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Hemodynamic effects in pulmonary circulation were measured in three young patients having proved fat embolism following trauma. The increase of pulmonary artery pressure, even in the early phase, was typical. The direction of the therapy to normalise the hemodynamic changes was the most important part of the therapeutic management.
During fetal life and the transition to extra-uterine air breathing, pulmonary vascular tone is regulated by a complex, interactive group of mechanisms. Arachidonic acid metabolites play an important role in this regulation. Although prostaglandins may not be central to regulation of the resting fetal pulmonary circulation, PGI2 acts to modulate tone and thereby maintain pulmonary vascular resistance relatively constant. PGI2 also may play an important role as one of the components involved in the major changes that occur with the onset of air breathing. Leukotrienes, also metabolites of arachidonic acid and potent smooth muscle constrictors, may play an active role in maintaining the normally high fetal pulmonary vascular resistance, because leukotriene receptor blockade or synthesis inhibition increases pulmonary blood flow about eight-fold; the presence of leukotrienes in fetal tracheal fluid further supports this. In addition to PGI2, vascular endothelial cells produce other vasoactive factors. These include potent vasodilators, such as endothelium-derived relaxing factor (EDRF). EDRF, known to be nitric oxide (NO) and often called endothelium-derived nitric oxide (EDNO), is produced by endothelial cells in response to varied stimuli, generally involving specific receptors and the activation of endothelial NO synthetase (eNOS); subsequent smooth muscle relaxation is produced by a NO/guanylyl cyclase/cGMP-mediated mechanism. NO clearly is involved in regulation of vascular tone in the fetal pulmonary circulation, although it plays a far more important role in the postnatal transition to air breathing. Superfused fetal sheep pulmonary arteries release NO when stimulated with bradykinin. In fetal lambs the vasodilating effects of bradykinin are attenuated by methylene blue and resting tone falls with N(omega)-nitro-L-arginine, an inhibitor of NO synthesis, suggesting that a NO/cGMP-dependent mechanism continuously modulates or offsets the increased tone of the resting fetal pulmonary circulation. Inhibition of NO synthesis blocks the pulmonary vasodilation with oxygenation of fetal lungs in utero. Shear stress-induced NO production as well as the relationship of oxygenation to NO production further support the important function of NO in the transition. Although endothelin-1 (ET-1) has potent vasoactivity as well as ontogenetic differences in effect on pulmonary vascular resistance, its exact physiological role has not been defined. Adrenomedullin and calcitonin gene-related peptide (CGRP), two additional vasoactive substances, have profound, and prolonged, vasodilating effects in the fetal pulmonary circulation. Their physiological roles have not yet been established.
The aim of this review is to outline the characteristics of pulmonary circulation in health and disease and to define the value of exhaled NO (eNO) as a means to assess the involvement of pulmonary circulation in pathology. The discovery of the endocrine role of the endothelium has generated great interest in its potential role in regulating the vascular tone of the pulmonary vascular bed. Nitric oxide (NO)-mediated, endothelium-dependent relaxation has been demonstrated in the pulmonary arteries of animals and humans. Changes in the NO pathway in pulmonary hypertension are not completely understood. It is clear that NO has an important role in modulating the response to acute hypoxia, increased flow, and shear stress. The amount of exhaled NO (eNO) in different species may be easily measured, reflecting the overall NO metabolism from the lung (thus including epithelial, endothelial and other cell activity). The development of pulmonary hypertension secondary to systemic (systemic sclerosis, chronic heart failure) or pulmonary (COPD) diseases appears to be associated with a decrease in eNO production both at rest and during exercise. Chronic inhalation of NO appears to protect against pulmonary hypertension in animal models. Exhaled NO is attracting interest for its in vivo ability to represent the features of pulmonary circulation in pathology.
Substantial removal of the vasoconstrictor peptide endothelin-1 (ET-1) by the pulmonary circulation has been reported to occur in perfused guinea pig and rat lungs. We examined the uptake of ET-1 by coronary and pulmonary circulations of the rabbit by measuring single-pass extraction of ET-1 in the isolated heart and lung. In separate experiments, each organ was perfused at 30 ml/min with Krebs-albumin (3%) solution. A bolus of 125I-ET-1 and [14C]dextran in 0.3 ml Krebs-albumin solution was injected, and extraction of endothelin (EET), relative to that of an intravascular reference indicator, [14C]dextran, was determined by multiple indicator-dilution technique. EET was 5 +/- 2% (SE) in the heart and 49 +/- 4% in the lung. Increasing flow rate in the lung preparation to approximate the mean transit time in the heart preparation did not significantly alter EET. Despite insignificant uptake of ET-1, the coronary circulation extracted an angiotensin-converting enzyme inhibitor (351A) and metabolized a synthetic angiotensin-converting enzyme substrate (benzoyl-phenyl-alanyl-proline), both properties of the normal pulmonary circulation. We therefore conclude that there is no significant ET-1 uptake in the coronary vascular bed.
An effect of isosorbide dinitrate on blood pressure values in the pulmonary circulation and the right heart has been investigated in 25 patients with a history of the first transmural myocardial infarction. Group I including 12 patients has been given 5 mg isosorbide nitrate in a 60-minute intravenous infusion while group II of 13 patients has been given 10 mg of the drug in the same way. Both groups have been matched in clinical data and blood pressure value in the pulmonary circulation which has been normal. Pulmonary blood pressure has been measured with Swan-Ganz catheter prior to the administration of drug, and 15, 30, 45 and 60 minutes following an infusion. Isosorbide dinitrate in a dose of 5 mg did not decrease blood pressure in the pulmonary circulation statistically significantly. The differences in blood pressure falls did exceed 9%. Filling pressure in the right ventricle did not change either while systolic blood pressure decrease by 16.6%. A double dose of isosorbide dinitrate reduced blood pressure in the pulmonary artery by about 1/3 of the baseline value, and blood pressure in the right ventricle (mean right atrial pressure) by 57.2%. Both systolic and diastolic arterial pressures were reduced. Isosorbide dinitrate reduced blood pressure in the pulmonary circulation in patients who underwent myocardial infarction, and hypotensive effect has been dose-related. A reduction in the right ventricular filling pressure has been a one of important mechanisms decreasing pulmonary pressures.
Pulmonary circulation was evaluated in normal subjects and in post-embolic patients. Eight normal subjects, 3 patients with acute pulmonary embolism and 8 patients with chronic thromboembolic pulmonary hypertension underwent CT of the chest. High-resolution CT and angio-CT were performed to study pulmonary parenchyma and pulmonary arteries, respectively. CT showed thrombi in the main or interlobar pulmonary arteries in all 3 cases of acute pulmonary embolism and in 4 of 8 patients affected with chronic thromboembolic pulmonary hypertension. The diameters of the main pulmonary and right interlobar arteries correlated with systolic pulmonary artery pressure (p < 0.001), as measured by right heart catheterization. In the patients affected with chronic thromboembolic pulmonary hypertension, the ratio of the calibers of the segmental arteries to the corresponding bronchi was markedly higher, which was observed also in the patients with acute pulmonary embolism. The bronchial arteries were dilated in 4 of 8 cases of chronic thromboembolic pulmonary hypertension. Lung density was significantly high in the perihilar compartment in the patients with acute thromboembolic hypertension, but not in normal controls and in the cases of acute pulmonary embolism. In conclusion, CT can help to diagnose pathological pulmonary circulation. Particularly, the ratio of the diameters of the segmental arteries to the corresponding bronchi can be useful to evaluate blood circulation.
The authors suggested that a mammal immediately accommodates well to nonpulsatile flow in the systemic circulation. In the current study, nonpulsatile pulmonary blood flow using a centrifugal pump was established in chronic models to analyze its influence on the pulmonary circulation. A pulsatile right ventricular assist device (RVAD) was implanted to draw blood from both the right atrium and ventricle and send blood to the pulmonary artery in six goats. After 2 weeks, the pulsatile pump was quickly replaced with a centrifugal pump without anesthesia, and a 100% non-pulsatile pulmonary blood flow was obtained. Cardiac output was kept at 80-120 ml/kg/min during the experiments. No changes were observed in hemodynamic parameters, including pulmonary arterial pressure, pulmonary vascular resistance index, and blood gas data, after the immediate depulsation of the pulmonary blood flow. There was also no significant change in the ventral to dorsal tissue blood flow ratio of the lower lobe of the right lung, which was calculated by a colored microsphere method, between pulsatile and non-pulsatile pulmonary blood perfusion. These results suggest that pulmonary function, including blood flow distribution, is not affected by non-pulsatile pulmonary circulation for periods up to 14 days.
Study of the structural features of the pulmonary circulation in various types of congenital heart disease makes it possible to correlate function and structure in the fetal and newborn lung. We applied quantitative morphometric techniques to the injected and inflated lungs of newborn infants who had died with obstruction to left ventricular outflow from aortic atresia, stenosis, or coarctation. The structure and development of the pulmonary circulation was judged by the number of arteries and veins and their size and wall structure, with particular attention to vessels within the respiratory unit. The study established for the first time that the structure of the pulmonary circulation is modified by the antenatal abnormalities in blood flow that occur through the heart and great vessels in the presence of congenital heart disease. Fetal multiplication of intra-acinar arteries in aortic atresia and stenosis is increased as also is the muscularity of both pre- and intra-acinar arteries and veins, muscle extending into smaller and more peripheral vessels than is normal at birth. When the pulmonary circulation is normal before birth but arterial pressure and flow are abnormally increased at birth, as in coarctation with patent ductus and ventricular septal defect, an increase in arterial diameter and muscularity is apparent within the first week of life.
Lung hypoplasia (LH) is a serious cause of neonatal compromise, but little is known of its functional effects on the pulmonary circulation. Our aim was to characterize birth-related changes in the pulmonary circulation of newborn lambs with LH and to compare them with alterations in respiratory function. LH was induced in six ovine fetuses by the creation of a tracheo-amniotic shunt as well as amniotic fluid drainage starting at 105.6+/-1.5 (mean+/-SEM) days of gestation (term approximately 147 d). At 139.9+/-0.3 d, fetuses were exteriorized under anesthesia to implant vascular catheters and an ultrasonic flow probe around the left pulmonary artery. The lambs then were delivered and ventilated for 2 h, during which systemic and pulmonary artery pressures, left pulmonary blood flow, and measures of respiratory function were recorded. At autopsy, lungs were weighed and volume was measured at 20 cm H2O. In LH lambs, lung weight was 25% lower and respiratory system compliance was 30% lower than in controls. Mean pulmonary blood flow in LH lambs was 42% lower and pulmonary vascular resistance was 138% higher than in controls. Morphometry showed that volume density of pulmonary arteries in LH was 30% lower than in controls. We conclude that, in this LH model, changes in ventilatory indices were proportional to the change in lung size, whereas changes in the pulmonary circulation were greater than the change in lung size and were associated with reduced density of pulmonary arteries. LH severely impairs normal adaptation of the pulmonary circulation in the perinatal period.
OBJECTIVE: The aim of this study was to assess the effect of 4-aminopyridine, a Kv channel inhibitor, on the pulmonary circulation of Tibetan sheep. It has been reported that chronic hypoxia downregulates the 4-aminopyridine (4AP)-sensitive Kv channel (which governs the membrane potential (Em) of pulmonary vascular smooth muscle cells in pulmonary vessels) without a change in 4AP sensitivity. METHODOLOGY: Pulmonary haemodynamic indices and blood gas analyses were measured in six young male animals in an altitude chamber that was adjusted to simulated altitudes of 0 m, 2260 m, and 4500 m. Drip infusion of 4AP, 10 mg/h for 3 h, was started and continued during the study. RESULTS: With the increase in altitude mean pulmonary artery pressure increased and mean PaO(2) decreased. 4AP had no effect on the levels of mean PPA, mean pulmonary artery wedge pressure, cardiac output, and mean PaO(2), mean PaCO(2), and mean pH at any altitude but tended to alter heart rate and mean arterial pressure at altitudes of 2260 m and 4500 m. CONCLUSION: It is concluded that the 4AP-sensitive Kv channel does not play a role in pulmonary vascular tone in high-altitude active Tibetan sheep. Their pulmonary vascular oxygen sensing appears not to involve Kv channels.
A comprehensive radionuclide study of pulmonary circulation disorders in 55 children with acute pyo-destructive pneumonia (at the age of 1 month to 13 years) revealed the degree of vascular network reduction, pulmonary regional specific activity and changes in the time of the blood flow in the pulmonary circulation microcirculatory channel. These indices of disturbed pulmonary hemodynamics in combination with the results of total perfusion deficiency can serve as diagnostic markers of pulmonary circulation pathology and define a tendency to the generalization of a pyo-destructive process or enhancement of the blood flow of compensatory nature as well as prognosis of a course of disease.
Assessment of the fluid mechanics of the pulmonary circulation has been hindered by the relative inaccessibility of the pulmonary vascular bed. Current understanding is based largely on analyses of mathematical models which have been used to simulate hemodynamic characteristics within an architectural representation of that bed. These representations have ranged from simple, lumped parameter structures to anatomically realistic structures based on measurements of casts of the irregular branching network of pulmonary arteries and veins. Nonlinear models have been studied to determine the effects of vessel taper and within beat geometrical variations as cross-sectional shapes change from circular to elliptical and small vessels undergo recruitment, distention, and collapse as a result of the shifting balance in alveolar, pleural, and capillary pressures. This article reviews current concepts of pulmonary circulatory fluid mechanics focusing on mathematical models and relevant hemodynamic studies.
The effects of dopamine, (+/-)-dobutamine (racemic mixture) and (-)-dobutamine on alpha-adrenoceptor-mediated vasoconstriction were evaluated in the pulmonary circulation of the anesthetized dog. The drugs were studied in the absence and presence of propranolol (1 mg/kg, i.v.) in order to assess beta-adrenoceptor-mediated effects in the pulmonary circulation. Intra-arterial administration of dopamine, (+/-)-dobutamine and (-)-dobutamine elicited dose-dependent increases in pulmonary perfusion pressure, reflecting increases in pulmonary vascular resistance. In control animals, dopamine elicited the largest increases in pulmonary perfusion pressure (45% above resting pulmonary pressure) followed by (-)-dobutamine (30% increase) and (+/-)-dobutamine (15% increase). The pressor effects of dopamine in the pulmonary circulation were mediated by both postjunctional vascular alpha 1- and alpha 2-adrenoceptors, since prazosin, (100 micrograms/kg, i.v.), a selective alpha 1-adrenoceptor antagonist, and rauwolscine (100 micrograms/kg, i.v.), a selective alpha 2-adrenoceptor antagonist, both inhibited the vasopressor response elicited by dopamine to roughly equivalent degrees. Pulmonary vasoconstriction produced by (+/-)-dobutamine and (-)-dobutamine was mediated primarily by postsynaptic vascular alpha 1-adrenoceptors, although alpha 2-adrenoceptor-mediated vasoconstriction was observed. In propranolol-pretreated animals, the increase in pulmonary perfusion pressure elicited by dopamine and (-)-dobutamine was qualitatively and quantitatively similar to that observed in control animals, suggesting that these agents have little activity on vascular beta 2-adrenoceptors in the pulmonary circulation. In marked contrast, the maximum pulmonary vasopressor response obtained with (+/-)-dobutamine were greater in propranolol-pretreated animals, indicating that (+/-)-dobutamine also has the capacity to stimulate pulmonary vascular beta 2-adrenoceptors which mediate pulmonary vasodilation that, in part, mask alpha-adrenoceptor-mediated pulmonary vasoconstriction. Since the (-)-enantiomer of dobutamine has little or no beta 2-adrenoceptor agonist activity, the beta 2-adrenoceptor-mediated effect of (+/-)-dobutamine must result from the (+)-enantiomer as has been previously proposed. The results of the present study indicate that dopamine has a greater propensity for increasing pulmonary vascular resistance, and therefore pulmonary arterial blood pressure, relative to (+/-)-dobutamine. This results, at least in part, from the relatively weaker activity of dopamine in stimulating pulmonary vascular beta 2-adrenoceptors which mediate vasodilation.(ABSTRACT TRUNCATED AT 400 WORDS)
Nitric oxide plays an important role in modulating pulmonary vascular tone. All three isoforms of nitric oxide synthase (NOS), neuronal (nNOS, NOS I), inducible (iNOS, NOS II), and endothelial (eNOS, NOS III), are expressed in the lung. Recent reports have suggested an important role for eNOS in the modulation of pulmonary vascular tone chronically; however, the relative contribution of the three isoforms to acute modulation of pulmonary vascular tone is uncertain. We therefore tested the effect of targeted disruption of each isoform on pulmonary vascular reactivity in transgenic mice. Isolated perfused mouse lungs were used to evaluate the effect of selective loss of pulmonary nNOS, iNOS, and eNOS with respect to hypoxic pulmonary vasoconstriction (HPV) and endothelium-dependent and -independent vasodilation. eNOS null mice had augmented HPV (225 +/- 65% control, P < 0.02, mean +/- SE) and absent endothelium-dependent vasodilation, whereas endothelium-independent vasodilation was preserved. HPV was minimally elevated in iNOS null mice and normal in nNOS null mice. Both nNOS and iNOS null mice had normal endothelium-dependent vasodilation. In wild-type lungs, nonselective NOS inhibition doubled HPV, whereas selective iNOS inhibition had no detectable effect. In intact, lightly sedated mice, right ventricular systolic pressure was elevated in eNOS-deficient (42.3 +/- 1.2 mmHg, P < 0.001) and, to a lesser extent, in iNOS-deficient (37.2 +/- 0.8 mmHg, P < 0.001) mice, whereas it was normal in nNOS-deficient mice (30.9 +/- 0.7 mmHg, P = not significant) compared with wild-type controls (31.3 +/- 0.7 mmHg). We conclude that in the normal murine pulmonary circulation 1) nNOS does not modulate tone, 2) eNOS-derived nitric oxide is the principle mediator of endothelium-dependent vasodilation in the pulmonary circulation, and 3) both eNOS and iNOS play a role in modulating basal tone chronically.
Twenty persons living at an altitude of 2,240 meters were studied in order to examine the relative roles of passive and active factors in the genesis of pulmonary arterial hypertension in obesity (overweight, 75 +/- 39 percent). Pulmonary arterial hypertension was present in 80 percent (16) of the patients (mean pulmonary arterial systolic pressure, 45 +/- 17 mm Hg). In 95 percent (19) of the 20 patients, resistance to pulmonary flow at the end of diastole was increased (estimated mean pulmonary arteriolar resistance, 210 +/- 144 dynes.sec.cm-5; mean pulmonary arterial diastolic-pulmonary wedge pressure gradient 7.86 +/- 1.40 mm Hg). The mean arterial oxygen pressure was 50 +/- 9 mm Hg, the arterial carbon dioxide tension was 37 +/- 6 mm Hg and the arterial pH was 7.42 +/- 0.08. Since the pulmonary arterial systolic pressure has been reasonably predicted (r = 0.91; P < 0.001), it would appear that the compliance of the elastic pulmonary arteries in obese patients follows a normal pattern. The behavior of the right ventricular end-diastolic pressure at rest (mean change, 4.6 mm Hg; P < 0.001) and of the pulmonary wedge pressure (mean change, 4.7 mm Hg; P < 0.001) during passive lifting of the legs was indirect evidence of the increase in pulmonary blood volume. The presence of an abnormal resistance to pulmonary blood flow at the end of diastole is suggestive of a decrease in the distention of the pulmonary microcirculation. The pulmonary arterial diastolic-pulmonary wedge pressure gradient and the pulmonary arterial diastolic pressure were related to arterial oxygen unsaturation (r = 0.70; P < 0.05) but not to the concentration of hydrogen ions; thus hypercapnic acidemia appears as a secondary factor in the genesis of pulmonary arterial hypertension at high atitudes. The explanation could be the relative hyperventilation of high altitudes, with a compensatory metabolic alkalosis. The increased pulmonary blood volume and the alveolar hypoxia are the main causes in the pathogenesis of pulmonary arterial hypertension in the grossly obese patient at this altitude.
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The direct effects on the pulmonary circulation of static and fluctuation airway pressure were compared in intact close-chest infant lambs with reactive pulmonary vasculature under alpha-chloralose anesthesia. A preparation developed to permit independent ventilation of right and left lungs and independent measurement of right and left lung blood flow was employed to separate direct from indirect effects of unilateral airway pressure changes on pulmonary vascular resistance (PVR). Both static and fluctuating unilateral airway pressure interventions directly elevated ipsilateral PVR. For purposes of comparison mean alveolar pressure (PA) was estimated for both static and fluctuating trials. Fluctuating interventions increased PVR more than did static trials at comparable levels of PA. Substantially less PA was needed to double ipsilateral PVR by fluctuating than by static interventions (16 vs. 26 mmHg, respectively). These data indicate that, in the intact animal with reactive pulmonary vasculature, both PA and the waveform of airway pressure applied can influence PVR.