Vagal afferent and reflex responses to changes in surface osmolarity in lower airways of dogs.

In anesthetized dogs we examined the sensitivity of afferent vagal endings in the lungs to changes in airway fluid osmolarity. Injection of 0.25-0.5 ml/kg water or hyperosmotic sodium chloride solutions (1,200-2,400 mmol/l) into a lobar bronchus caused bradycardia, arterial hypotension, apnea followed by rapid shallow breathing, and contraction of tracheal smooth muscle. All effects were abolished by vagotomy. We examined the sensory mechanisms initiating these effects by recording afferent vagal impulses arising from the lung lobe into which the liquids were injected. Water stimulated pulmonary and bronchial C-fibers and rapidly adapting receptors; isosmotic saline and glucose solutions were ineffective. Hyperosmotic saline (1,200-9,600 mmol/l, 0.25-1 ml/kg) stimulated these afferents in a concentration-dependent manner. Stimulation began 1-10 s after the injection and sometimes continued for several minutes. Responses of slowly adapting stretch receptors varied. Our results suggest that non-isosmotic fluid in the lower airways initiates defense reflexes by stimulating pulmonary and bronchial C-fibers and rapidly adapting receptors. Conceivably, stimulation of these afferents as a result of evaporative water loss from airway surface liquid could contribute to exercise-induced asthma.     

Effects of histamine on bronchial artery blood flow and bronchomotor tone

The effects of aerosolized 5% histamine (10 breaths) on bronchial artery blood flow (Qbr), airflow resistance (RL), and pulmonary and systemic hemodynamics were studied in mechanically ventilated sheep anesthetized with pentobarbital sodium. Histamine increased mean Qbr and RL to 252 +/- 45 and 337 +/- 53% of base line, respectively. This effect was significantly different from base line for 30 min after challenge. The histamine-induced increase in RL was blocked by pretreatment with the histamine H1 receptor antagonist, chlorpheniramine, whereas the histamine-induced elevation in Qbr was prevented by the H2 antagonist, metiamide. Both responses were blocked only when both antagonists were present. Changes in Qbr were not directly associated with alterations in systemic and pulmonary hemodynamics or arterial blood gas composition. In vitro histamine caused a dose-dependent contraction of ovine bronchial artery strips that was prevented by H1 antagonist. The H2 agonist, impromidine, caused relaxation of precontracted arterial strips and was more potent and efficacious than histamine, whereas H1 agonists failed to elicit a relaxant response. Thus these findings indicate that histamine aerosol induces a vasodilation in the bronchial vascular bed; histamine has a direct effect on Qbr that is independent of alterations in RL, systemic and pulmonary hemodynamics, or arterial blood gas composition; and, histamine-induced bronchoconstriction is mediated predominantly by H1-receptors, whereas increased Qbr is controlled predominantly by H2-receptors, probably located in resistance vessels. This local effect of histamine on Qbr may have important implications in the pathophysiology of bronchial asthma and pulmonary edema.     

Measurement of bronchial arterial blood flow and bronchovascular resistance in sheep

We studied the bronchial arterial blood flow (Qbr) and bronchial vascular resistance (BVR) in sheep prepared with carotid-bronchial artery shunt. Nine adult sheep were anesthetized, and through a left thoracotomy a heparinized Teflon-tipped Silastic catheter was introduced into the bronchial artery. The other end of the catheter was brought out through the chest wall and through a neck incision was introduced into the carotid artery. A reservoir filled with warm heparinized blood was connected to this shunt. The height of blood column in the reservoir was kept constant at 150 cm by adding more blood. Qbr was measured, after interrupting the carotid-bronchial artery flow, by the changes in the reservoir volume. The bronchial arterial back pressure (Pbr) was measured through the shunt when both carotid-bronchial artery and reservoir Qbr had been temporarily interrupted. The mean Qbr was 34.1 +/- 2.9 (SE) ml/min, Pbr = 17.5 +/- 3.3 cmH2O, BVR = 3.9 +/- 0.5 cmH2O X ml-1 X min, mean pulmonary arterial pressure = 21.5 +/- 3.6 cmH2O, and pulmonary capillary wedge pressure (Ppcw) = 14.3 +/- 3.7 cmH2O. We further studied the effect of increased left atrial pressure on these parameters by inflating a balloon in the left atrium. The left atrial balloon inflation increased Ppcw to 25.3 +/- 3.1 cmH2O, Qbr decreased to 21.8 +/- 2.4 ml/min (P less than 0.05), and BVR increased to 5.5 +/- 1.0 cmH2O.ml-1.min (P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)     

Bronchial circulation in pulmonary artery occlusion and reperfusion

Obstruction of pulmonary arterial blood flow results in minimal biochemical and/or morphological changes in the involved lung. If the lung is reperfused, a syndrome of leukopenia and lung edema occurs. We used the radiolabeled microsphere technique to measure the response of the bronchial circulation in rabbits to acute pulmonary artery occlusion (PAO) and to pulmonary artery reperfusion. We found that the bronchial blood flow (Qbr) decreased from a base line of 0.37 +/- 0.10 to 0.09 +/- 0.04 (SE) ml.min-1.g dry lung-1 (P less than or equal to 0.05) after 4 h of PAO. In a separate group of animals, Qbr 24 h after PAO remained low (0.20 +/- 0.07 ml.min-1.g dry lung-1, P = 0.06). Qbr during PAO was inversely correlated with the wet-to-dry ratio after reperfusion (r = -0.68, P = 0.06). Qbr did not change during 4 h of reperfusion. We speculate that a critical level of Qbr may be necessary during PAO to prevent ischemia/reperfusion injury from occurring.     

Late-phase bronchial vascular responses in allergic sheep

Sheep were classified on the basis of their airway response to Ascaris suum antigen aerosols as allergic or nonsensitive. Allergic sheep were classed as acute or dual responders. Acute responders had only an immediate increase in mean airflow resistance after antigen, whereas dual responders had an immediate and late-phase (6-8 h after antigen challenge) increase in mean airflow resistance; nonsensitive sheep had minimal airway responses to antigen (less than 30% increase from base line). The sheep were anesthetized 2 wk later and, after a left thoracotomy, were challenged with antigen to determine bronchial vascular responses; bronchial artery blood flow was measured with an electromagnetic flow probe. Airway responses to antigen aerosol challenge were similar in the anesthetized and conscious animals. The mean fall in bronchial vascular resistance (BVR) immediately after antigen challenge was similar in acute and dual responders (41 +/- 7 and 47 +/- 9% of base line, respectively). In dual responders, late-phase airway responses were preceded by a significant increase from base line in Qbr and a fall in bronchovascular resistance (BVR). The mean fall in BVR 6-8 h after antigen challenge in documented dual responders was significantly different from bronchial vascular responses in acute responders (59 +/- 3 vs. 89 +/- 10%, respectively). Sheep without airway responses to A. suum had no significant changes in bronchial hemodynamics or airways mechanics. Late-phase-associated changes in BVR are a specific response to antigen challenge and may be a sensitive index of mediators being released.(ABSTRACT TRUNCATED AT 250 WORDS)     

Temperature alters bronchial blood flow response to pulmonary arterial obstruction

Lobar bronchial blood flow has been reported to increase and decrease acutely after pulmonary arterial obstruction (PAO). Because bronchial blood flow (Qbr) to the trachea and bronchi is influenced by inspired air temperature, we investigated whether temperature differences could explain these disparate results. In 10 open-chested dogs the left lower lobe (LLL) was isolated and perfused in situ with autologous blood at a controlled temperature with an independent vascular circuit. The abdomen and the chest of the dog were enclosed in a Plexiglas box in which air was fully humidified and temperature could be regulated. Qbr, determined by the reference flow technique using 16 micron microspheres, was measured before and 30 min after onset of PAO with the air in the box being either at 27 or 39 degrees C and with warmed LLL blood (37 degrees C) in the latter condition. Anastomotic bronchial blood flow [Qbr(s-p), determined as overflow from the closed LLL vascular circuit and measured in ml X min-1 X 100 g dry lung wt-1 X 100 Torr mean systemic pressure-1] was measured continuously at both temperatures. Both before and after PAO, Qbr and Qbr(s-p) were closely correlated: Qbr (ml/min) = 1.12 + 0.978Qbr(s-p); R = 0.912. This was true regardless of the presence or the absence of pulmonary flow, showing that the distribution of bronchial blood flow between the anastomotic and the nonanastomotic portion does not change acutely during PAO. When the air in the box was 27 degrees C, Qbr(s-p) was 19.5 +/- 5.2 (SE) and increased to 38.6 +/- 8.1 with PAO (P less than 0.007).(ABSTRACT TRUNCATED AT 250 WORDS)     

Adenosine contributes to hypoxia-induced forearm vasodilation in humans.

In humans, hypoxia leads to increased sympathetic neural outflow to skeletal muscle. However, blood flow increases in the forearm. The mechanism of hypoxia-induced vasodilation is unknown. To test whether hypoxia-induced vasodilation is cholinergically mediated or is due to local release of adenosine, normal subjects were studied before and during acute hypoxia (inspired O(2) 10.5%; approximately 20 min). In experiment I, aminophylline (50-200 microg. min(-1). 100 ml forearm tissue(-1)) was infused into the brachial artery to block adenosine receptors (n = 9). In experiment II, cholinergic vasodilation was blocked by atropine (0.4 mg over 4 min) infused into the brachial artery (n = 8). The responses of forearm blood flow (plethysmography) and forearm vascular resistance to hypoxia in the infused and opposite (control) forearms were compared. During hypoxia (arterial O(2) saturation 77 +/- 2%), minute ventilation and heart rate increased while arterial pressure remained unchanged; forearm blood flow rose by 35 +/- 6% in the control forearm but only by 5 +/- 8% in the aminophylline-treated forearm (P < 0.02). Accordingly, forearm vascular resistance decreased by 29 +/- 5% in the control forearm but only by 9 +/- 6% in the aminophylline-treated forearm (P < 0.02). Atropine did not attenuate forearm vasodilation during hypoxia. These data suggest that adenosine contributes to hypoxia-induced vasodilation, whereas cholinergic vasodilation does not play a role.     

A muscarinic agonist inhibits reflex bronchoconstriction in normal but not in asthmatic subjects

Muscarinic receptors of the M2 subtype, which inhibit acetylcholine release from cholinergic nerves (autoreceptors), have been described in animal and human bronchi in vitro. We investigated whether these receptors may be involved in feedback inhibition of cholinergic reflex bronchoconstriction induced by sulfur dioxide (SO2) in seven nonasthmatic atopic subjects and in six mild asthmatic subjects. In a control experiment, total respiratory resistance (Rrs) was increased by 30 +/- 5% in nonasthmatic and by 60 +/- 18% in asthmatic subjects. In nonasthmatic subjects, pilocarpine, an agonist of muscarinic M2-autoreceptors, increased Rrs by 15 +/- 5% and addition of SO2 increased Rrs to 21 +/- 5% above base line, which was not significantly greater than after pilocarpine alone. Histamine gave a comparable bronchoconstriction (25 +/- 3% increase in Rrs) and SO2 further increased Rrs to 39 +/- 6% above base line (P less than 0.05). Thus pilocarpine appears to inhibit SO2-induced bronchoconstriction in nonasthmatic subjects, and this effect is not explained by an increase in airway tone. In asthmatic subjects, pretreatment with pilocarpine increased Rrs by 31 +/- 8% and SO2 further increased Rrs to 88 +/- 17% above base line. SO2 alone gave a 60 +/- 18% increase in Rrs. Our results suggest that feedback inhibitory muscarinic receptors may be present on cholinergic nerves in normal airways and that there may be a dysfunction of this feedback mechanism in asthmatic airways. This might be contributory to exaggerated cholinergic reflex bronchoconstriction in asthma.     

Methacholine causes reflex bronchoconstriction

To determine whether methacholine causes vagally mediated reflexconstriction of airway smooth muscle, we administered methacholine tosheep either via the bronchial artery or as an aerosol via tracheostomyinto the lower airways. We then measured the contraction of anisolated, in situ segment of trachealis smooth muscle and determinedthe effect of vagotomy on the trachealis response. Administeringmethacholine to the subcarinal airways via the bronchial artery(0.5-10.0 µg/ml) caused dose-dependent bronchoconstriction andcontraction of the tracheal segment. At the highest methacholine concentration delivered, trachealis smooth muscle tension increased anaverage of 186% over baseline. Aerosolized methacholine (5-7 breaths of 100 mg/ml) increased trachealis tension by 58% and airwaysresistance by 183%. As the bronchial circulation in the sheep does notsupply the trachea, we postulated that the trachealis contraction wascaused by a reflex response to methacholine in the lower airways.Bilateral vagotomy essentially eliminated the trachealis response andthe airways resistance change after lower airways challenge (either viathe bronchial artery or via aerosol) with methacholine. We concludethat 1) methacholine causes asubstantial reflex contraction of airway smooth muscle and2) the assumption may not be validthat a response to methacholine in humans or experimental animalsrepresents solely the direct effect on smooth muscle.

     

Independent control of mucosal and total airway blood flow during hypoxemia

In the larger airways, the blood circulation forms a subepithelial (mucosal) and outer (peribronchial) microvascular network. This raises the possibility that blood flow in these two networks is regulated independently. We used hypoxemia as a stimulus to induce changes in tracheal mucosal blood flow normalized for systemic arterial pressure (Qtr n) measured with an inert soluble gas technique and total bronchial blood flow (Qbr) and normalized Qbr (Qbrn) measured with an electromagnetic flow probe in anesthetized sheep. Fifteen minutes of hypoxemia [PO2 40 +/- 7 (SD) Torr] decreased mean Qtr n from 1.1 +/- 0.4 to 0.8 +/- 0.4 ml.min-1.mmHg-1.10(2) (-27%; P less than 0.05; n = 7) and increased mean Qbr n from 12.1 +/- 3.2 to 17.1 +/- 5.4 ml.min-1.mmHg-1.10(2) (+41%; P less than 0.05; n = 6). The rise in Qbr correlated with cardiac output (r = 0.68; P less than 0.05). Phentolamine pretreatment (0.1 mg/kg iv) blunted the hypoxemia-related decrease of mean Qtr n (-8%; P = NS). Tyramine (2.5 mg) applied locally to the trachea decreased mean Qtr n significantly after 30 and 45 min by 31 and 19%, respectively (P less than 0.05). 6-Hydroxydopamine (0.2 mg 4 times for 1 h locally applied) prevented the hypoxemia-induced as well as local tyramine-induced decrease in mean Qtr n (0 and 0%).(ABSTRACT TRUNCATED AT 250 WORDS)     

TNF-alpha induced bronchial vasoconstriction

The pro-inflammatory characteristics of tumor necrosis factor-alpha (TNF-alpha) have been extensively characterized in in vitro systems. Furthermore, this cytokine has been shown to play a pivotal role in airways inflammation in asthma. Since the airway vasculature also performs an essential function in inflammatory cell transit to the airways, experiments were performed to determine the effects of TNF-alpha on bronchial vascular resistance (BVR). In anesthetized, ventilated sheep, the bronchial artery (BA) was cannulated and perfused with autologous blood. BVR was defined as inflow pressure/flow and averaged 6.3 +/- 0.2 mmHg. ml(-1). min(-1) (+/-SE) for the 25 sheep studied. Recombinant human TNF-alpha (10 microg for 20 or 40 min) infused directly into the BA resulted in a significant decrease in BVR to 87% of baseline (P < 0.05). This vasodilation was followed by a reversal of tone by 120 min and a sustained increase in BVR to 126% of baseline (P < 0.05). Since others have shown TNF-alpha caused coronary vasoconstriction through endothelial release of endothelin-1 (ET-1), an ET-1 antagonist was used to block bronchial vasoconstriction. BQ-123, a selective ET(A) receptor antagonist, was delivered to the bronchial vasculature prior to TNF-alpha challenge. Attenuation of bronchial vasoconstriction was observed at 120 min (P < 0.03). Thus TNF-alpha causes bronchial vasoconstriction by the secondary release of ET-1. Although TNF-alpha exerts pro-inflammatory actions on most cells of the airways, vasoactive properties of this cytokine likely further contribute to the inflammatory status of the airways.     

Cigarette smoke in lungs evokes reflex increase in tracheal submucosal gland secretion in dogs.

Stimulation of pulmonary C-fibers (PCs) by capsaicin and of rapidly adapting receptors (RARs) by reduced lung compliance reflexly increases airway submucosal gland secretion in dogs. Because both PCs and RARs are stimulated by cigarette smoke (nicotine being the primary stimulus), we performed experiments in anesthetized open-chest artificially ventilated dogs (with aortic nerves cut) to determine whether cigarette smoke reflexly stimulates airway secretion. We measured submucosal gland secretion by counting the hillocks in a 1.2-cm2 field of tracheal epithelium coated with tantalum dust. Secretion was stimulated by delivery of 40-320 ml smoke from high-nicotine cigarettes to the lower trachea, secretion rate increasing from 7.4 +/- 1.3 to 48.1 +/- 5.1 hillocks.cm-2.min-1. Results of cutting the pulmonary vagal branches or carotid sinus nerves or both indicated that the secretory response was initiated by stimulation of lower respiratory vagal afferents and augmented several seconds later by stimulation of carotid chemoreceptors. Results of cooling the cervical vagus nerves to 7 and 0 degrees C indicated that most of the vagally mediated increase in secretion was due to stimulation of afferent lung C-fibers.     

Bronchial circulation and cyclooxygenase products in acute lung injury

The role of cyclooxygenase products in the response of the bronchial circulation to acute lung injury was examined in 30 dogs. By use of an open-chest preparation the left lower lobe (LLL) pulmonary circulation was isolated, continuously weighed, and perfused in situ. The anastomotic bronchial blood flow [Qbr(s-p)] was measured as the rate of increase in the volume of the LLL-perfusion circuit. Four groups of dogs were studied. In group A, six dogs received cyclooxygenase inhibition (COI) with either indomethacin (2 mg/kg) or ibuprofen (10 mg/kg). In group B (n = 10) lung injury caused by airway instillation of glucose (15 mg) with glucose oxidase (500 micrograms/kg) (G/GO) or LLL pulmonary arterial infusion of alpha-napthyl thiourea (ANTU, 2 mg/kg). Group C (n = 10) received COI, and 30 min later injury was induced as above with either ANTU or G/GO. Group D (n = 4) received COI immediately after anesthesia; then, 30 min after completion of the surgical preparation, injury was induced with ANTU or G/GO. After COI, Qbr(s-p) decreased to 35 +/- 9% of the basal values (P less than 0.05). After administration of ANTU or G/GO, Qbr(s-p) increased irrespective of whether COI was present. 6-Ketoprostaglandin F1 alpha (6-keto-PGF1 alpha) and thromboxane B2 (TxB2) were measured by radioimmunoassay in the LLL pulmonary artery and systemic venous blood, demonstrating an increase in 6-keto-PGF1 alpha due to surgical preparation and confirming complete COI in those animals receiving COI immediately after anesthesia. These findings demonstrate that 1) the bronchial circulation is capable of a sevenfold increase in flow in response to acute lung injury.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pulmonary C-fiber stimulation by capsaicin evokes reflex cholinergic bronchial vasodilation in sheep.

We investigated changes in bronchial blood flow (Qbr) associated with capsaicin-induced stimulation of pulmonary C-fibers in seven anesthetized and two unanesthetized sheep. A Doppler flow probe chronically implanted around the common bronchial artery provided a signal (delta F, kHz) linearly related to bronchial arterial blood velocity (Vbr, cm/s), which was proportional to Qbr. An index of bronchial vascular conductance (Cbr, in arbitrary units) was calculated as the ratio of Vbr to systemic arterial pressure (Pa). Right atrial injection of capsaicin evoked a prompt pulmonary chemoreflex (apnea, bradycardia, and hypotension), with immediate increases in Vbr (average +34%) and Cbr (+63%) that reached a maximum approximately 7 s after the injection. A second increase in Vbr, but not in Cbr, occurred approximately 12 s later, coinciding with an increase in Pa. Vagal cooling (0 degrees C) prevented the pulmonary chemoreflex; it also abolished the immediate increases in Vbr and Cbr in four of six sheep and substantially reduced them in two sheep; it did not affect the late increases in Vbr and Pa. Results after atropine indicated that the immediate increases in Vbr and Cbr were mainly cholinergic. In two sheep a small residual vasodilation survived combined cholinergic and adrenergic blockade and may have been due to peripheral release of neurokinins.     

Reduction in airway hyperresponsiveness to methacholine by the application of RF energy in dogs.

We delivered controlled radio frequency energy to the airways of anesthetized, ventilated dogs to examine the effect of this treatment on reducing airway narrowing caused by a known airway constrictor. The airways of 11 dogs were treated with a specially designed bronchial catheter in three of four lung regions. Treatments in each of the three treated lung regions were controlled to a different temperature (55, 65, and 75 degrees C); the untreated lung region served as a control. We measured airway responsiveness to local methacholine chloride (MCh) challenge before and after treatment and examined posttreatment histology to 3 yr. Treatments controlled to 65 degrees C as well as 75 degrees C persistently and significantly reduced airway responsiveness to local MCh challenge (P < or = 0.022). Airway responsiveness (mean percent decrease in airway diameter after MCh challenge) averaged from 6 mo to 3 yr posttreatment was 79 +/- 2.2% in control airways vs. 39 +/- 2.6% (P < or = 0.001) for airways treated at 65 degrees C, and 26 +/- 2.7% (P < or = 0.001) for airways treated at 75 degrees C. Treatment effects were confined to the airway wall and the immediate peribronchial region on histological examination. Airway responsiveness to local MCh challenge was inversely correlated to the extent of altered airway smooth muscle observed in histology (r = -0.54, P < 0.001). We conclude that the temperature-controlled application of radio frequency energy to the airways can reduce airway responsiveness to MCh for at least 3 yr in dogs by reducing airway smooth muscle contractility.     

Reflex tracheal contraction evoked in dogs by bronchodilator prostaglandins E2 and I2

Bronchodilator prostaglandins E2 and I2 may cause airway irritation and bronchoconstriction in human subjects. These experiments were designed to test the hypothesis that this paradoxical bronchoconstriction is a vagal reflex triggered by stimulation of airway afferents. We recorded smooth muscle tension in an innervated upper tracheal segment in anesthetized dogs and injected prostaglandins into the general circulation or into a bronchial artery or administered them as aerosol to the lungs. Prostaglandins usually caused tracheal contraction, which survived vagal cooling to 5-7 degrees C but was abolished at 0 degrees C. Vagally mediated tracheal contraction was also evoked when prostacyclin was injected into the pulmonary circulation of dogs whose pulmonary and systemic circulations were independently pump perfused. Recordings of afferent vagal impulses indicated that bronchial arterial injection of prostaglandins stimulated bronchial C-fibers; aerosols of prostaglandin stimulated pulmonary and bronchial C-fibers and C-fibers in extrapulmonary airways. We postulate that in susceptible human subjects concentrations of these prostaglandins too low to have direct bronchodilator effects may cause reflex bronchoconstriction by stimulating afferent vagal C-fibers in the lower airways.     

Response of the bronchial circulation to acute hypoxemia and hypercarbia in the dog

We have examined the effect of acute hypoxemia and hypercarbia on bronchial blood flow (Qbr) in 10 anesthetized, ventilated, open-chest dogs using a modification of the radioactive microsphere technique. After surgery, dogs were divided into two groups of five. Group 1 was ventilated for 30 min with each of the following gas mixtures: 1) room air; 2) 15% O2-85% N2; 3) 10% O2-90% N2, and group 2 with 1) room air; 2) 5% CO2-30% O2-65% N2; 3) 10% CO2-30% O2-60% N2. Measurements of pulmonary arterial, left atrial and aortic pressures, cardiac output, and blood gases were made before injection of 46Sc-, 153Gd-, and 103Ru-labeled microspheres into the left atrium as a marker of Qbr. After the final measurements, dogs were killed and the lungs removed and the parenchyma stripped off the large and small airways of the left lung. Knowing the radioactivity in the trachea, bronchi, parenchyma, and in the blood from the reference-flow sample and also the aortic and left atrial pressures, total and regional Qbr, and bronchovascular resistance (BVR) were calculated. Results showed that acute hypoxemia (10% O2) caused a significant (P less than 0.05) decrease in Qbr and increase in BVR and acute hypercarbia (10% CO2) caused a significant (P less than 0.05) increase in Qbr and decrease in BVR.     

Ligation of the bronchial artery in sheep attenuates early pulmonary changes following exposure to smoke.

Smoke inhalation can produce acute pulmonary edema. Previous studies have shown that the bronchial arteries are important in acute pulmonary edema occurring after inhalation of a synthetic smoke containing acrolein, a common smoke toxin. We hypothesized that inhalation of smoke from burning cotton, known to contain acrolein, would produce in sheep acute pulmonary edema that was mediated by the bronchial circulation. We reasoned that occluding the bronchial arteries would eliminate smoke-induced pulmonary edema, whereas occlusion of the pulmonary artery would not. Smoke inhalation increased lung lymph flow from baseline from 2.4 +/- 0.7 to 5.6 +/- 1.2 ml/0.5 h at 30 min (P < 0.05) to 9.1 +/- 1 ml/0.5 h at 4 h (P < 0.05). Bronchial artery ligation diminished and delayed the rise in lymph flow with baseline at 2.8 +/- 0.7 ml/0.5 h rising to 3.1 +/- 0. 8 ml/0.5 h at 30 min to 6.5 +/- 1.5 ml/0.5 h at 240 min (P < 0.05). Wet-to-dry ratio was 4.1 +/- 0.2 in control, 5.1 +/- 0.3 in smoke inhalation (P < 0.05), and 4.4 +/- 0.4 in bronchial artery ligation plus smoke-inhalation group. Smoke inhalation after occlusion of the right pulmonary artery resulted in a wet-to-dry ratio after 4 h in the right lung of 5.5 +/- 0.8 (P < 0.05 vs. control) and in the left nonoccluded lung of 5.01 +/- 0.7 (P < 0.05). Thus the bronchial arteries may be major contributors to acute pulmonary and airway edema following smoke inhalation because the edema occurs in the lung with the pulmonary artery occluded but not in the lungs with bronchial arteries ligated.     

Impaired endothelium-mediated vasodilation is not the principal cause of vasoconstriction in heart failure

The extent to which abnormal endothelium-dependent vasodilator mechanisms contribute to abnormal resting vasoconstriction and blunted reflex vasodilation seen in heart failure is unknown. The purpose of this study was to test the hypothesis that the resting and reflex abnormalities in vascular tone that characterize heart failure are mediated by abnormal endothelium-mediated mechanisms. Thirteen advanced heart-failure patients (New York Heart Association III-IV) and 13 age-matched normal controls were studied. Saline, acetylcholine (20 microg/min), or L-arginine (10 mg/min) was infused into the brachial artery, and forearm blood flow was measured by venous plethysmography at rest and during mental stress. At rest, acetylcholine decreased forearm vascular resistance in normal subjects, but this response was blunted in heart failure. During mental stress with intra-arterial acetylcholine or L-arginine, the decrease in forearm vascular resistance was not greater than during saline control in heart failure [saline control vs. acetylcholine (7 +/- 3 vs. 6 +/- 3, P = NS) or vs. L-arginine (9 +/- 2 units, P = NS)]. The increase in forearm blood flow was not greater than during saline control in heart failure [saline control vs. acetylcholine (1. 2 +/- 0.3 vs. 1.3 +/- 0.3, P = NS), or vs. L-arginine (1.2 +/- 0.2 ml x min(-1) x 100 ml(-1), P = NS)]. Furthermore, during mental stress with nitroprusside, the decrease in forearm vascular resistance was not greater than during saline control [saline control vs. nitroprusside (7 +/- 3 vs. 5 +/- 4 ml x min(-1) x 100 g(-1), P = NS)], and the increase in forearm blood flow was not greater than during saline control [saline control vs. nitroprusside (1.2 +/- 0.3 vs. 1.3 +/- 0.5 ml x min(-1) x 100 g(-1), P = NS)]. Because the endothelial-independent agent nitroprusside was unable to restore resting and reflex vasodilation to normal in heart failure, we conclude that impaired endothelium-mediated vasodilation with acetylholine-nitric oxide cannot be the principal cause of the attenuated resting- or reflex-mediated vasodilation in heart failure.     

A peptidergic component to vagally induced tracheal vasodilation in the dog.

The purpose of the study was to determine the extent that peptidergic afferent and efferent pathways contribute to vagally induced vasodilation in the trachea of the dog. The change in vascular resistance of the tracheal branch of the cranial thyroid artery and the trachealis responses were determined in 28 anesthetized, paralyzed, and mechanically ventilated dogs. After propranolol (2 mg/kg) and phentolamine (1.5 mg/kg), stimulation of the superior laryngeal nerves (NS; 15 Hz, 7 V, 2 ms, 30 s) caused a decrease in vascular resistance of 11.7 +/- 0.8% and a tracheal contraction of 5.2 +/- 4.7 cmH2O. Atropine (1.5 mg/kg) reduced the fall in vascular resistance to 4.7 +/- 0.8% (P less than 0.01), whereas tracheal contraction was abolished. Thiorphan (1.5 mg), a neutral endopeptidase inhibitor, augmented the decrease in vascular resistance (8.8 +/- 0.6%; P less than 0.01) to NS. After hexamethonium (0.5 mg/kg), NS still caused a small decrease in TVR (2.9 +/- 0.9%; P less than 0.05), which was abolished by capsaicin. In atropinized dogs, capsaicin reduced the fall in vascular resistance after NS; the residual vasodilation was virtually abolished by hexamethonium. Acetylcholine (10(-3) mg/kg) decreased vascular resistance (15.7 +/- 3.0%), and the effect was abolished by atropine. We conclude that there is noncholinergic nonadrenergic vagally induced tracheal vasodilation that is peptidergic. The peptidergic vasodilation appears to be mediated by both afferent and efferent pathways.