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Nitric oxide (NO) is important in modulating increased pulmonary vascular tone. Whereas in other systems it is believed that the action of NO is mediated through guanosine 3',5'-cyclic monophosphate (cGMP) and protein kinase G (PKG), the validity of this pathway in the pulmonary circulation has not been established. Using isolated salt-perfused normotensive and hypertensive rat lungs, we studied the effects of the soluble guanylyl cyclase inhibitor, 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), and the PKG inhibitors, KT5823, Rp-8-pCPT-cGMPS, and (N-[2-(methylamino)ethyl]-5-isoquinolinesulfonamide) (H-8), on pulmonary vascular resistance. In isolated normotensive lungs, ODQ-mediated inhibition of soluble guanylyl cyclase augmented hypoxic pulmonary vasoconstriction, whereas the PKG inhibitors had no effect. Despite the marked differences in the physiological effect, ODQ and Rp-8-pCPT-cGMPS inhibited PKG activity to a similar degree as determined by a back-phosphorylation assay showing decreased PKG-mediated phosphorylation of serine 1755 on the D-myo-inositol 1,4,5-trisphosphate receptor. In hypertensive lungs, inhibition of soluble guanylyl cyclase by ODQ increased perfusion pressure by 101 +/- 20% (P < 0.05), an increase similar to that seen with inhibition of NO synthase (NOS), confirming an essential role for cGMP. In contrast, KT5823, Rp-8-pCPT-cGMPS, and H-8 (used in doses 5- to 100-fold in excess of their reported inhibitory concentrations for PKG) caused only a small increase in baseline perfusion pressure (14 +/- 2%, P = not significant from vehicle control). Effectiveness of PKG inhibition in the hypertensive lungs was also confirmed with the back-phosphorylation assay. These studies suggest that whereas NO-mediated modulation of vascular tone in the normotensive and hypertensive pulmonary circulation is dependent on cGMP formation, activation of PKG may not be essential.
Although gene delivery to the pulmonary circulation has both experimental and therapeutic potential, the delivery methods, distribution of transgene, and subsequent inflammatory response have been poorly characterized to date. To address these issues, we utilized a 0.76-mm OD (outside diameter) end hole catheter inserted into the internal jugular vein of adult Sprague-Dawley rats, directing the tip into a pulmonary capillary wedge position. We then compared infusion of polycationic lipid:DNA complexes to replication-defective adenovirus with respect to magnitude and distribution of transgene expression using either chloramphenicol acetyltransferase (CAT) or human placental alkaline phosphatase (hpAP) reporter genes. Both lipid:DNA and adenovirus resulted in detectable transgene expression, though maximum lung CAT activity using lipid (gamma AP-DLRIE/DOPE) was approximately 2% of maximum activity using adenovirus (Ad-CAT). Further characterization of expression after transfection with 10(8) pfu (plaque forming units) of Ad-CAT demonstrated persistence of transgene for at least 14 days (lung CAT activity 27% of maximum). Alkaline phosphatase staining demonstrated that both large and small pulmonary arteries as well as the alveolar wall expressed transgene. Although little inflammatory response was detected in conduit arteries, a predominantly mononuclear cell infiltrate surrounded small pulmonary arteries as well as the alveolar spaces in transfected areas of lung. We conclude that percutaneous catheter-mediated gene delivery to the pulmonary circulation in rats using non-viral and viral vectors is feasible. Although an inflammatory response to first generation replication-defective adenovirus was detected, it appeared to be largely restricted to the distal pulmonary circulation and airspace. This technique should prove useful for investigations requiring overexpression of novel genes in the pulmonary artery wall, and could ultimately be used to develop gene-based therapies for pulmonary vascular diseases.
Pulmonary human vasomotor effects of purine nucleotides are unknown. We compared hemodynamic and gasometric effects of ATP vs ADO, using equimolar infusion rate, on 18 chronically hypoxemic COPD patients. ATP infusion (1 and 2 micro Mole per kilo over 20 min) induced pulmonary vasodilation, with a significant decrease of Ppa (-14% -p = 0.025), PVR (-26.6% p = 0.05) and PaO2 (-10.9% p = 0.025). No change was observed when ADO and control solvent were infused. The pulmonary vasodilator effect of infused ATP on COPD patients, seems to be independent of circulating ADO.
OBJECTIVE: To study the hemodynamic changes of pulmonary circulation during simulated weightlessness. METHOD: 12 subjects were studied using echocardiography and electrocardiography during head-down tilt (HDT) of -30 degrees lasting for 45 min. RESULT: Right ventricular ejection time increased significantly (P<0.05); peak velocity of pulmonary arterial blood flow decreased significantly (P<0.05); acceleration time of pulmonary arterial blood flow did not change significantly; significant decrease of right ventricular output occurred at the 10th minute and the 30th minute (P<0.05); pre-ejection period significantly decreased at the 30th minute and recovery. Heart rate, mean velocity of pulmonary arterial blood flow, and acceleration of pulmonary arterial blood flow did not change significantly; left ventricular cardiac output, stroke volume and blood pressure remained constant throughout the experiment. CONCLUSION: Changes of the parameters of pulmonary circulation suggested that pulmonary resistance increased, and the increase of pulmonary resistance maybe be the direct cause of the increase of pulmonary arterial pressure.
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BACKGROUND: The aims of the present study were to determine whether maternal hyperoxygenation affects human fetal pulmonary circulation and whether there is a gestational age-related response in the fetal pulmonary circulation to maternal hyperoxygenation during the second half of gestation. METHODS AND RESULTS: Twenty women between 20 and 26 weeks of gestation and 20 women between 31 and 36 weeks of gestation with normal singleton pregnancies were randomized to receive either 60% humidified oxygen or medical compressed air (room air) by a face mask. Fetal aortic and pulmonary valve; ductus arteriosus (DA); and right (RPA), left (LPA), and distal (DPA) pulmonary artery blood velocity waveforms were obtained by Doppler ultrasound before, during, and after maternal administration of either 60% oxygen or room air. Left and right ventricular cardiac outputs, DA volume blood flow, and RPA and LPA volume blood flows (Qp) were calculated. Foramen ovale volume blood flow (left ventricular cardiac output-Qp) was estimated. Pulsatility index (PI) values of DA, RPA, LPA, and DPA were calculated. Maternal hyperoxygenation did not change any of the measured fetal parameters between 20 and 26 weeks, whereas between 31 and 36 weeks, the PI values of RPA, LPA, and DPA decreased (P<.0001) and the PI of DA increased (P<.0001). In addition, Qp increased (P<.001), and DA volume blood flow (P<.01) and foramen ovale volume blood flow (P<.03) decreased. Left and right ventricular cardiac outputs were unchanged. All changes returned to baseline after maternal hyperoxygenation was discontinued. CONCLUSIONS: Reactivity of the human fetal pulmonary circulation to maternal hyperoxygenation increases with advancing gestation; this suggests that fetal pulmonary circulation is under acquired vasoconstriction at least after 31 to 36 weeks of gestation.
Vascular resistance in the mammalian pulmonary circulation is affected by many endogenous agents that influence vascular smooth muscle, right ventricular myocardium, endothelial function, collagen and elastin deposition, and fluid balance. When the balance of these agents is disturbed, e.g. by airway hypoxia from high altitude or pulmonary obstructive disorders, pulmonary hypertension ensues, as characterized by elevated pulmonary artery pressure (P(PA)). Among neuropeptides with local pulmonary artery pressor effects are endothelin-1 (ET-1), angiotensin II (AII), and substance P, and among mitigating peptides are calcitonin gene-related peptide (CGRP), adrenomedullin (ADM), atrial natriuretic peptide (ANP), vasoactive intestinal peptide (VIP) and ET-3. Moreover, somatostatin28 (SOM28) exacerbates, whereas SOM14 decreases P(PA) in hypoxic rats, with lowering and increasing of lung CGRP levels, respectively. Pressure can also be modulated by increasing or decreasing plasma volume (VIP and ANP, respectively), or by induction or suppression of vascular tissue remodeling (ET-1 and CGRP, respectively). Peptide bioavailability and potency can be regulated through hypoxic up- and down- regulation of synthesis or release, activation by converting enzymes (ACE for AII and ECE for ET-1), inactivation by neutral endopeptidase and proteases, or by interaction with nitric oxide (NO). Moreover, altered receptor density and affinity can account for changed peptide efficacy. For example, upregulation of ET(A) receptors and ET-1 synthesis occurs in the hypoxic lung concomitantly with reduced CGRP release. Also, receptor activity modifying protein 2 (RAMP2) has been shown to confer ADM affinity to the pulmonary calcitonin-receptor-like receptor (CRLR). We recently detected the mRNA encoding for RAMP2, CRLR, and the CGRP receptor RDC-1 in rat lung. The search for an effective, lung selective treatment of pulmonary hypertension will likely benefit from exploring the imbalance and restoring the balance between these native modulators of intrapulmonary pressure. For example, blocking of the ET-1 receptor ET(A) and vasodilation by supplemental CGRP delivered i. v. or via airway gene transfer, have proven to be useful experimentally.
Drugs with pharmacological activity limited to the pulmonary circulation are not at present available. Serotonin antagonists, specific thromboxane A2 inhibitors and prostacyclin may offer new possibilities for the treatment of certain forms of pulmonary arterial hypertension (PAH), but their clinical efficacy remains to be evaluated. Vasodilators simultaneously influence the pulmonary and systemic vascular resistances, and their overall hemodynamic effects in patients with PAH are therefore unpredictable. Therapeutic trials with such drugs should be closely monitored to avoid serious adverse reactions. Oral administration of beta-adrenergic agents, such as salbutamol or terbutaline, is preferable to digoxin in the treatment of patients with right ventricular failure due to chronic obstructive bronchitis. Right ventricular failure following massive pulmonary embolism may be aggravated by reduced blood flow through the right coronary artery. Increase of aortic perfusion pressure (e.g. noradrenaline) should be considered as a therapeutic measure in patients with arterial hypotension.
Degradation of prostaglandins (PGs) during passage through the human pulmonary circulation was investigated by measuring the transpulmonary plasma PGF2 alpha difference during continuous intravenous infusion of PGF2 alpha (5-10 mug/min). Seven patients with cardiological disorders and two patients with extensive pulmonary abnormalities were investigated during diagnostic cardiac catheterization. PGF2 alpha levels were measured by radioimmunoassay. The seven cardiac patients were found to have transpulmonary PGF2 alpha differences of 47-88%, indicating metabolism of the PG in the lungs. A patient with extensive bronchiectasis had an apparently normal transpulmonary PGF2alpha difference despite gross abnormalities in routine lung function tests. A patient with primary pulmonary arterial hypertension showed no metabolism of PGF2alpha in the pulmonary circulation. The results show that PG degradation is an aspect of normal lung function and suggest that it becomes imparied when extensive pulmonary vascular damage exists.
Effects of nonpulsatile flow on pulmonary circulation was examined experimentally. Tendency to accumulate extravascular lung water as compared with pulsatile flow was of particular interest.
Fluid is transferred cephalad in microgravity and simulated microgravity, and the pulmonary circulation is the first to be affected. Blood and fluid contents in the lungs increase, but unevenly distributed among various zones of the lungs. Blood vessels in the lungs are filled and distend. Capillary changes have been observed in the animal model of simulated microgravity. Studies about the changes of regulative function of pulmonary circulation are relatively rare. Observations of the reactivity of pulmonary vessels may help to understand the mechanisms of the changes in pulmonary circulation during microgravity.
Hereford calves were exposed in a temperature-controlled hypobaric chamber to environmental temperatures of -2 to 1 degree C (cold) at altitudes of 1,524 m (resident altitude) and 3,048 m 1) to characterize the effects of cold exposure on the pulmonary circulation; 2) to examine the role of cold-induced hypoventilation on the pulmonary circulation; and 3) to examine the interaction between cold and hypoxia on the pulmonary circulation. Cold exposure produced a significant increase in pulmonary arterial pressure (Ppa), pulmonary arterial wedge pressure (Ppaw), and pulmonary vascular resistance (PVR) at both 1,524 and 3,048 m without affecting cardiac output. Concomitantly, cold exposure caused reductions in minute ventilation, respiratory rate, end-tidal O2 tension (PETO2), and arterial O2 tension (PaO2). Tidal volume, end-tidal CO2 tension, and arterial CO2 tension increased. Neither arterial pH nor O2 consumption changed during cold exposure. These results indicated that both pulmonary arterial and venous vasoconstriction were responsible for the pulmonary hypertension associated with cold exposure. Acute exposure to 3,048 m during cold exposure produced increases in Ppa and PVR that were similar to those elicited by cold exposure at 1,524. It was concluded that altitude exposure neither attenuated nor potentiated the effect of cold exposure on the pulmonary circulation; rather, altitude and cold exposure interacted additively. O2 administered during cold exposure to restore PETO2 and PaO2 to control values partially restored Ppa and PVR to control values. This suggested that a portion of the pulmonary hypertension associated with cold exposure was due to hypoxic pulmonary vasoconstriction elicited by the cold-induced alveolar hypoventilation.
223 cases with pulmonary tuberculosis sequelae underwent the examinations of arterial blood gases, pulmonary function or right cardiac catheterization. Especially 86 cases were investigated of pulmonary hemodynamics. We discussed about the findings on chest X-ray film--emphysematous change; fibrosis, bronchiectasis, cavity; atelectasis, pneumonectomy; pleural peel; thoracoplasty--in tuberculosis sequelae to influence pulmonary hypertension, about pulmonary hemodynamics, in the past history, with or without right heart failure, about the difference between tuberculosis sequelae and chronic obstructive pulmonary disease (COPD) in pulmonary hemodynamics, and about prognosis in patients with tuberculosis sequelae. The summary of results was as follows: 1. The most influential chest X-ray finding on pulmonary hypertension is pleural peel. 2. In cases without right heart failure in the past, the values of arterial blood gases, pulmonary function and pulmonary hemodynamics were better. The effect of reduction of pulmonary arteriolar resistance was good in cases without right heart failure under the condition of oxygen inhalation. 3. Pulmonary artery mean pressure in tuberculosis sequelae tended to be higher than in COPD under the even conditions of PaO2 and FEV1/prVC%. Nocturnal desaturation was more in tuberculosis sequelae. 4. Prognosis of tuberculosis sequelae was poor in patients with pulmonary hypertension though there was no statistical significance at present. In conclusion, for the early diagnosis and management of pulmonary circulatory disorder in tuberculosis sequelae, we thought it was important to follow the clinical course with special attention to chest X-ray findings, to start oxygen therapy before right heart failure takes place, and to make an effort to extend the indication of home oxygen therapy.
Although the pulmonary blood vessels receive an ample supply of nerves, it has been difficult to prove that these nerves operate in the regulation of the pulmonary circulation. In the present study, using the isolated lobe of the lung perfused in situ, waves in pulmonary arterial pressure were induced and were shown, as in the case of Traube-Hering waves in the systemic circulation, to be nervous in origin.
Parameters of gas exchange and pulmonary circulation were measured in five healthy test subjects during 120-day head-down tilt test and early recovery. During the first half of the bed rest study CO2 tension in arterial blood increased significantly. During the second half of the study oxygen and carbon dioxide tension decreased significantly. The mechanisms of these changes are discussed.
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