Decrease In Ppa Research Articles

Pulmonary haemodynamic changes in patients with severe COPD

Worsening gas exchange during exercise and during exacerbations of COPD contributes to systemic hypoxaemia and reduces quality of life. However, pulmonary haemodynamic changes under such conditions are not well understood. Right heart catheterization was performed in six patients with severe COPD (%FEV(1) < 50%) during rest, exercise and during an exacerbation. Pulmonary artery pressure (Ppa) was slightly elevated at rest. The Ppa, as well as pulmonary artery wedge pressure (Pawp) and cardiac index were significantly increased during bicycle ergometer exercise. In contrast, pulmonary vascular resistance increased significantly during an exacerbation accompanied by a slightly increased Ppa. Supplemental oxygen resulted in significant decreases in Ppa and Pawp during exercise and Ppa during exacerbations. In patients with COPD, haemodynamic changes in the pulmonary circulation may differ during exercise and with exacerbations. Supplementary oxygen is beneficial and associated with reductions in pulmonary arterial pressures.

Zardaverine and aerosolised iloprost in a model of acute respiratory failure.

In this study, the impact of aerosolised prostacyclin (PGI2) and iloprost in the absence or presence of subthreshold intravascular doses of the dual-selective phosphodiesterase-3/4 inhibitor zardaverine was investigated in an experimental model of acute respiratory failure. In perfused rabbit lungs, continuous infusion of the thromboxane-A2-mimetic U46619 provoked pulmonary hypertension, accompanied by progressive lung oedema formation and severe ventilation-perfusion mismatch with predominance of shunt flow (increasing from approximately 2 to 58%, as assessed by the multiple inert gas elimination technique). Aerosolisation of PGI2 (in total 1.05 microg x kg(-1) for 15 min caused a decrease in pulmonary artery pressure (Ppa) and a limitation of maximum shunt flow to approximately 37%. When nebulised PGI2 was combined with subthreshold intravascular zardaverine, which did not affect pulmonary haemodynamics per se, the duration of the PGI2 effect was increased. Aerosolisation of 3 microg x kg(-1) PGI2 resulted in a transient decrease in Ppa and a reduction in shunt flow. In the presence of subthreshold zardaverine, the effects of this PGI2 dose were only marginally increased. Aerosolisation of iloprost (in total 0.7 microg x kg(-1)) for 15 min caused a more sustained decrease in Ppa, some enhanced reduction of oedema formation as compared with PGI2 and a decrease in shunt flow to approximately 32%. Most impressively, when combined with subthreshold zardaverine, iloprost suppressed oedema formation to <15% and shunt flow to approximately 8%. In conclusion, combined use of aerosolised iloprost and subthreshold systemic phosphodiesterase-3/4 inhibitor may result in selective intrapulmonary vasodilation, a reduction in oedema formation and an improvement in ventilation-perfusion matching in acute respiratory failure.

Pulmonary vascular effects of dobutamine in experimental pulmonary hypertension.

To characterize the dose-related effects of dobutamine on pulmonary vascular tone and associated changes in right ventricular afterload in canine microembolic lung injury . Prospective, interventional study. University laboratory. Ten anesthetized and ventilated dogs. Right heart catheterization for the measurement of pulmonary vascular resistance by multipoint mean pulmonary artery pressure (Ppa)/cardiac output (Q) plots, partitioning of pulmonary vascular resistance by the occlusion method, and determination of pulmonary arterial input impedance from spectral analysis of Ppa and Q waves, in ten anesthetized and ventilated dogs, before and after induction of acute microembolic lung injury, and without or with 5, 10, 15, and 20 microg.kg(-1).min(-1) dobutamine. Microembolic pulmonary hypertension was associated with a shift of Ppa/Q plots to higher pressures, a slight decrease in the arterial component of pulmonary vascular resistance, a decrease in characteristic impedance, and an increase in the pulsatile component of right ventricular hydraulic load. At baseline, dobutamine had no effect on Ppa/Q plots at 5 and 10 microg.kg(-1).min(-1) but increased Ppa at 15 and 20 microg.kg(-1).min(-1). In microembolic pulmonary hypertension, the only effect of dobutamine on Ppa/Q plots was a decrease in Ppa at 20 microg.kg(-1).min(-1). Dobutamine had no effect on the partitioning of pulmonary vascular resistance or on pulmonary arterial input impedance spectrum. Dobutamine at doses up to 10 microg.kg(-1).min(-1) has no flow-independent effect on the normal or the acutely hypertensive pulmonary circulation. Higher doses may be constricting or dilating depending on preexisting tone.

Flow-mediated release of nitric oxide in isolated, perfused rabbit lungs.

The effects of changing perfusate flow on lung nitric oxide (NO) production and pulmonary arterial pressure (Ppa) were tested during normoxia and hypoxia and after N(G)-monomethyl-L-arginine (L-NMMA) treatment during normoxia in both blood- and buffer-perfused rabbit lungs. Exhaled NO (eNO) was unaltered by changing perfusate flow in blood-perfused lungs. In buffer-perfused lungs, bolus injections of ACh into the pulmonary artery evoked a transient increase in eNO from 67 +/- 3 (SE) to 83 +/- 7 parts/billion with decrease in Ppa, whereas perfusate NO metabolites (pNOx) remained unchanged. Stepwise increments in flow from 25 to 150 ml/min caused corresponding stepwise elevations in eNO production (46 +/- 2 to 73 +/- 3 nl/min) without changes in pNOx during normoxia. Despite a reduction in the baseline level of eNO, flow-dependent increases in eNO were still observed during hypoxia. L-NMMA caused declines in both eNO and pNOx with a rise in Ppa. Pulmonary vascular conductance progressively increased with increasing flow during normoxia and hypoxia. However, L-NMMA blocked the flow-dependent increase in conductance over the range of 50-150 ml/min of flow. In the more physiological conditions of blood perfusion, eNO does not reflect endothelial NO production. However, from the buffer perfusion study, we suggest that endothelial NO production secondary to increasing flow, may contribute to capillary recruitment and/or shear stress-induced vasodilation.

PAF increases vascular permeability without increasing pulmonary arterial pressure in the rat.

In vivo pulmonary arterial catheterization was used to determine the mechanism by which platelet-activating factor (PAF) produces pulmonary edema in rats. PAF induces pulmonary edema by increasing pulmonary microvascular permeability (PMP) without changing the pulmonary pressure gradient. Rats were cannulated for measurement of pulmonary arterial pressure (Ppa) and mean arterial pressure. PMP was determined by using either in vivo fluorescent videomicroscopy or the ex vivo Evans blue dye technique. WEB 2086 was administered intravenously (IV) to antagonize specific PAF effects. Three experiments were performed: 1) IV PAF, 2) topical PAF, and 3) Escherichia coli bacteremia. IV PAF induced systemic hypotension with a decrease in Ppa. PMP increased after IV PAF in a dose-related manner. Topical PAF increased PMP but decreased Ppa only at high doses. Both PMP (88 +/- 5%) and Ppa (50 +/- 3%) increased during E. coli bacteremia. PAF-receptor blockade prevents changes in Ppa and PMP after both topical PAF and E. coli bacteremia. PAF, which has been shown to mediate pulmonary edema in prior studies, appears to act in the lung by primarily increasing microvascular permeability. The presence of PAF might be prerequisite for pulmonary vascular constriction during gram-negative bacteremia.

Low-dose systemic phosphodiesterase inhibitors amplify the pulmonary vasodilatory response to inhaled prostacyclin in experimental pulmonary hypertension.

Inhalation of aerosolized prostaglandin I(2) (PGI(2)) causes selective pulmonary vasodilation, but the effect rapidly levels off after termination of nebulization. In experimental pulmonary hypertension in intact rabbits, provoked by continuous infusion of the stable thromboxane mimetic U46619, the impact of intravenous phosphodiesterase (PDE) inhibitors on pulmonary and systemic hemodynamics was investigated in the absence and the presence of aerosolized PGI(2). We employed the monoselective inhibitors motapizone (PDE 3), rolipram (PDE 4), and zaprinast (PDE 5), as well as the dual-selective blockers zardaverine and tolafentrine (both PDE 3/4). All PDE inhibitors dose-dependently reduced the pulmonary artery pressure (Ppa), with doses for an approximately 20% decrease in pulmonary vascular resistance being 5 microgram/kg for motapizone, 25 microgram/kg for rolipram, 500 microgram/kg for zardaverine, 1 mg/kg for zaprinast, and 1 mg/kg for tolafentrine. Additive efficacy was noted when combining the monoselective 3 plus 4, 3 plus 5, and 4 plus 5 inhibitors. In parallel with the pulmonary vasorelaxant effect, all PDE inhibitors caused a decrease in systemic arterial pressure and an increase in cardiac output. Nebulized PGI(2) (56 ng/kg. min) reduced the U46619-evoked increase in Ppa by approximately 30%. This vasorelaxant effect was fully lost within 10 min after termination of PGI(2) nebulization. Coapplication of subthreshold doses of intravenous PDE inhibitors, which per se did not affect pulmonary and systemic hemodynamics, resulted in a marked prolongation of the post-PGI(2) decrease in Ppa for all blockers (motapizone at 2.2 microgram/kg, rolipram at 5.5 microgram/kg, zaprinast at 100 microgram/kg). The most effective agents, zardaverine (50 microgram/kg) and tolafentrine (100 microgram/kg), augmented the maximum Ppa drop during nebulization by approximately 30-50% and prolonged the post-PGI(2) pulmonary vasodilation to > 30 min, without affecting systemic arterial pressure and arterial oxygenation. We conclude that subthreshold systemic doses of monoselective PDE 3, 4, and 5 inhibitors and in particular dual-selective PDE 3/4 inhibitors cause significant amplification of the pulmonary vasodilatory response to inhaled PGI(2), while limiting the hypotensive effect to the pulmonary circulation. Combining nebulized PGI(2) with low-dose systemic PDE inhibitors may thus offer a therapeutic strategy to achieve selective pulmonary vasodilation in acute and chronic pulmonary hypertension.

Polycythemia impairs vasodilator response to acetylcholine in patients with chronic hypoxemic lung disease.

To investigate whether polycythemia associated with chronic hypoxemic lung disease (CHLD) increases vascular resistance by altering endothelium-derived nitric oxide (NO), we examined the responses to acetylcholine (ACh) infusions (5, 10, and 15 mg/min) on hemodynamics and gas exchange in 21 patients with CHLD of varying severity. Patients were classified into two groups based on whether their hemoglobin (Hb) level was less or greater than 15.5 g/dl. In the normocythemic patients (Hb = 13.6 +/- 0.3 g/100 ml, n = 10), ACh decreased pulmonary artery pressure (Ppa) from 30 +/- 2 mm Hg 26 +/- 2 mm Hg (p < 0.01); pulmonary vascular resistance (PVR), from 5.1 +/- 0.4 U/m2 to 3.4 +/- 0.3 U/m2 (p < 0.001); systemic arterial pressure (Psa), from 111 +/- 4 mm Hg to 108 +/- 4 mm Hg (p < 0.05); and systemic vascular resistance (SVR), from 27 +/- 2 U/m2 to 22 +/- 2 U/m2 (p < 0.01); and also increased the cardiac index (CI), from 3.8 +/- 0.2 to 4.7 +/- 0.3 L/min/m2 (p < 0.001). PaO2 fell from 59 +/- 3 mm Hg to 48 +/- 3 mm Hg (p < 0.001) whereas venous admixture (Qs/Qt) rose from 32 +/- 4% to 44 +/- 4% (p < 0.01). In contrast, in patients with polycythemia (17.7 +/- 0.5 g/100 ml, n = 11) ACh failed to produce any changes in PaO2 (49 +/- 2 mm Hg versus 51 +/- 2 mm Hg, p = NS), Ppa (34 +/- 1 mm Hg versus 33 +/- 1 mm Hg, p = NS), PVR (6.7 +/- 0.9 U/m2 versus 6.9 +/- 0.8 U/m2, p = NS) or Psa, but slightly increased the CI, from 3.6 +/- 0.3 L/min/m2 to 3.9 +/- 0.3 L/min/m2 (p < 0.01), and Qs/Qt, from 40 +/- 4% to 45 +/- 3% (p < 0.05). In the 21 patients, negative correlations with Hb concentrations were found for ACh-induced changes in PVR (r = -0.57, p < 0.01), Ppa (r = -0.46, p < 0.01), CI (r = -0.5, p < 0.05), PaO2 (r = -0.79, p < 0.01), and Qs/Qt (r = -0.79, p < 0.01). In the six polycythemic patients who received isovolemic hemodilution, with a decrease in Hb concentration from 18.6 +/- 0.9 g/dl to 15.3 +/- 0.3 g/dl as a result, infusion of ACh, which was without effect before hemodilution, caused decreases in Ppa from 28 +/- 1 mm Hg to 23 +/- 1 mm Hg (p < 0.05) and in PVR from 5.7 +/- 0.8 U/m2 to 3.6 +/- 0.5 U/m2 (p < 0.02), as well as an increase in CI from 3.4 +/- 0.4 L/min/ m2 to 4.1 +/- 0.4 L/min/m2 (p < 0.05). In contrast to ACh, inhaled NO (40 ppm) induced pulmonary vasodilation in both the normocythemic and polycythemic groups. Our results show that high hematocrit (Hct) levels inhibit endothelium-dependent vasodilation in response to ACh in patients with CHLD, possibly through inactivation of endothelial-derived NO by Hb.

RESPONSIVENESS AND SENSITIVITY TO INHALED NITRIC OXIDE CHANGES WITH AGE IN ISOLATED LUNGS OF DEVELOPING NEWBORN LAMBS. † 2059

In a recent study, we found that sodium nitroprusside (SNP) attenuated hypoxic vasoconstriction more in 2 day (d) than 1 month (m) old lamb lungs (J Appl Physiol 79: 824, 1995), suggesting that pulmonary vascular responsiveness to endothelium-derived nitric oxide decreases with age. However, SNP may have different effects than nitric oxide (NO) on vascular smooth muscle. Therefore, in this study we compared pulmonary artery dose-responses to inhaled NO (2.5 - 100 ppm) in indomethacin-treated 1d and 1m lamb lungs ventilated with 4% O2 (hypox). All lungs were perfused with autologous blood at a constant flow of 100 ml/kg.min. Data are expressed as mean pulmonary artery pressure(Ppa in mmHg) ± SEM. Groups were compared by ANOVA (* different at p< 0.05). Inhaled NO caused a significantly greater decrease in hypox Ppa in 1d compared to 1m lungs. Maximal dilation occurred at 100 ppm NO at both ages. 5 ppm NO caused a 49±8.2% decrease in Ppa relative to maximal dilation in 1d lungs, but only a 25.1±13% decrease in 1m lungs. Over 10 ppm NO were required to cause a 50% decrease in Ppa in 1m lungs. Thus, 1d lungs appeared more responsive and sensitive to NO. Whether this was due to higher baseline Ppa in 1d lungs or to age-dependent differences in metabolism of cGMP(or other steps in signal transduction) remains to be determined. Support: American Heart Assoc, MD Affiliate, Inc. Table

INHALED NITRIC OXIDE (NO) FOLLOWING RECONSTRUCTIVE SURGERY FOR CONGENITAL HEART DISEASE: FACTORS ASSOCIATED WITH IMPROVEMENT IN GAS EXCHANGE.† 157

Infants undergoing reconstructive cardiac surgery for congenital heart disease (CHD) may develop pulmonary hypertension due to reactive pulmonary vasculature despite technically successful surgery. Inhaled NO reduces pulmonary vascular resistance in this setting. However, optimal dose and duration of treatment have not been correlated with pretreatment status. We investigated if there was time dependency in NO-induced improvement in either arterial oxyhemoglobin saturation (SaO2) or directly measured pulmonary arterial pressure (Ppa) and if duration of treatment was correlated with perioperative factors. Nine infants with complex CHD, median age 7 weeks(range: 1 day to 17 months), were treated with NO (20-40 ppm) for either severe oxyhemoglobin desaturation (n=7) or for elevated Ppa (n=2) following reconstructive surgery. Eight of nine patients responded, as defined by a rise in SaO2 of ≥ 5% or by decrease in Ppa of ≥ 10% of baseline. Time to peak SaO2 response is shown for the responders treated for decreased SaO2. There was no correlation between duration of need for NO (range of 48-200 hrs.) as determined by daily brief trials without NO and duration of cardiopulmonary bypass (CPB) time (range: 60 to 210 minutes). There was also no correlation between the 0.5 hr. response to NO and the duration of need for NO. Two of nine patients died, including one with pre-treatment SaO2 of 20% who showed no response and one who demonstrated acute decrease in Ppa. No NO-related toxicity was detected. Inhaled NO can improve gas exchange and pulmonary hypertension acutely following surgery, but the maximum response to inhaled NO may not be achieved for several hours. Neither the initial response to NO nor CBP time predicts duration of need for NO. Table

NIFEDIPINE PREVENTS PULMONARY HYPERTENSION BUT DOES NOT PREVENT IMPAIRED ENDOTHELIUM DEPENDENT PULMONARY DILATION IN NEWBORN PIGS EXPOSED TO CHRONIC HYPOXIA. † 1976

Pulmonary hypertension developed and pulmonary dilation to the endothelium dependent agent acetylcholine (Ach) was blunted when newborn pigs were exposed to alveolar hypoxia (J. Appl. Physiol. 77:2853, 1994 and Ped. Res. 30:391A, 1994). To see if treatment with the calcium channel blocker nifedipine would prevent the development of pulmonary hypertension and prevent impaired pulmonary dilatory responses to Ach, we maintained 1-3 day old pigs in a chamber filled with either room air (Control) or 11% O2 (Chronic Hypoxia) for 10 days. Some of the Chronic Hypoxia piglets were given nifedipine, 3-5 mg/kg sublingually tid (Nifedipine). The pigs were anesthetized and catheters placed for in vivo measurement of pulmonary arterial pressure (Ppa), pulmonary wedge pressure (Pw), and determination of cardiac output by the thermodilution technique. Lungs were then excised and perfused with a mixture of blood and 3% albumin-saline. We maintained flow constant at 50 (ml/min)/kg and measured Ppa responses to Ach (10-5 M). PVR was greater in Chronic Hypoxia pigs than in either Control or Nifedipine treated chronic hypoxia pigs. The decrease in Ppa with Ach was less in isolated lungs from both Chronic Hypoxia and Nifedipine treated chronic hypoxia pigs than from Control pigs. Thus, nifedipine treatment prevented the development of pulmonary hypertension during chronic hypoxia in newborn pigs. However, responses to the endothelium dependent vasodilator Ach were blunted in lungs of both chronica hypoxia and nifedipine-treated chronic hypoxia pigs. Nifedipine treatment may prevent pulmonary hypertension but may not prevent all of the functional pulmonary vascular changes that occur with chronic hypoxia in newborns. Supported by Am Heart Assoc.Table

Inhaled nitric oxide does not alter the longitudinal distribution of pulmonary vascular resistance

Because the effects of inhaled nitric oxide (NO) may be localized to its site of delivery, we studied the effects of inhaled NO on the longitudinal distribution of pulmonary vascular resistance during pulmonary hypertension in perfused rabbit lungs. Before NO administration, pulmonary hypertension was produced by infusion of the thromboxane A2 mimetic U-46619 in all lungs. Pulmonary vascular resistance was divided into arterial, microvascular, and venous components by arterial and venous occlusion techniques. In the buffer-perfused lung, all doses of inhaled NO (5, 20, and 80 ppm) produced small decreases (approximately 3 mmHg) in pulmonary arterial pressure (Ppa), with equivalent proportional reductions in all segmental vascular resistances. Similar results were obtained after an extended inhaled NO dose range of 20, 80, and 240 ppm. In the buffer-perfused lung, inhibition of endogenous NO synthesis with NG-nitro-L-arginine methyl ester (L-NAME) potentiated the effects of U-46619. Subsequent inhaled NO administration produced larger decreases (approximately 7 mmHg) in Ppa with equivalent proportional reductions in all segmental vascular resistances. In the blood-perfused lung, L-NAME did not alter baseline pulmonary pressures. Administration of inhaled NO during U-46619-induced pulmonary hypertension produced dose-related decreases in Ppa. The highest dose (80 ppm) of inhaled NO decreased Ppa by 3.5 mmHg, with equivalent proportional reductions in all segmental vascular resistances.(ABSTRACT TRUNCATED AT 250 WORDS)

Inhaled nitric oxide partially reverses hypoxic pulmonary vasoconstriction in the dog.

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.

Effect of inhaled nitric oxide on pulmonary hemodynamics after acute lung injury in dogs.

Increased pulmonary vascular resistance (PVR) and mismatch in ventilation-to-perfusion ratio characterize acute lung injury (ALI). Pulmonary arterial pressure (Ppa) decreases when nitric oxide (NO) is inhaled during hypoxic pulmonary vasoconstriction (HPV); thus NO inhalation may reduce PVR and improve gas exchange in ALI. We studied the hemodynamic and gas exchange effects of NO inhalation during HPV and then ALI in eight anesthetized open-chest mechanically ventilated dogs. Right atrial pressure, Ppa, and left ventricular and arterial pressures were measured, and cardiac output was estimated by an aortic flow probe. Shunt and dead space were also estimated. The effect of 5-min exposures to 0, 17, 28, 47, and 0 ppm inhaled NO was recorded during hyperoxia, hypoxia, and oleic acid-induced ALI. During ALI, partial beta-adrenergic blockade (propranolol, 0.15 mg/kg i.v.) was induced and 74 ppm NO was inhaled. Nitrosylhemoglobin (NO-Hb) and methemoglobin (MetHb) levels were measured. During hyperoxia, NO inhalation had no measurable effects. Hypoxia increased Ppa (from 19.8 +/- 6.1 to 28.3 +/- 8.7 mmHg, P < 0.01) and calculated PVR (from 437 +/- 139 to 720 +/- 264 dyn.s.cm-5, P < 0.01), both of which decreased with 17 ppm NO. ALI decreased arterial PO2 and increased airway pressure, shunt, and dead space ventilation. Ppa (19.8 +/- 6.1 vs. 23.4 +/- 7.7 mmHg) and PVR (437 +/- 139 vs. 695 +/- 359 dyn.s.cm-5, P < 0.05) were greater during ALI than during hyperoxia. No inhalation had no measureable effect during ALI before or after beta-adrenergic blockade. MetHb remained low, and NO-Hb was unmeasurable. Bolus infusion of nitroglycerin (15 micrograms) induced an immediate decrease in Ppa and PVR during ALI.(ABSTRACT TRUNCATED AT 250 WORDS)

Receptor mechanism of thrombin-mediated pulmonary vasodilation in neonates

A recently identified peptide sequence exposed after proteolytic cleavage of the NH2-terminus of the thrombin receptor mimics some cellular effects of alpha-thrombin. To determine whether a proteolytic action of thrombin is required for vasoactivity, we examined the vascular effects of modified thrombins and synthetic NH2-terminus peptide sequences of the thrombin receptor (TRPs) in isolated piglet lungs. Lungs of piglets 1-6 days old were perfused with recirculating Ringer-albumin solution at a constant flow of 60 ml/min. We measured the pulmonary artery pressure (Ppa) and segmental distribution of pulmonary vascular resistance (using the double occlusion method) in response to injections of human alpha-thrombin, modified thrombins, and TRP-14 and TRP-7 (i.e., 14 and 7 amino acid NH2-terminus peptides of the cleaved thrombin receptor). alpha-Thrombin produced a rapid and transient decrease in Ppa; the magnitude and duration [time for one-half recovery (t1/2 R)] of the vasodilation responses were concentration dependent [t1/2 R values of 1.4 +/- 0.1 and 3.3 +/- 2.4 min (mean +/- SE) at concentrations of 10(-10) and 10(-9) M, respectively]. The vasodilation was due primarily to a decrease in precapillary resistance. Proteolytically active, but binding-impaired gamma-thrombin was a less potent vasodilator and proteolytically inactive D-phenylalanyl-prolyl-arginine-chloromethyl ketone (PPACK)-alpha-thrombin did not induce vasodilation. TRP-14 was also a pulmonary vasodilator with a t1/2R value of 0.8 +/- 0.09 min at a concentration of 10(-7) M; both TRP-14 and TRP-7 were approximately 3-log less potent than equimolar alpha-thrombin.(ABSTRACT TRUNCATED AT 250 WORDS)

Mechanisms of endothelin‐1‐induced pulmonary vasodilatation in neonatal pigs.

1. We determined the contributions of three independent vasodilator mechanisms (cyclo-oxygenase metabolites, nitric oxide and ATP-sensitive potassium channels) in the mediation of pulmonary vasomotor effects of endothelin-1 (ET-1) in neonatal pigs. 2. Lungs of piglets (2.7 +/- 0.3 days old) were perfused at constant flow (60 ml min-1) with recirculating Ringer-albumin solution. We measured pulmonary artery pressure (Ppa) and the distribution of pulmonary vascular resistance using the double-occlusion method. 3. ET-1 (10(-12)-10(-9) M) produced concentration-dependent pulmonary vasodilatation. ET-1 (10(-9) M) decreased Ppa from 24.5 +/- 3.1 to 17.0 +/- 3.0 cmH2O with a nadir occurring at 1 min, followed by a slow return to baseline over 60 min (time for half-recovery (t1/2R) of 17.2 min). The decrease in Ppa was the result of pulmonary precapillary vasodilatation. Endothelin-3 (ET-3) (10(-12) and 10(-11) M) also induced vasodilatation comparable to equimolar concentrations of ET-1, whereas the selective ETB receptor agonist IRL 1620 at equimolar concentrations caused a more protracted vasodilatation response. 4. Neither the cyclo-oxygenase inhibitor indomethacin (10(-5) M) nor the KATP+ (ATP-sensitive) potassium channel blocker glibenclamide (10(-5) M) significantly altered the baseline Ppa; moreover, neither inhibitor affected the ET-1-induced vasodilatation, indicating the lack of involvement of cyclo-oxygenase metabolites and KATP+ channel activity in the mediation of the pulmonary vasodilator response to ET-1. 5. Addition of 10(-5) M reduced haemoglobin, which antagonizes the action of nitric oxide (NO), increased Ppa over prehaemoglobin levels. Haemoglobin significantly decreased the duration (t1/2R, 3.8 +/- 0.7 min) of pulmonary vasodilatation to ET-1, but did not abolish the initial phase of the response. L-N-Monomethylarginine, an inhibitor of NO synthesis, either alone or in combination with haemoglobin, similarly reduced the duration of ET-1-induced pulmonary vasodilatation. 6. The ETA receptor antagonist [Dpr1-Asp15]-ET-1 (Dpr, diaminoproprionic acid) had no effect on pulmonary vasodilatation induced by ET-1, ET-3 or IRL 1620 (suc-(Glu9,Ala11,15)-ET-1(8-21)). This finding combined with the observed relative potencies of the peptides (IRL 1620 > ET-1 = ET-3) suggests that pulmonary vasodilatation was mediated by activation of the non-selective ETB receptor. 7. The results indicate that the sustained ET-1-induced pulmonary vasodilatation in neonates is probably mediated via ETB receptor activation and that it is critically dependent on NO.

K+ATP-channel activation causes marked vasodilation in the hypertensive neonatal pig lung.

We studied the potential role of ATP-sensitive potassium (K+ATP) channel activation in mediating pulmonary vasodilation in newborn piglets. Piglet lungs (n = 14, ages 1-4 days) were artificially perfused with recirculating Ringer solution containing bovine serum albumin and statistically inflated using 95% O2-5% CO2. We measured pulmonary arterial pressure (Ppa) and distribution of pulmonary vascular resistance (using double-occlusion method). Under resting conditions (Ppa 13.7 +/- 1.6 cmH2O, mean +/- SE), the K+ATP channel agonist BRL 38227 (lemakalim, 10(-7) and 10(-6) M) caused small dose-dependent pulmonary vasodilation. This response was diminished by the K+ATP-channel blocker glibenclamide (10(-5) M). Pretreatment of lungs with indomethacin (10(-5) M) and N omega-nitro-L-arginine (10(-5) M) to inhibit cyclooxygenase- and nitric oxide (NO)-related vasodilation, respectively, resulted in a marked increase in the baseline Ppa to 85.6 +/- 11.2 cmH2O. Injection of BRL 38227 (10(-7) M and 10(-6) M) in these lungs decreased Ppa to 72.5 +/- 8.5 (P < 0.01) and 19.3 +/- 0.9 cmH2O (P < 0.01), respectively; the corresponding times for half-recovery of Ppa (t1/2R) were 5.7 +/- 4.3 and > 20 min. Glibenclamide (10(-5) M) abolished the response to 10(-7) M BRL 38227 and significantly diminished (P < 0.05) the decreases in Ppa and t1/2R in response to 10(-6) M BRL 38227 but not to acetylcholine (10(-10) M). We conclude that activation of K+ATP channels has a minimal role in maintaining basal pulmonary vasomotor tone but is able to induce marked vasodilation when NO and cyclooxygenase-dependent vasodilatory mechanisms are inhibited.

Analysis of the structure of the muscular pulmonary arteries in patients with pulmonary hypertension and COPD: National Institutes of Health nocturnal oxygen therapy trial.

We examined the cardiovascular function as well as the structure of the muscular pulmonary arteries in patients who had died while enrolled in the National Institutes of Health nocturnal oxygen therapy trial (NOTT). The cardiovascular function of the patients classified into groups based on the severity of the pulmonary hypertension was examined, and we compared the morphologic data in these groups to those obtained from age-matched controls who died with no evidence of cardiovascular disease. The groups with severe pulmonary hypertension had markedly increased pulmonary vascular resistance but similar cardiac index to the group with only mild hypertension. In the structural analyses, we found definite alterations in arterial structure from the control population: the patients who had pulmonary hypertension had markedly increased percentages of intima and media. These differences were most pronounced in the medium and larger muscular arteries. The degree of pulmonary hypertension did not appear to alter vascular structure consistently, although there was a trend towards an increase in muscle media in the smaller vessels. When the patients were classified into a group who responded to oxygen administration by a decrease in Ppa, and an age- and Ppa-matched group who did not respond, there were no differences in vascular structure between these groups, although both groups had greater percentages of intima and media compared to the control group. We conclude that, in patients with pulmonary hypertension secondary to chronic obstructive pulmonary disease (COPD), there are structural alterations of the muscular pulmonary arteries, but these do not correlate with either the severity of the pulmonary hypertension or the ability of the pulmonary vasculature to respond to oxygen administration.

Effect of hydralazine on vascular mechanics in a canine lobar preparation of pulmonary embolism

We studied the effect of hydralazine (H) on pulmonary vascular mechanics in an isolated, in situ, canine lobe model of normal and increased pulmonary vascular resistance (Rp) produced by Gelfoam embolization (GE). Pulmonary pressure-flow (P-Q) curves from 24 lobes were obtained at baseline and after each intervention. Hemodynamic parameters for analysis included: the mean critical closing pressure (Ppai), vascular conductance (1/Rp), lobar flow (QL), and the pulmonary inflow pressure (Ppa) at different levels (50, 100, 200, 400, and 600 ml/min) of a fixed flow. After the preparation was stabilized, the 24 lobes were classified into 2 groups. For group 1 (n = 8) we studied the effect of H on the normal pulmonary vasculature. In group 2 (n = 16) we studied the effect of GE. Following GE, this group was further divided in half. For group 2A (n = 8) we followed the natural history of GE with measurements at 15 and 60 min. For group 2B (n = 8) measurements were done 15 min after GE and repeated again 15 min after the infusion of H. For group 1 lobes, H promoted a significant decrease (p less than 0.001) in Ppa at fixed flows of 200, 400, and 600 ml/min compared to baseline, with no change in Ppa for flows below 100 ml/min. QL and 1/Rp increased (p less than 0.01), and there was not any significant change in Ppai. In group 2A lobes, GE produced an increase in Ppa at all levels of flow (p less than 0.01), QL and 1/Rp decreased (p less than 0.05), and there was an increase in Ppai (p less than 0.05). These changes remained stable over the 60 min of observation. For group 2B lobes, GE produced the same hemodynamic changes as in group 2A, and the infusion of H caused a decrease in Ppa at flows between 100 and 300 ml/min. (p less than 0.01) with no change in Ppa at flows below 100 ml/min. QL and 1/Rp increased (p less than 0.01) and Ppai did not change compared to 15 min after GE. We conclude that in the normal canine pulmonary vasculature as well as in the model of GE, H decreased Rp and did not affect mean critical closing pressure, all of which may be explained by an increase in vascular conductance due to an increase in vascular distensibility.

Developmental changes in vascular responses to histamine in normoxic and hypoxic lamb lungs

This study of newborn (3-10 day old) and juvenile (6-8 mo old) in situ isolated lamb lungs was undertaken to determine whether 1) histamine receptor blockade accentuates hypoxic pulmonary vasoconstriction more in newborns than in juveniles, 2) histamine infusion causes a decrease in both normoxic pulmonary vascular resistance and hypoxic pulmonary vasoconstriction in newborns, and 3) the H1-mediated dilator response to infused histamine in newborns is due to enhanced dilator prostaglandin release. Pulmonary arterial pressure (Ppa) was determined at baseline and in response to histamine (infusion rates of 0.1-10.0 micrograms.kg-1 min-1) in control, H1-blocked, H2-blocked, combined H1- and H2-blocked, and cyclooxygenase-inhibited H2-blocked lungs under "normoxic" (inspired O2 fraction 0.28) and hypoxic (inspired O2 fraction 0.04) conditions. In newborns, H1-receptor blockade markedly accentuated baseline hypoxic Ppa, and H2-receptor blockade caused an increase in baseline normoxic Ppa. In juveniles, neither H1 nor H2 blockade altered baseline normoxic or hypoxic Ppa. Histamine infusion caused both H1- and H2-mediated decreases in Ppa in normoxic and hypoxic newborn lungs. In juvenile lungs, histamine infusion also caused H2-mediated decreases in Ppa during both normoxia and hypoxia. During normoxia, histamine infusion caused an H1-mediated increase in normoxic Ppa in juveniles as previously seen in mature animals; however, during hypoxia there was an H1-mediated decrease in Ppa at low doses of histamine followed by an increase in Ppa. Combined histamine-receptor blockade markedly reduced both dilator and pressor responses to histamine infusion. Indomethacin failed to alter the H1-mediated dilator response to histamine in newborns.(ABSTRACT TRUNCATED AT 250 WORDS)

Continuous, low dose of hydralazine, reduces acute hypoxic pulmonary hypertension without a corresponding fall in systemic arterial pressure.

Administration of hydralazine in patients with pulmonary hypertension has been reported to cause excessive systemic vasodilatation, limiting its clinical utility (N Engl J Med 1982; 306: 1326). We studied the effects of hydralazine on hypoxic pulmonary vasoconstriction (HPV) in chronically instrumented sheep and evaluated whether different methods of intravenous administration could prevent severe systemic hypotension. Mean left atrial, pulmonary and systemic arterial pressures (Pla, Ppa and Psa mmHg), cardiac output (CO, l/min, electromagnetic flowmeter) and heart rate were measured continuously. Systemic (SVR) and pulmonary vascular resistances (PVR) were calculated by Psa/CO and (Ppa-Pla)/CO, respectively. Following a 30 min baseline period, we initiated hypoxia with mixture of 10% oxygen in nitrogen. After 20 min of hypoxia we then performed the following two experiments: Group A-Hydralazine (10 micrograms/kg/min) was infused continuously for a further 20 min of hypoxia (n = 6); Group B-Hydralazine (400 micrograms/kg) was administered as a single bolus, followed by an additional 20 min of hypoxia (n = 6). In both Groups A and B, hypoxia produced a prominent pulmonary hypertensive response. Continuous infusion of hydralazine (Group A) significantly decreased the hypoxic values of Ppa and PVR from 25.1 +/- 1.1 to 21.7 +/- 1.6 mmHg (p less than 0.01) and from 4.82 +/- 0.50 to 4.17 +/- 0.40 mmHg/l/min (p less than 0.05), respectively. In Group B, hydralazine as a bolus also significantly decreased HPV, with Ppa dropping from 20.9 +/- 0.9 to 18.3 +/- 1.5 mmHg (p less than 0.05) and PVR falling from 4.98 +/- 0.55 to 4.34 +/- 0.53 mmHg/l/min (p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)