Control Of Pulmonary Vascular Tone Research Articles

Blockage of the adenosine A2B receptor prevents cardiac fibroblasts overgrowth in rats with pulmonary arterial hypertension

Sustained pressure overload and fibrosis of the right ventricle (RV) are the leading causes of mortality in pulmonary arterial hypertension (PAH). Although the role of adenosine in PAH has been attributed to the control of pulmonary vascular tone, cardiac reserve, and inflammatory processes, the involvement of the nucleoside in RV remodelling remains poorly understood. Conflicting results exist on targeting the low-affinity adenosine A2B receptor (A2BAR) for the treatment of PAH mostly because it displays dual roles in acute vs. chronic lung diseases. Herein, we investigated the role of the A2BAR in the viability/proliferation and collagen production by cardiac fibroblasts (CFs) isolated from RVs of rats with monocrotaline (MCT)-induced PAH. CFs from MCT-treated rats display higher cell viability/proliferation capacity and overexpress A2BAR compared to the cells from healthy littermates. The enzymatically stable adenosine analogue, 5′-N-ethylcarboxamidoadenosine (NECA, 1–30 μM), concentration-dependently increased growth, and type I collagen production by CFs originated from control and PAH rats, but its effects were more prominent in cells from rats with PAH. Blockage of the A2BAR with PSB603 (100 nM), but not of the A2AAR with SCH442416 (100 nM), attenuated the proliferative effect of NECA in CFs from PAH rats. The A2AAR agonist, CGS21680 (3 and 10 nM), was virtually devoid of effect. Overall, data suggest that adenosine signalling via A2BAR may contribute to RV overgrowth secondary to PAH. Therefore, blockage of the A2AAR may be a valuable therapeutic alternative to mitigate cardiac remodelling and prevent right heart failure in PAH patients.

TRPV4: physiological role and therapeutic potential in respiratory diseases.

Members of the family of transient receptor potential (TRP) channels have been implicated in the pathophysiology of a host of lung diseases. The role of these multimodal cation channels in lung homeostasis is thought to stem from their ability to respond to changes in mechanical stimuli (i.e., shear and stretch), as well as to various protein and lipid mediators. The vanilloid subfamily member, TRPV4, which is highly expressed in the majority of lung cell types, is well positioned for critical involvement in several pulmonary conditions, including edema formation, control of pulmonary vascular tone, and the lung response to local or systemic inflammatory insults. In recent years, several pharmacological inhibitors of TRPV4 have been developed, and the current generation of compounds possess high affinity and specificity for TRPV4. As such, we have now entered a time where the therapeutic potential of TRPV4 inhibitors can be systematically examined in a variety of lung diseases. Due to this fact, this review seeks to describe the current state of the art with respect to the role of TRPV4 in pulmonary homeostasis and disease, and to highlight the current and future roles of TRPV4 inhibitors in disease treatment. We will first focus on genera aspects of TRPV4 structure and function, and then will discuss known roles for TRPV4 in pulmonary diseases, including pulmonary edema formation, pulmonary hypertension, and acute lung injury. Finally, both promising aspects and potential pitfalls of the clinical use of TRPV4 inhibitors will be examined.

NADPH oxidase-derived ROS and the regulation of pulmonary vessel tone

Pulmonary vessel constriction results from an imbalance between vasodilator and vasoconstrictor factors released by the endothelium including nitric oxide, endothelin, prostanoids, and reactive oxygen species (ROS). ROS, generated by a variety of enzymatic sources (such as mitochondria and NADPH oxidases, a.k.a. Nox), appear to play a pivotal role in vascular homeostasis, whereas elevated levels effect vascular disease. The pulmonary circulation is very sensitive to changes in the partial pressure of oxygen and differs from the systemic circulation in its response to this change. In fact, the pulmonary vessels contract in response to low oxygen tension, whereas systemic vessels dilate. Growing evidence suggests that ROS production and ROS-related pathways may be key factors that underlie this differential response to oxygen tension. A major emphasis of our laboratory is the role of Nox isozymes in cardiovascular disease. In this review, we will focus our attention on the role of Nox-derived ROS in the control of pulmonary vascular tone.

Role of Rho-kinase signaling and endothelial dysfunction in modulating blood flow distribution in pulmonary hypertension

Rho-kinase-mediated vasoconstriction and endothelial dysfunction are considered two primary instigators of pulmonary arterial hypertension (PAH). However, their contribution to the adverse changes in pulmonary blood flow distribution associated with PAH has not been addressed. This study utilizes synchrotron radiation microangiography to assess the specific role, and contribution of, Rho-kinase-mediated vasoconstriction and endothelial dysfunction in PAH. Male adult Sprague-Dawley rats were injected with saline (Cont-rats) or monocrotaline (MCT-rats) 3 wk before microangiography was performed on the left lung. We assessed dynamic changes in vessel internal diameter (ID) in response to 1) the Rho-kinase inhibitor fasudil (10 mg/kg iv); or 2) ACh (3 μg · kg⁻¹ · min⁻¹), sodium nitroprusside (SNP, 5 μg · kg⁻¹ · min⁻¹), and N(ω)-nitro-l-arginine methyl ester (l-NAME, 50 mg/kg iv). We observed that MCT-rats had fewer vessels of the microcirculation compared with Cont-rats. The fundamental result of this study is that fasudil improved pulmonary blood flow distribution and reduced pulmonary pressure in PAH rats, not only by dilating already-perfused vessels (ID > 100 μm), but also by restoring blood flow to vessels that had previously been constricted closed (ID < 100 μm). Endothelium-dependent vasodilation was impaired in MCT-rats primarily in vessels with an ID < 200 μm. Moreover the vasoconstrictor response to l-NAME was accentuated in MCT-rats, but only in the 200- to 300-μm vessels. These results highlight the importance of Rho-kinase-mediated control and endothelial control of pulmonary vascular tone in PAH. Indeed, an effective therapeutic strategy for treating PAH should target both the smooth muscle Rho-kinase and endothelial pathways.

New therapies for pulmonary arterial hypertension: an update on current bench to bedside translation

Importance of the field: Treatments of pulmonary arterial hypertension (PAH) that have so far proven efficacious are all based on the restoration of endothelium control of pulmonary vascular tone and structure, by administration of prostacyclins, endothelin receptor antagonists and phosphodiesterase-5 inhibitors. However, results remain unsatisfactory, with persistent high mortality, insufficient clinical improvement and no convincing report of any reversal of the disease process.Areas covered in this review: New antiproliferative approaches that aim to actively limit pulmonary vascular remodeling are being sought. Several such treatments have shown promise in experimental models and in preliminary clinical studies. Noteworthy among these are dichloroacetate, survivin antagonists, nuclear factor of activated T-cell inhibitors, PPAR-γ agonists, tyrosine kinase inhibitors, Rho-kinase inhibitors, statins, vasoactive intestinal peptide, soluble guanylate cyclase stimulators/activators, adrenomedullin, elastase inhibitors, serotonin reuptake inhibitors, anti-inflammatory agents, and bone marrow-derived progenitor cells.What the reader will gain: Update on various strategies targeting proliferative, inflammatory and regenerating processes currently under evaluation in patients with PAH.Take home message: In spite of favorable results in experimental models, none of these strategies has achieved the ultimate goal of curing PAH. Further developments will depend on progress made in our pathobiological understanding of the disease and carefully designed randomized, controlled trials.

Integrated control of pulmonary vascular tone by endothelin and angiotensin II in exercising swine depends on gender

The lungs are now recognized as an active metabolic organ that is a major determinant of the plasma concentrations of the vasoconstrictors endothelin (ET) and ANG II. Several studies have suggested a complex interaction between ET and ANG II in the systemic and coronary vascular beds that is different at rest and during exercise. To date, the interaction between these vasoconstrictor peptides has barely been investigated in relation to the pulmonary vascular bed. Consequently, we investigated the integrated control of pulmonary vasomotor tone by ET and ANG II in 24 chronically instrumented swine (15 female and 9 male) at rest and during graded treadmill exercise. In the systemic circulation, ANG II type 1 (AT(1)) receptor blockade with irbesartan and mixed ET(A)/ET(B) blockade with tezosentan each produced vasodilation. The systemic vasodilator effect of ET(A)/ET(B) blockade was enhanced after AT(1) blockade in female swine, whereas a trend toward an increase was observed in male swine. In the pulmonary circulation, AT(1) receptor blockade had no effect on pulmonary vascular tone in male swine, whereas it resulted in an unexpected increase in pulmonary vasomotor tone in female swine. ET(A)/ET(B) receptor blockade did not result in a decrease in pulmonary vasomotor tone at rest but produced a decrease in vasomotor tone during exercise in both genders. This pulmonary vasodilation by ET(A)/ET(B) receptor blockade was enhanced after prior AT(1) blockade in female swine but not in male swine. In conclusion, in both the systemic and pulmonary circulation of female swine, ANG II inhibits the vasoconstrictor influence of ET. This interaction is gender specific. The observation that plasma ET levels were not altered by AT(1) blockade in either gender suggests that the interaction between these vasoconstrictors occurs locally in the vasculature.

Bronchial epithelium-associated pulmonary arterial muscle relaxation in the rat is absent in the fetus and suppressed by postnatal hypoxia

We recently reported the existence of a bronchial epithelium-derived relaxing factor (BrEpRF) capable of reducing pulmonary arterial smooth muscle force generation in the newborn rat. We reasoned in this study that BrEpRF has physiological significance in the control of pulmonary vascular tone. We hypothesized that the release and/or activity of this factor can be stimulated and is suppressed prenatally or under hypoxic conditions postnatally. Therefore, we evaluated the pathways stimulated by the BrEpRF in fetal and newborn rat intrapulmonary arteries mounted with their adjacent bronchi in a wire myograph under both normoxic and hypoxic conditions. Under normoxic conditions, BrEpRF release/activation was observed in newborn vessels following methacholine stimulation of M(2) muscarinic receptors, which was mediated via a nitric oxide (NO)-dependent mechanism involving the phosphatidylinositol 3-kinase pathway. Hypoxia suppressed the BrEpRF-dependent modulation of basal and methacholine-induced pulmonary arterial muscle tone in newborn vessels without altering endothelium-dependent or -independent NO-mediated relaxation. In fetal pulmonary arteries studied under normoxic conditions, BrEpRF neither was active under basal conditions nor could it be stimulated with methacholine. We conclude that release/activation of the BrEpRF occurs by an oxygen-dependent mechanism in the newborn and is suppressed during late fetal life. These results suggest that the BrEpRF may be involved in postnatal adaptation of the pulmonary circulation and that its suppression may contribute to hypoxic pulmonary vasoconstriction.

The role of 5-hydroxytryptamine in the control of pulmonary vascular tone in a rabbit model of pulmonary hypertension secondary to left ventricular dysfunction

The role of 5-hydroxytryptamine (5-HT) in a rabbit model of pulmonary hypertension (PHT) secondary to left ventricular dysfunction was investigated. Following pulmonary artery catheterisation under anaesthesia, 5-HT (1–400 μg kg −1 i.v.) was administered before and after either 5-HT 2A receptor antagonism with ketanserin (0.5 mg kg −1) or infusion of the nitric oxide synthase inhibitor, l-NAME (30 μmol min −1). Eight week coronary artery ligated rabbits demonstrate increased mean pulmonary arterial pressure (PAP) compared to controls (17.0±0.5 versus 12.0±0.5 mmHg, P<0.001) accompanied by right ventricular hypertrophy. 5-HT alone produced a greater pulmonary pressor response in rabbits with PHT (increase of 7.5±1.2, n=12 c.f. 3.5±0.4 mmHg in shams, n=12, P<0.01). Ketanserin had no effect on basal PAP in either PHT or control rabbits but inhibited the response to 5-HT in both groups. The response to 5-HT following l-NAME was increased in both groups and was greater in rabbits with PHT (an increase of 20.1±2.9, n=6 c.f. 11.4±1.8 mmHg, n=6, P<0.05). These results suggest that the difference shown in the in vivo pulmonary response to exogenous 5-HT is mediated largely through 5-HT 2A receptors in this model. However, activity of endogenous 5-HT at the 5-HT 2A receptors is not responsible for maintaining the raised basal PAP through vasoconstriction in PHT rabbits once PHT has developed.

Evaluation of pulmonary hypertension in heart transplant candidates.

Assessment of the pulmonary circulation and right ventricular function is a cornerstone in the evaluation of the patient as a potential heart transplant recipient. The importance of pulmonary hypertension is linked to outcomes in the posttransplant period. Preoperative pulmonary vascular resistance is an independent risk factor for early death after heart transplantation. Pulmonary hypertension can be classified as reversible, or irreversible if not rapidly responsive to pharmacologic maneuvers. However, in most patients, the major component is likely to reverse with vasodilators, because of the central role played by the endothelium in the control of pulmonary vascular tone. To discriminate between patients with reversible and irreversible pulmonary hypertension, provocative therapies are used, and baseline and the postprovocation hemodynamic parameters are measured. To date, there is no reliable hemodynamic threshold beyond which right ventricular failure is certain to occur, nor are there values below which right ventricular failure is always avoidable. Because of this uncertainty, it becomes clear that only through careful preoperative assessment can this life-threatening condition be recognized preoperatively and, hence, managed in the posttransplant recovery period.

Characterisation of cyclic nucleotide phosphodiesterase isoforms in the media layer of the main pulmonary artery

Cyclic nucleotides are involved in the control of pulmonary vascular tone. In the present study, we measured the cyclic nucleotide specific phosphodiesterase (PDE) activity in the media of bovine isolated main pulmonary artery (MPA). Total cAMP- and cGMP-PDE activities were measured in microsomal and cytosolic fractions. Both cyclic nucleotides were hydrolysed in these subcellular fractions at consistently higher rate in the cytosolic than in the microsomal fraction. Using different classes of PDE modulator, at least four PDE isoforms (PDE1, 3, 4 and 5) were identified in these fractions. PDE3 (cilostamide-sensitive), PDE4 (rolipram-sensitive) and PDE5 (zaprinast- and DMPPO-sensitive) isoforms appeared as the main isozymes implicated in the cAMP and cGMP hydrolytic activities. Calcium–camodulin stimulated PDE activity (PDE1) was mainly present in the cytosolic fraction. PDE2, although present, had a lower hydrolytic activity since addition of its specific inhibitor, erythro-9-(2-hydroxy-3nonyl)adenine (EHNA), to a combination of inhibitors of PDE3, 4 and 5 produced no further significant reduction in the enzymatic activity. Resolution of PDE activities from the cytosolic fraction using anion exchange chromatography confirmed this finding. Functional experiments performed in endothelium-denuded rings of rat MPA revealed that all specific PDE inhibitors used relaxed precontracted vascular smooth muscle preparations in a concentration-dependent manner. The rank order of potency was cilostamide >zaprinast>rolipram>>EHNA. The present study demonstrates the presence in the smooth muscle cells-containing layer of MPA of PDE1, 3, 4 and 5 isoforms and suggests that PDE3, 4 and 5 are the main enzymes involved in the control of vascular tone.

Role of tyrosine phosphatase in the modulation of pulmonary vascular tone.

In the vascular system, synthesis of the potent vasodilator nitric oxide (NO) is tightly regulated by the constitutively expressed endothelial NO synthase (eNOS). Activity of eNOS is controlled by Ca2+/calmodulin and various seryl/threonyl protein kinases. Less is known about the importance of phosphorylation and dephosphorylation of tyrosyl residues. Therefore the role of tyrosine phosphatase on the modulation of isolated rat pulmonary artery tone has been assessed. Inhibition of tyrosine phosphatase by sodium orthovanadate (SOV, 1x10(-6) M) significantly: 1) increased phenylephrine-induced vasoconstriction and 2) decreased endothelium-dependent relaxation to acetylcholine, but had no effect on endothelium-independent relaxation to the NO donor, sodium nitroprusside. In phenylephrine-precontracted pulmonary arterial rings, SOV (1x10(-7)-1x10(-5) M) had no effect on vascular tone but significantly relaxed rings which were pretreated with the NO-synthase inhibitor, N(omega)-nitro-L-arginine-methyl ester (L-NAME). SOV-induced relaxation in the presence of L-NAME was, however, abolished by glibenclamide. In conclusion, inhibition of tyrosine phosphatase altered pulmonary vascular tone by increasing vasoconstrictor response to phenylephrine and decreasing endothelium-dependent relaxation to acetylcholine. Furthermore, the tyrosine phosphatase inhibitor, sodium orthovanadate, exhibited original vasodilator properties which were only observed when nitric oxide synthesis was inhibited. Thus a new pathway involving the inhibitory effect of nitric oxide on a glibenclamide-sensitive diffusible relaxing factor, that might play an important role in the control of pulmonary vascular tone is described.

Pulmonary hypertension secondary to left ventricular dysfunction: the role of nitric oxide and endothelin-1 in the control of pulmonary vascular tone.

1. Using an in vivo model of pulmonary hypertension (PHT) secondary to left ventricular dysfunction (LVD), the pulmonary arterial response to the nitric oxide synthase (NOS) blocker L-NAME (30 micromol.min(-1) i.v.) and the subsequent responses to cumulatively administered endothelin-1 (ET-1) (0.001 -- 4 nmol.kg(-1) i.v.) or big ET-1 (0.1 -- 2.0 nmol.kg(-1) i.v.) were studied. Additionally, the effect of the non-selective ET-1 receptor antagonist, SB209670, was investigated. 2. Eight weeks after coronary artery ligation or sham operation, rabbits demonstrated increased mean pulmonary arterial pressure (PAP) accompanied by right ventricular hypertrophy. 3. Blockade of NOS caused a greater increase in basal PAP (increased by 7.7 +/- 1.1 mmHg c.f. 3.8 +/- 1.0 mmHg in controls, P<0.05) and uncovered a greater pulmonary pressor response to exogenous ET-1 in rabbits with PHT (increased by 10.2 +/- 2.3 mmHg c.f. 4.9 +/- 1.0 mmHg in controls, P<0.05). 4. Big ET-1 evoked a pulmonary pressor effect, in both groups of rabbits, that was increased following blockade of NOS and was more potent in rabbits with PHT. 5. The non-selective ET-1 receptor antagonist, SB209670, reduced basal PAP (from 16.9 mmHg to 15.9 mmHg, P < 0.05) in rabbits with PHT and blocked the response to ET-1 in the presence of L-NAME. 6. In conclusion, the results demonstrate that basal NO activity masks a pulmonary pressor response to exogenously administered ET-1. An increased responsiveness to ET-1 was shown in the pulmonary arterial bed of rabbits with PHT secondary to LVD, implicating a pathophysiological role for ET-1 in this model.

Endothelial Cells Freshly Isolated from Resistance-Sized Pulmonary Arteries Possess a Unique K+ Current Profile

We have, for the first time, developed a reliable method for freshly isolating viable endothelial cells from resistance-sized rat pulmonary arteries. The endothelial origin of these cells was confirmed using indirect immunofluorescence, utilizing fluorescently labeled low-density lipoprotein. Biophysical and pharmacological patch-clamp experiments conducted under quasiphysiological cationic gradients revealed that these cells had a mean resting membrane potential of ∼−38 mV and displayed a delayed-rectifying K+ current. Immunohistochemical staining of rat lung cross-sections revealed an abundance of KV1.5 channel protein in pulmonary endothelium. This is the first report of a delayed-rectifying K+ current in endothelial cells of resistance-sized pulmonary arteries. Since changes in membrane potential associated with K+ channel activity affect release of vasoactive substances from endothelial cells, this finding has important implications for understanding the mechanisms underlying control of pulmonary vascular tone.

The ET(A)-Receptor Antagonist LU 135252 Prevents the Progression of Established Pulmonary Hypertension Induced by Monocrotaline in Rats.

BACKGROUND: An imbalance between the nitric oxide (NO) and endothelin systems may contribute to the development of pulmonary hypertension (PH). We evaluated the effect of the specific ET(A)-receptor antagonist LU 135252 (LU) in rats with established monocrotaline (MCT)-induced PH and the involvement of NO in the control of pulmonary vascular tone. METHODS AND RESULTS: Two weeks after MCT, rats developed PH with a right ventricular pressure (RVP) of 42.3 +/- 8.5 vs 28.2 +/- 4.1 mmHg for controls (mean +/- SD, P <.05). Daily oral therapy with LU (50 mg/kg) or saline was started 2 weeks post-MCT injection for 20 days. LU increased the survival rate nonsignificantly from 41.7% to 66.7%. The surviving MCT + saline rats showed severe PH (RVP of 82.5 +/- 8.9 mmHg) and RV hypertrophy with a right-to-left ventricle + septum weight ratio of 69.6% +/- 10.2%, which were improved by LU to 53.5 +/- 11.1 mmHg and 53.7% +/- 9.9%, respectively (P <.01). In isolated lungs, pulmonary vascular compliance was reduced by PH and unaffected by LU therapy. After the NO synthase inhibitor N(omega)-nitro-L-arginine (10(-4) mol/L), compliance was further reduced, although much less so, in the LU-treated group (P <.01). CONCLUSIONS: In this model, ET(A) antagonist therapy has a favorable effect on survival and pulmonary hemodynamics and reduces the dependency on NO for the attenuation of reduced vascular compliance.

10 The pulmonary circulation in lung diseases

Summary In most cases of pulmonary hypertension, the pulmonary circulation retains its ability to dilate or to contract further, because of the release of vasoconstrictor as well as vasodilator mediators. The vascular endothelium synthesizes vasoconstrictor and vasodilator mediators, thereby playing a major role in the control of pulmonary vascular tone. Whether endogenous NO is involved in the maintenance of the normally low basal pulmonary vascular tone remains unsettled. However, many studies indicate that NO is released during hypoxia and lung injury, and counteracts the increase in P pa. Many data suggest that endogenous ETs could mediate pulmonary hypertension. ET receptor antagonists may prove valuable therapy for lung diseases associated with pulmonary hypertension. Inhaled NO selectively reduces P pa in various pulmonary hypertensive states and improves gas exchange in many patients with acute lung injury. Inhaled NO may therefore play a role in the treatment of pulmonary hypertension and/or lung injury. However, its long-term toxicity is not yet defined, and its clinical value needs to be evaluated in controlled trials. Complex interactions exist between the pulmonary circulation, the RV and the LV in health and disease. A better understanding of these interactions could promote valuable therapeutic strategies for RV pressure overload.

Role of endothelium in the maintenance of low pulmonary vascular tone in normal children : Celermajer DS, Dollery C, Burch M, Beanfield JE Circulation 89:2041–2044, 1994

BACKGROUNDResting vascular tone is low in the normal pulmonary circulation, and experimental studies have suggested that this may be due to the continuous release of endothelium-derived nitric oxide (NO), a locally acting vasodilator. We have investigated whether NO contributes to the normal control of pulmonary vascular tone and resistance in children.METHODS AND RESULTSWe studied the hemodynamic effects of NG-monomethyl-L-arginine (L-NMMA), a specific inhibitor of NO synthesis, on the pulmonary circulation of six children 2 to 17 years old (mean, 9 years) with congenital heart disease but normal pulmonary blood flow, pressure, and resistance (all had isolated left heart obstructive lesions). The diameter of a segmental pulmonary artery and pulmonary blood flow velocity were measured by quantitative angiography and intra-arterial Doppler catheters. There was a consistent, dose-dependent fall in pulmonary blood flow velocity in response to three increasing doses of L-NMMA (compared with baseline, flow vel...

Role of endothelium in the maintenance of low pulmonary vascular tone in normal children.

Resting vascular tone is low in the normal pulmonary circulation, and experimental studies have suggested that this may be due to the continuous release of endothelium-derived nitric oxide (NO), a locally acting vasodilator. We have investigated whether NO contributes to the normal control of pulmonary vascular tone and resistance in children. We studied the hemodynamic effects of NG-monomethyl-L-arginine (L-NMMA), a specific inhibitor of NO synthesis, on the pulmonary circulation of six children 2 to 17 years old (mean, 9 years) with congenital heart disease but normal pulmonary blood flow, pressure, and resistance (all had isolated left heart obstructive lesions). The diameter of a segmental pulmonary artery and pulmonary blood flow velocity were measured by quantitative angiography and intra-arterial Doppler catheters. There was a consistent, dose-dependent fall in pulmonary blood flow velocity in response to three increasing doses of L-NMMA (compared with baseline, flow velocity fell to 75 +/- 7%, 62 +/- 8%, and 40 +/- 10%, P < .01). Flow velocity returned to control values with subsequent infusion of L-arginine, the substrate for NO. Thereafter, acetylcholine, an endothelium-dependent dilator, produced an increase in flow velocity (56 +/- 10% greater than baseline, P < .01). Arterial diameter was unchanged during L-NMMA and L-arginine infusions, indicating that the major effect of each agent is to alter vascular tone distal to the segmental pulmonary arteries. The dilator action of endothelium-derived NO contributes to the maintenance of low resting pulmonary tone in normal children. Impairment of NO production may contribute to the elevated pulmonary vascular resistance that complicates some cases of congenital heart disease.

Role of Endothelium in the Control of Pulmonary Vascular Tone

In addition to passive factors, pulmonary vascular tone is under the control of adrenergic, cholinergic, NANC vasodilator nerves and humoral mechanisms. Hypoxic pulmonary vasoconstriction plays an important role in the active control of pulmonary vascular tone. Adrenergic nerves, HPV and vasoconstrictor humoral substances are the vasoconstricting forces, whereas cholinergic, NANC mechanisms and vasodilator humoral substances are the dilating factors. Basal and stimulated release of NO from endothelial cells also represents dilating force. Thus, a balance between these two sets of opposing forces determines the normal resting pulmonary vascular tone. Disturbance of this balance may result in or/and contribute to the development of some pulmonary vascular diseases such as pulmonary hypertension. Endothelium-derived NO plays an important role in the regulation of pulmonary vascular tone. It inhibits adrenergic contraction, hypoxic pulmonary vasocon-striction and the contractile response to many vasoconstrict...

In vivo detection of endothelium dependent and independent pulmonary artery relaxation in children.

In vitro studies have suggested an important role for the endothelium in the control of pulmonary vascular tone, but endothelium dependent and independent relaxation of pulmonary arteries have not been studied in children in vivo. The response of the pulmonary circulation to graded infusions of acetylcholine (an endothelial dependent vasodilator) and to nitroprusside (a dilator not dependent on endothelium) was studied in 10 children aged four to 16 years who had normal pulmonary haemodynamics. Arterial diameter was measured by quantitative angiography, and pulmonary blood flow velocity was measured with a 3F intra-arterial Doppler catheter placed in a lower lobe segmental artery. There was a dose dependent increase in flow velocity in response to acetylcholine (maximum response 93%) (SEM 7%), and an increase of 51% (8%) in response to nitroprusside. By contrast, segmental artery diameter was unchanged during acetylcholine infusion in all patients, and increased only modestly in response to nitroprusside (5% (1%)). The most important site of action of endothelium dependent and independent pulmonary vasodilators is distal to the segmental pulmonary arteries. Despite low resting tone in the pulmonary circulation, endothelium dependent vasodilatation can be shown in vivo. This may allow study of the role of endothelial dysfunction in children with abnormal pulmonary haemodynamic secondary to congenital heart disease.

THE ROLE OF EDRF IN THE MAINTENANCE OF BASAL PULMONARY VASOMOTOR TONE IN THE NEONATAL PIGLET

To begin to understand the role of EDRF in the control of pulmonary vascular tone in the neonate we studied isolated lungs from pigs (age 14.5±0.3 days, weight 3.2±0.3 kg) perfused at 100ml·min−1 kg with autologous blood under zone 3 conditions. Pulmonary artery (Pa), left atrial (Pv) and airway pressures were continuously monitored. To determine the potential for stimulated release of EDRF we infused a 0.1 mg bolus of acetylcholine (ACH), and to block EDRF production we added NG-nitro-L-arginine methylester (NAME) to the blood to achieve a concentration of 10−3M.ACH was given prior to and after NAME, prior to NAME ACH was a vasodilator and after NAME ACH was a vasoconstrictor. The 50% increase in Pa with the addition of NAME suggests that the basal production of EDRF from L-arginine has a modulating role in the control of pulmonary vascular tone in the isolated lungs from neonatal pigs. The change in response to ACH from a vasodilator to a vasoconstrictor following NAME suggests that the vasodilator action of ACH was mediated by EDRF production. Interference with EDRF synthesis may lead to the development of neonatal pulmonary hypertensive diseases.