Human Pulmonary Circulation Research Articles

BQ123, an ETA Receptor Antagonist, Inhibits Endothelin-1-mediated Proliferation of Human Pulmonary Artery Smooth Muscle Cells

Endothelin (ET-1) has been shown to be co-mitogenic for vascular smooth muscle cells (SMC) from human systemic arteries. A more modest growth-promoting effect has also been described in SMC from the bovine and porcine pulmonary circulation. Whether ET-1 has mitogenic properties in the human pulmonary circulation, and which ET receptor subtype mediates this response, is unknown. We first examined the effects of ET-1, ET-3, and the selective ETB agonist, Sarafotoxin 6c, on human pulmonary artery SMC growth. Cells were harvested from normal lung transplant donors. Growth was assessed by change in cell number 3 days after stimulation of quiescent cells. ET-1 in the presence of 0.3% serum produced a dose-dependent increase (82 +/- 1.5%) in cell number (threshold, 10(-11) M; maximal, 10(-7) M). ET-3 also stimulated growth (36 +/- 3.8%) but was less potent than ET-1 (threshold, 10(-9) M; maximal, 10(-7) M). The ETB selective agonist Sarafotoxin 6c had no proliferative effect. The effects of BQ123, a selective ETA receptor antagonist, on ET-1-induced growth were then assessed. BQ123 inhibited (threshold, 1.5 x 10(-7) M; maximal, 1.5 x 10(-5) M) ET-1-induced growth but had no effect on proliferation stimulated by the non-ET receptor-mediated growth factors, platelet-derived growth factor BB and 5-hydroxytryptamine. These results suggest that ET-1 is a potent co-mitogen for human proximal pulmonary artery SMC and that this effect is transduced by selective activation of the ETA receptor.

A nonlinear fluid model for pulmonary blood circulation

In this paper, we apply a quasi-one-dimensional unsteady nonlinear fluid model to study human pulmonary circulation. Eighteen generations of blood vessels composed of the branching arterial, capillary and venous distensible vessel segments make up the complete pulmonary circulation. The numerical result gives satisfactory agreement with the physiological experimental data: a dramatic pressure drop occurs in the arterioles and postcapillaries, a negative transmural pressure is shown in the postcapillary and small venous segments, a large reverse flow occurs in the main pulmonary artery during the diastolic period, and the reverse flow decreases gradually along the pulmonary tree. In the microgravity case where g = 180 cm s −2, the computation illustrated the effect of gravity force on the blood distribution in the different parts of the pulmonary circulation. The effect of gravity on the total output is not obvious. The effect of local factors which initiate the variations of the geometrical or mechanical parameters of pulmonary circulation can be simulated quantitatively by this model. The proposed model can be very useful for clinical practice and for studying the extreme cases which are very difficult to investigate by experiments.

Endothelium-derived relaxing factors and the human pulmonary circulation

The vasodilator effect of acetylcholine on the pulmonary circulation was first described over 30 years ago, however, the mechanism remained unknown until Furchgott described the endothelium-dependent relaxation of certain vasodilators. It was not until 1987 that endothelium-derived relaxant factor (EDRF) was demonstrated to dilate human pulmonary arteries in vitro. Despite this work, the physiologic role of EDRF in the pulmonary circulation is not known. It has been suggested that hypoxia-induced inhibition of EDRF action or release from pulmonary artery endothelial cells may have a role in hypoxic pulmonary vasoconstriction (HPV) but present evidence suggests that loss of EDRF activity is not directly involved in the phenomenon of HPV. It is more likely that EDRF is released from pulmonary artery endothelial cells during hypoxia and this released EDRF then modulates HPV. If EDRF does modulate HPV in vivo then the role of EDRF in the altered HPV found in disease merits attention. It is known that in disease states such as acute lung injury and pneumonia there is loss or attenuation of HPV which inevitably leads to increased V/Q mismatch and hypoxemia. Whether this attenuation of HPV is due to release of an endogenous vasodilator such as EDRF is presently being investigated. Additionally, there is in vitro evidence that loss of EDRF activity may be important in the genesis of pulmonary hypertension such as found in severe cystic fibrosis. During the next decade the role of EDRF in the human pulmonary circulation in both health and disease will undoubtedly be elucidated.

Neural influences on the human pulmonary circulation as a defence reaction to volume depletion

The role of the automatic nervous system in the regulation of pulmonary vasomotility in man is unsettled and great emphasis is usually given to changes in flow as the main regulating mechanism. In order to simulate hypovolemia, which might reduce the mechanical influence of flow and disclose a neural mechanism, we decreased venous return through balloon distention in the inferior vena cava in 12 normal subjects, during right heart catheterization performed for diagnostic purposes. Caval obstruction was graduated to reduce cardiac output, right atrial and pulmonary arterial pressures, without altering systemic arterial pressure and heart rate. The sympathetic nervous system was activated by arithmetic and cold pressor tests. During the former, the increase in cardiac output was more than halved by venous return restraint, as compared to the unrestrained condition, and clear pulmonary vasoconstriction, instead of vasodilatation, was observed. During the cold test, cardiac output remained almost steady, in the absence as in the presence of balloon expansion. In both conditions pulmonary arteriolar resistance rose, but in the latter this increase was more than doubled. This study suggests that the autonomic nervous system is involved in the regulation of pulmonary vasomotility in man, its role being unveiled when the mechanical influence of flow is reduced by mimicking a hypovolemic state.

Unpredictable zero drift in intravascular micromanometer tipped catheters during long term pulmonary artery pressure recording: implications for catheter design.

Zero drift may be a cause of imprecision when micromanometer tipped catheters are used for intravascular pressure measurement over long periods of time. Drift of only a few mm Hg may represent a significant error when accurate recording of low vascular pressures is required. To overcome this problem a micromanometer tipped catheter has been modified so that it can be calibrated easily while it is in the circulation. Laboratory testing has demonstrated that when zero drift occurs this intravascular "reference calibration" is a valid linear function of true zero (r = 0.999). As the sensitivity of the catheter is unaffected by zero drift, it is possible to measure pressure accurately by compensating for this zero drift. During dynamic testing of two catheters, there was a mean net drift over 24 h of -0.54 mm Hg. Clinical evaluation of the catheter was undertaken in the human pulmonary circulation in eight patients (two for 48 h, five for 24 h and one for 8 h). In contrast to the laboratory findings, over the first 4 h after catheterisation there was a phase of rapid zero drift: the net drift was -1.9 (SD 3.3) mm Hg with a range of drift of 5.5 (7.4) mm Hg. Subsequently there was gradual drift: the net drift between 4 and 24 h was -0.44 (2.1) mm Hg with a range of drift of 2.8(1.0) mm Hg; and the net drift between 24 and 48 h was 3.7(2.1) mm Hg with a range of drift of 4.1(1.9) mm Hg. During long term intravascular pressure measurement with micromanometer tipped catheters, zero drift may occur unpredictably and should be quantified.

The Human Pulmonary Circulation: its form and function in health and disease

The Human Pulmonary Circulation: its form and function in health and disease

The Human Pulmonary Circulation: its Form and Function in Health and Disease

Journal Article The Human Pulmonary Circulation: its Form and Function in Health and Disease Get access The Human Pulmonary Circulation: its Form and Function in Health and Disease. Third edition, Peter Harris and Donald Heath. Pp. xiv + 702, illustrated. Churchill Livingstone, Edinburgh, London, Melbourne, New York, 1986. £85.00 D C Flenley D C Flenley Professor Department of Respiratory Medicine, City Hospital, Edinburgh EH10 5SB Search for other works by this author on: Oxford Academic Google Scholar Postgraduate Medical Journal, Volume 63, Issue 739, May 1987, Page 417, https://doi.org/10.1136/pgmj.63.739.417 Published: 01 May 1987

The Human Pulmonary Circulation: Its Form and Function in Health and Disease.

The Human Pulmonary Circulation: Its Form and Function in Health and Disease.

The Human Pulmonary Circulation: Its Form and Function in Health and Disease

The third edition of The Human Pulmonary Circulation: Its Form and Function in Health and Disease by Peter Harris, MD, and Donald Heath, MD, is a classic textbook dealing with all aspects of pulmonary circulation, including developmental anatomy, structure-function relationships, fundamental concepts related to pressure and flow, and the pathology, clinical presentation, and treatment of common (chronic bronchitis and emphysema) and less common (dietary pulmonary hypertension) pulmonary diseases. Since the last edition in 1977, the authors have updated all their chapters and references, although the number of references is relatively small and selective, and added a new, important chapter on the pulmonary endothelial cell. In particular, the chapters on the structure and function of vascular smooth muscles, primary pulmonary hypertension, pulmonary veno-occlusive disease, and portal and pulmonary hypertension are state-of-the-art. The chapter on pharmacology of the pulmonary circulation is complete and reflects the many controversies still extant in this area.

Book ReviewThe Human Pulmonary Circulation: Its form and function in health and disease

Book ReviewThe Human Pulmonary Circulation: Its form and function in health and disease

Cholinergic innervation of the human pulmonary circulation.

The cholinergic innervation of the pulmonary circulation was studied in man. Both extra- and intrapulmonary branches of the pulmonary artery and vein are provided with a cholinergic of the vein. In the main branches of the pulmonary vessels, the existence of two nerve plexuses, a superficial and a deep one, was observed. The superficial plexus is localized in the outer adventitial layer while the deeper plexus is localized in the adventitial-medial transitional zone. In smaller arteries and veins, the existence of a single plexus (adventitial-medial) was observed. In some specimens, the presence of diffuse masses of acetylcholinesterase (AChE)-positive material or elbow-shaped AChE-positive formations was observed. The nature of these formations as well as the possible functional role of a cholinergic system in the pulmonary circulation are discussed.

Altitude and the human pulmonary circulation.

Pulmonary arterial hypertension in man at altitude was first demonstrated by Rotta, Canepa. Hurtado. Velasquez & Chavez (1956). One year before Vega (1955) had published the first comprehensive clinical account of high altitude pulmonary oedema. Since the mid-sixties. interest in both pulmonary hypertension and pulmonary oedema at altitude has continued to generate a great deal of clinical and experimental research.

Prostaglandin F-2α functions as a local hormone on human airways

Vasoactive hormones may be classified either as ‘local’ or as ‘circulating’, depending on whether they are or are not removed by the pulmonary circulation. Prostaglandin F-2α is partially removed by the human pulmonary circulation. We examined the hypothesis that, with respect to the human lung, PGF-2α functions as a local mediator. Prostaglandin F-2α was given to normal and asthmatic subjects via both intravenous and aerosolized routes, and we measured specific airway conductance, spirometry, functional residual capacity, and closing volume. Aerosolized PGF-2α induced significant changes of all measured parameters in both normals and asthmatics, while intravenous PGF-2α-induced changes were limited to the FVC in both normals and asthmatics. The data suggest that intravenous PGF-2α induces constriction of peripheral lung units. The greater sensitivity of the peripheral lung units of asthmatics versus normals to PGF-2α, suggest that the increased sensitivity of airway smooth muscle of asthmatics versus normals to PGF-2α is not restricted to the conducting airways, but extends to the smooth muscle of the peripheral lung units. The data is consistent with the hypothesis that, with respect to the lung, PGF-2α functions as a local hormone, but, furthermore, suggest that, possible of greater importance than the definition of a hormone as ‘local’ or ‘circulating’, is the definition of the intrinsic properties of the muscles on which the hormone is exerting its effects.

Main pulmonary artery distention: A potential mechanism for acute pulmonary hypertension in the human newborn infant

Balloon-induced distention of the main pulmonary artery causes acute pulmonary hypertension and reflex pulmonary vasoconstriction in animals. Pulmonary artery pressure responses caused by MPA balloon inflation were measured in ten human newborn infants with cardiac failure (n = 5) or persistent fetal circulation (n = 5). During balloon inflation distal mean PAP increased significantly while cardiac rate remained unchanged. MPA distention caused greater increases of PAP in those infants with lower resting PAP. The greatest balloon-induced increases of PAP were observed in infants recovering from PFC. The existence of a pulmonary artery reflex and its possible role in the regulation of the human fetal and neonatal pulmonary circulation is discussed.

The Human Pulmonary Circulation: Its Form and Function in Health and Disease

The Human Pulmonary Circulation: Its Form and Function in Health and Disease. By Peter Harris, M.D., Ph.D., F.R.C.P. and Donald Heath, M.D., Ph.D., F.R.C.P., F.R.C.Path.; second edition, 1977. Edinburgh: Churchill Livingstone, Melbourne: Longman Cheshire Pty Ltd, 9 1/2”×7”, pp. 726 with illustrations. Price: $A78.40.

Behavior of the human pulmonary circulation during head-up tilt

Pulmonary blood volume (PBV), flow, and pressures were measured in 15 cardiopulmonary normal subjects, while supine and at 60 degrees head-up passive tilt. PBV, cardiac index (CI), right ventricular diastolic volume (VDVR), and mean pulmonary arterial (Ppa), venous (Pv), and mean right atrial (Pra) pressures all decreased during the first 4 min of tilting, with little subsequent change thereafter, to 30 min. Relative changes of CI, PBV, and VDVR were of similar magnitude (25--30%; mean Ppa and Pv fell 3.2 and 2.3 Torr, respectively. From measurements of thoracic dimensions and changes in intravascular pressures, we calculate that 11% of the pulmonary vascular bed falls into zone I condition, 34% goes from zone III to zone II, and 55% remains in zone III condition during tilt. A highly significant correlation exists between PBV and CI (P less than 0.001), with no significant change in pulmonary mean transit time during tilt. Significant correlations also exist between PBV and Pra (P less than 0.001), Pv (P less than 0.01), and Ppa (P less than 0.05). We conclude that outflow pressure plays a significant role in determining PBV during head-up tilt, but the major determinant is venous return to the right heart.

Pharmacological and pathological responses of the human pulmonary circulation to drugs

Pharmacological and pathological responses of the human pulmonary circulation to drugs

Investigation on the nonlinearity of a physiological system

This paper describes a technique for investigation of nonlinearity in a physiological system. The technique involves replacing the system nonlinearity by considering the presence of a signal additional to the basic linear model of the system actuated over the normal signal and effectively nonlinearising the basic model. The technique is illustrated by considering the system determining the right-ventricular dynamics in the human pulmonary-circulation process. The basic model of the system is derived and synthesised and the form of the nonlinearising signal is investigated. The use of the additional signal in deriving an exact model of the system is illustrated.

Free passage of lysine-vasopressin through the human pulmonary circulation.

The systemic pressure responses to lysine-vasopressin injected into the pulmonary artery were compared to those resulting from administration into the ascending aorta in six patients undergoing diagnostic right and left heart catheterization. Pulmonary injections exerted the same degree of pressor activity as aortic injections. It is concluded that vasopressin is not detectably inactivated during a single passage through the human pulmonary circulation, confirming a phenomenon already noted in animals.

Fate of angiotensin I and II in the human pulmonary circulation

The systemic pressure response technic was applied in 4 patients undergoing diagnostic catheterization. Injections were made alternately into the pulmonary artery and the ascending aorta and the systemic arterial pressor responses to each of these two routes of administration were compared. In 2 subjects, the pressor potency of angiotensin II given by way of the pulmonary artery was identical to that resulting from aortic injections, thus indicating the absence of pulmonary extraction of the octapeptide. In 2 other patients, angiotensin I was twice as potent by the pulmonary than by the aortic route; this could have resulted only from the marked conversion of the inactive decapeptide under the influence of pulmonary converting-enzyme activity. These data provide the clinical confirmation of previous animal observations pointing to the important role played by the lungs in the renin-angiotensin system. Application of the systemic pressure response technic has proved to be easy and safe during cardiac catheterization in man, and it can now be used to study the fate of vasoactive drugs or hormones in the pulmonary circulation.