis

Hypoxic pulmonary vasoconstriction is considered to be the primary cause of pulmonary hypertension and cor pulmonale in adult patients with cystic fibrosis (CF). The acute effect on pulmonary haemodynamics of a single sublingual dose of nifedipine 20 mg has been studied in 9 adult patients with CF. Nifedipine significantly attenuated the rise in mean pulmonary artery pressure and pulmonary vascular resistance induced by inhalation of a 13% oxygen gas mix. It also slightly reduced baseline pulmonary artery pressure and pulmonary vascular resistance and lowered pulmonary artery hypertension in the patients. Oxygen delivery was unchanged. Nifedipine is potentially useful for the treatment of hypoxic pulmonary hypertension in patients with CF.

Cyclooxygenase Inhibition Potentiates the Pulmonary Vascular Responses to Ethanol in Dogs

The effects of ethanol on pulmonary hemodynamics and the role of arachidonic acid metabolites in mediating these responses were studied in the isolated, blood-perfused canine lung lobe. Ethanol added directly to the venous reservoir at a concentration of 0.01 or 0.1% did not alter the pulmonary vascular resistance, however, 1.0% ethanol increased (p less than 0.05) the pulmonary resistance. Indometacin, a cyclooxygenase inhibitor, significantly increased baseline pulmonary vascular resistance and markedly potentiated the pulmonary vascular responses to the three concentrations of ethanol. Addition of nordihydroguaiaretic acid (NDGA), a lipoxygenase inhibitor, followed by indometacin, did not diminish the indometacin-induced increases in basal tone or enhancement of the responses to ethanol indicating that leukotrienes are not involved in mediating the responses to ethanol. These results suggest that in isolated, blood-perfused dog lung lobe, a high concentration of ethanol increases the pulmonary vascular resistance and that cyclooxygenase inhibition markedly potentiated the responses to ethanol by reducing the production of vasodilator prostaglandin, most probably prostacyclin.

Long-term indoramin therapy in congestive heart failure: A double-blind, randomized, parallel placebo-controlled trial

Twenty-one patients with moderately severe congestive heart failure participated in a double-blind, randomized, parallel placebo-controlled trial designed to evaluate the effects of long-term (2 months) indoramin therapy on rest and exercise hemodynamics, exercise capacity and clinical status of patients with this clinical syndrome. The long-term administration of indoramin in patients (mean dose 50 mg every 12 hours) caused a mild reduction from baseline values in supine rest mean systemic blood pressure and, after dosing, elicited a significant reduction in systemic and pulmonary vascular resistances, pulmonary capillary wedge pressure and heart rate as well as a mild increase in stroke volume. Long-term indoramin therapy caused a small decrease, as compared with baseline exercise responses, in systemic and pulmonary vascular resistance and pulmonary capillary wedge pressure at submaximal levels of exercise. It did not alter hemodynamic variables at maximal exercise, exercise capacity or overall clinical status, compared with findings at baseline or with placebo.

Natural evolution of left ventricular haemodynamics following uncomplicated acute myocardial infarction

In an attempt to investigate the changes in left ventricular haemodynamics following uncomplicated myocardial infarction 95 patients with definite electrocardiographic signs of infarction, without clinical signs of cardiac failure, were monitored with a Swan Ganz catheter for the first 24 hours after admission to hospital. The median delay from onset of symptoms was 6.8 hours. Mean heart rate increased (83–86 beats/min; P < 0.05) while stroke volume index fell (38.4-36.6 ml/m 2; P < 0.05); cardiac index therefore remained unchanged during the observation period. As a result of a fall in arterial pressure both systemic vascular resistance and left ventricular stroke work index fell significantly ( P < 0.01). Pulmonary wedge pressure also fell (13.6-10.5 mm Hg; P < 0.001), but this fall was confined to patients whose initial reading was above the median of 13 mm Hg. Pulmonary wedge pressure fell both among the 41 patients who required some medical therapy (15.6-10.8 mm Hg; P < 0.001) and the 54 who received no medication throughout the 24 hours (12.0-9.8 mm Hg; P < 0.05). The 39 patients with anterior wall infarction had higher baseline pulmonary wedge pressure and systemic vascular resistance than the 42 with inferior wall infarction. Later the stroke volume and stroke work index were persistently lower reflecting the greater degree of impairment of left ventricular function in anterior wall infarction. In conclusion, following an uncomplicated myocardial infarction, cardiac index was maintained, despite a fall in stroke volume, by an increase in heart rate. Pulmonary wedge pressure showed both a spontaneous fall and a fall in those patients given additional medical therapy during the study period.