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Following ozone (O3) exposure, airways reactivity increases. We investigated the possibility that exposure to O3 causes a decrease in pulmonary perfusion, and that this decrease is associated with the increase in reactivity. Perfusion was measured with radiolabeled microspheres. A wedged bronchoscope was used to isolate sublobar segments in the middle and lower lobes of anesthetized dogs. Isolated segments were exposed to either O3 or an elevated alveolar pressure. Although increased alveolar pressure decreased microsphere density, exposure to 1 ppm O3 did not. Collateral system resistance rose significantly following exposure to O3 and to high pressure. These studies do not support the hypothesis that pulmonary perfusion is decreased following O3 exposure and is associated with subsequent increases in reactivity.

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Interstitial fibrosis may increase resistance to collateral flow (Rcoll) because of decreased lung volume and destruction of collateral channels or it may decrease Rcoll because of emphysematous changes around fibrotic regions. In addition, if interstitial fibrosis involves a small region of lung periphery, interdependence from surrounding unaffected lung should produce relatively large changes in volume of the fibrotic region during lung inflation. We studied the effects of interstitial fibrosis on collateral airflow by measuring Rcoll at functional residual capacity (FRC) in nine mongrel dogs before and 28 days after the local instillation of bleomycin into selected lung segments. In six of these dogs Rcoll was also measured at a higher lung volume (transpulmonary pressure = 12 cmH2O above FRC pressure). Rcoll increased in fibrotic lung segments following local treatment with bleomycin. With lung inflation (high transpulmonary pressure) Rcoll fell a similar proportion in fibrotic and nonfibrotic lung regions. These observations suggest that collateral resistance increases in fibrotic segments because lung volume decreases or because collateral pathways are involved directly in the fibrotic process. Compensatory increases in collateral communications do not occur. In addition, pulmonary interdependence does not cause disproportionate increases in volume and decreases in Rcoll of the fibrotic region during lung inflation.

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We investigated the effect of eliminating the bronchial circulation on recovery time from intravenous histamine challenge in canine lung periphery. Results from animals with intact bronchial circulations were compared with a second group in which the left lower lobe was isolated in situ. The pulmonary artery to this lobe was perfused and a bronchoscope was wedged in a small airway, which provided an index of resistance to airflow through the collateral system. The lobe was challenged with intravenous histamine, and the time constant of recovery (tau) from bronchoconstriction was measured. With or without pulmonary blood flow, elimination of the bronchial circulation increased tau 44.4 and 48.5%, respectively. This increase was similar to that found by stopping pulmonary blood flow alone (56.5%). Histamine challenges were also performed in sympathectomized or vagotomized animals with intact bronchial circulations. Neither of these conditions increased tau. We conclude that blood flow through the bronchial circulation affects the recovery time from intravenous histamine challenge in the lung periphery to a degree similar to that of the pulmonary circulation.

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The influence of blood flow through the pulmonary circulation on the time course of recovery of the lung periphery from challenge with three bronchoconstrictive agents was studied in dogs. The rate of perfusion of the left lower lobe was varied between 0 and 300 ml/min. A fiber-optic bronchoscope (OD = 5.5 mm) was wedged in a small airway in the same lobe, and resistance to airflow through the collateral system was continuously monitored. The lung was challenged with histamine aerosol for 1 min, or with intravenous boluses of histamine, acetylcholine, or methacholine. The time constant (tau) of recovery from each of the challenges was measured under the various pulmonary blood flow conditions. The mean tau of the recoveries from histamine was inversely related to the rate of blood flow. However, pulmonary blood flow had no effect on recovery from challenge with acetylcholine or methacholine, two agents metabolized by cholinesterase in lung tissue. From this study we conclude that recovery of the lung periphery from histamine is perfusion dependent, whereas recovery from acetylcholine or methacholine is perfusion independent. This suggests that the rate of blood flow through the pulmonary circulation could play an important role in recovery of the peripheral airways from certain mediators of bronchoconstriction.

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We studied the effects of the flow of dry air on collateral tone in the lung periphery. A bronchoscope was wedged in sublobar segments of anesthetized dogs, and measurements of collateral resistance (Rcs) were recorded before and after flow was increased from 200 to 2,000 ml/min for a 5-min period. Five minutes after exposure was completed, Rcs increased by an average of 117 +/- 25.2% (SE) over control. Maximum Rcs occurred 5 min after the challenge was concluded and required 48 +/- 10.5 min to return to base line. When flow rate was held constant and exposure period varied, Rcs increased with increased stimulus duration. With exposure times held constant, the response of the collateral system was positively associated with changes in stimulus strength (flow rate). No refractory period was observed with repetitive challenges. Finally, when dry air (delivered at 22 degrees C) and conditioned air (i.e., delivered at 28 degrees C; relative humidity = 80%) challenges were alternated in the same wedged segment, dry air produced a mean increase in Rcs of 93.2%, whereas challenge with warm moist air increased Rcs only 33.5%. Regardless of which challenge was presented first, dry air consistently produced a greater constrictor response. This response is similar to that observed in cold air- and exercise-induced asthma and indicates that the lung periphery in dogs, like larger airways in asthmatic subjects, has the potential to increase tone when exposed to dry air. Peripheral airways in dogs thus constitute a model that can be used for the investigation of exercise-induced asthma.

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Many clinical conditions are associated with an increase in abdominal pressure. While the effects on venous return have been studied in the past, little attention has been given to the effect of abdominal pressure on left-sided hemodynamic events. The effects of acute changes in abdominal pressure (Pab) on left ventricular (LV) hemodynamics and outflow distribution were evaluated in ten open-chest dogs, which had undergone right heart bypass to eliminate the influence of changes in Pab on systemic venous return. Pressures were measured in the left atrium (Pla), aorta (Pao), and stomach (Pab). Electromagnetic flow probes were positioned around the ascending aorta (Qaa), descending aorta (Qda) and the innominate or subclavian artery (Qin) to reflect total cardiac output and the respective regional caudad and cephalad blood flows. Compressing the abdomen to increase acutely Pab (9.2 +/- 0.6 torr) also significantly increased Pao (7.8 +/- 1.2 torr), Pla (1.7 +/- 0.4 torr), and Qin (15.2 +/- 4.5%), while Qaa (-9.5 +/- 2.0%) and Qda (-26.3 +/- 7.0%) significantly decreased. Opposite findings were obtained immediately after release of abdominal compression. Thus, an acute increase in Pab with a constant pulmonary artery inflow increased the afterload imposed on the left ventricle and redistributed LV output, with a reduction in flow to the abdomen. Part of the fall in Qaa and increase in Pla could be attributed to passive elevation of the diaphragm by the increase in Pab, i.e., heart-lung-diaphragm interdependence.(ABSTRACT TRUNCATED AT 250 WORDS)

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The present study was undertaken to determine whether beta-adrenoceptors could be physiologically detected in the lung periphery and whether they were under tonic stimulation in the resting state in anesthetized dogs. A fiberoptic bronchoscope was wedged in a sublobar segment of lung in anesthetized male mongrel dogs for measurement of resistance through the collateral system (Rcs). beta-Agents were delivered locally as aerosols through the bronchoscope, and the response was evaluated by changes in Rcs. Distilled water alone produced a mean increase of 8.5 +/- 2.43% (SE) in Rcs at 2 min in six dogs, whereas dl-isoproterenol produced a mean decrease of 8.9 +/- 2.10% (P less than 0.03), thus demonstrating the presence of submaximally stimulated beta-receptors. To test whether the beta-receptors were under tonic stimulation, we compared the effect of aerosolized d- and dl-propranolol in 5 dogs. d-Propranolol that lacks significant beta-blocking activity and dl-propranolol both produced large transient increases in Rcs. However, with d-propranolol, Rcs had returned to base line at 15 min, whereas with dl-propranolol Rcs remained elevated at a mean of 20% above base line for greater than 2 h (P less than 0.01). Local timolol aerosol also produced a sustained increase in Rcs. After pretreatment with reserpine or after bilateral adrenalectomy, both d- and dl-propranolol still produced large transient increases in Rcs, but dl-propranolol no longer produced a sustained increase. Neither isoproterenol nor atropine affected Rcs in the presence of dl-propranolol, nor did pretreatment with atropine affect the response of Rcs to dl-propranolol.(ABSTRACT TRUNCATED AT 250 WORDS)

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Phasic changes in lung blood volume (LBV) during the respiratory cycle may play an important role in the genesis of the respiratory wave in arterial pressure, or pulsus paradoxus. To better understand the effects of lung inflation on LBV, we studied the effect of changes in transpulmonary pressure (delta Ptp) on pulmonary venous flow (Qv) in eight isolated canine lungs with constant inflow. Inflation when the zone 2 condition was predominant resulted in transient decreases in Qv associated with increases in LBV. In contrast, inflation when the zone 3 condition was predominant resulted in transient increases in Qv associated with decreases in LBV. These findings are consistent with a model of the pulmonary vasculature that consists of alveolar and extra-alveolar vessels. Blood may be expelled from alveolar vessels but is retained in extra-alveolar vessels with each inflation. The net effect on LBV and thus on Qv is dependent on the zone conditions that predominate during inflation, with alveolar or extra-alveolar effects being greater when the zone 3 or zone 2 conditions predominate, respectively. Lung inflation may therefore result in either transiently augmented or diminished Qv. Phasic changes in left ventricular preload may therefore depend on the zone conditions of the lungs during the respiratory cycle. This may be an important modulator of respiratory variations in cardiac output and blood pressure.

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In previous work we studied responses to ozone (O3) in the lung periphery of anesthetized male mongrel dogs. O3 (0.1 ppm) delivered locally to the lung periphery through a bronchoscope wedged in a segmental airway increased collateral resistance (Rcs) 31.5 +/- 5%. Bilateral cervical vagotomy or pretreatment with atropine aerosol prevented these responses to O3. In the present study we asked two questions. First, is the vagus necessary for responses to 0.1 ppm O3 because it maintains base-line tone? Second, are physiological responses to O3 administered through a bronchoscope localized to the challenged region? To answer the first question, we increased base-line Rcs (38.4 +/- 11.8%) by administering an acetylcholinesterase inhibitor, neostigmine (aerosol), through the bronchoscope. Following neostigmine, O3 exposure increased Rcs (55.8 +/- 18.4%) only if the vagi were intact. To answer the second question, we introduced two bronchoscopes simultaneously into different regions of the lung. When O3 was delivered through one bronchoscope, responses were detected only in the exposed region. However, when the whole left lung was exposed to O3, the responses were also detected in the right lung, but only when the vagi were intact. We conclude that the lung has the capacity to respond to localized oxidant insult with vagally mediated responses limited to the region that is challenged. However, when a larger area is exposed, vagally mediated responses become generalized and affect both lungs.

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We developed a method for maintaining muscarinic tone in a small region of the lung periphery after vagotomy. A fiber-optic bronchoscope was wedged in a segmental airway of anesthetized male mongrel dogs and was used to deliver aerosols of distilled water (0.1 ml), neostigmine (0.022 mg), atropine (0.1 mg), and histamine (1.5 X 10(-4) mg). Measurements of resistance through the collateral system (Rcs) were used to monitor responses to these agents. Rcs increased 37.0 +/- 5.0% (mean +/- SE) after the administration of neostigmine and remained elevated for at least 50 min. The administration of neostigmine in vagotomized animals or in those where the obstructed lung segment was pretreated with atropine resulted in a small increase in Rcs that lasted only 2 min. When bilateral vagotomy was performed 10 min after neostigmine administration Rcs remained elevated for at least another 80 min. However, Rcs returned to baseline when atropine was administered 20 min after vagotomy, but increased when histamine was administered 50 min after atropine. We conclude that after neostigmine administration, parasympathetic tone, dependent on mediators released from the vagus nerve, can be maintained in the lung periphery after vagotomy.

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The hemodynamic effects of intermittent positive pressure ventilation (IPPV) have generally been considered straightforward, being dominated by the inspiratory reduction in systemic venous return. Paradoxically, there is considerable debate regarding the effects of PEEP. We have studied both right ventricular (RV) and left ventricular (LV) performance during a single IPPV respiratory cycle in dogs with intact circulatory systems or the right heart bypassed in open and closed chest conditions. We have found that the "reverse pulsus paradoxus" during inspiration reflects both transmission of the increased intrathoracic pressure to the thoracic aorta and an increase in LV stroke volume (SV). This inspiratory increase in LVSV has been found to be influenced by, but not dependent on: (a) respiratory variations in RVSV; (b) variations in functional residual capacity or tidal volume altering pulmonary venous return and the degree of physical compression of the heart by the lungs; (c) an inspiratory decrease in RV volume, increasing LV diastolic compliance and, thus, probably improving pulmonary venous return; (d) a decreased transmural aortic diastole pressure reflecting an effective decrease in LV afterload produced by both the general increase in intrathoracic pressure and the direct compression of the heart; and (e) variations in the pulmonary vascular volume as indicated by changes in the transmural LV end-diastolic pressure. An understanding of IPPV during a single respiratory cycle facilitates an appreciation of the steady state hemodynamic effects of IPPV with or without PEEP. Our results imply that measurements made only at end-expiration, ignoring inspiratory events, may have serious limitations. Furthermore, they suggest that IPPV with PEEP should be evaluated as a form of LV assist in LV failure.

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We studied responses of the lung periphery to short-term exposures of 1.0 ppm ozone (O3). A fiber-optic bronchoscope was wedged in a segmental airway of anesthetized male mongrel dogs and was used to deliver O3 to a small portion of lung. Measurements of resistance through the collateral system (Rcs) were used to monitor responses to O3. During a 30-min exposure to O3, Rcs increased within 2 min (early phase) and then continued to increase throughout the exposure. Bilateral cervical vagotomy or pretreatment with atropine prevented or reduced the response measured at 2 min but not the later increase in Rcs. The later increase was reduced with chlorpheniramine. The administration of indomethacin intravenously and as an aerosol did not alter the response. These results indicate that the early phase of the response to 1.0 ppm ozone in the lung periphery is mediated through the parasympathetic system, and the later phase of the response is related in part to histamine release. We found no evidence that metabolites of the cyclooxygenase pathway played a role in these responses. Furthermore, unlike responses to 0.1 ppm, responses to 1.0 ppm O3 are not characterized by the development of adaptation or tolerance.

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In previous studies, we demonstrated that local exposures to the lung periphery to 0.1 ppm ozone (O3) produce increases in resistance to flow through the collateral system (Rcs) which are prevented by vagotomy, and the local exposures to 1.0 ppm O3 produces increases in Rcs which are only partially mediated by the parasympathetic system. In the present studies, we evaluated the effects of short exposures to O3 on reactions to H2O and histamine in anesthetized male dogs when no residual effects of the O3 exposures could be detected. For this purpose a fiber-optic bronchoscope was wedged in a segmental airway of anesthetized dogs and was used to deliver O3, aerosols of H2O, histamine (1.5 X 10(-4) mg), and atropine (0.1 mg). Measurements of Rcs were used to monitor responses to these agents. Responses to three successive challenges with H2O and with histamine were not different from each other. A 30-min exposure to 0.1 ppm O3 between the first and second challenge did not alter responses to histamine or H2O. However, a 10-min exposure to 1.0 ppm O3 resulted in a significant increase in responses to both H2O and histamine. No correlation was noted between the magnitude of response to O3 and the increase in response to histamine or H2O following O3 exposure. Parasympathetic blockade (atropine or bilateral cervical vagotomy) abolished the increase in response to H2O but not the increase in response to histamine following exposure to 1.0 ppm O3.(ABSTRACT TRUNCATED AT 250 WORDS)

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We studied the cardiovascular effects of increasing intrathoracic pressure in an acute pentobarbital-anesthetized canine model of acute ventricular failure induced by large doses of propranolol. Left ventricular (LV) function curves were generated by volume loading from LV filling pressures of 5-20 Torr. The animals were ventilated by using intermittent positive-pressure ventilation with large tidal volumes (30 ml/kg). Chest and abdominal pneumatic binders were used to increase intrathoracic pressure. When compared with the control state, acute ventricular failure was associated with a decrease in the slope of the LV function curves (P less than 0.01). After binding the increase in intrathoracic pressure (1.1 +/- 1.6 to 12.1 +/- 2.4 Torr, P less than 0.01) was associated with an improvement in both right ventricular and LV function. Our study demonstrates that in this model of acute ventricular failure, increasing intrathoracic pressure improves cardiac function. We postulate that this observed improvement with increased intrathoracic pressure is due to reduced LV wall stress in a manner analogous to that seen with arterial vasodilator therapy in congestive heart failure.

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We studied the effects of ozone (O3) and histamine on the lung periphery. A fiber-optic bronchoscope was wedged in a segmental airway of anesthetized male mongrel dogs. Measurements of collateral resistance (Rcoll) were used to monitor responses to O3 and to histamine. Both agents were delivered locally through the bronchoscope. During a 30-min exposure to 0.1 ppm O3, Rcoll increased 31.5 +/- 5.1% within 2 min and then gradually decreased toward control levels in spite of continued exposure to O3. Within 15 min after the exposure ceased, Rcoll had returned to base line. Subsequent exposure to 0.1 ppm O3 did not increase Rcoll. During a 30-min exposure to 1.5 X 10(-6) mg/min histamine aerosol, Rcoll increased 21.5 +/- 5.0% within 2 min and persisted at an elevated level throughout the exposure. Subsequent exposures to histamine produced similar increases in Rcoll. Bilateral cervical vagotomy or pretreatment with atropine aerosol (0.1 mg) prevented responses to O3 but did not prevent responses to histamine. These results indicate that responses to O3, unlike responses to histamine in the lung periphery, are characterized by the rapid development of adaptation and tolerance and are mediated through the vagus nerves.

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The present study was designed to compare acute responses of the lung periphery to locally administered histamine in male and female dogs. A fiberoptic bronchoscope was wedged in peripheral airways of anesthetized dogs. Increasing doses of histamine were directed through the bronchoscope. Measurements of collateral resistance (Rcoll) were used to monitor responses to histamine and lung inflation. Baseline measurements of Rcoll were similar for both sexes. The males responded to histamine with greater increases in Rcoll than the females did. After doses of histamine (1.5 x 10(-6) mg for males and 1.5 x 10(-4) mg for females), which produced similar increases in Rcoll, the effects of lung inflation and the time course of the responses were similar for the two sexes. We conclude that male dogs exhibit greater reactivity to histamine than female dogs do. If these results apply to humans, it is possible that increased reactivity in the lung periphery contributes to the development of chronic obstructive pulmonary disease in males.

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The circulatory effects of iv injections of hyperosmolar solutions were studied both in intact dogs with aortic flow probes and in dogs using a standard right heart-bypass preparation. Serial iv injections of 20 ml of 10% NaCl or 50 ml of 25% mannitol produced reproducible episodic vasodilation characterized by falls in mean aortic pressure from 99 +/- 10 (SE) to 61 +/- 6 Torr and increases in aortic flow from 2.20 +/- 0.06 1/min to 3.12 +/- 0.28 (P less than 0.01). Systemic vascular resistance decreased (P less than 0.01) with each injection and serum osmolarity increased (P less than 0.01); however, there was a poor correlation between these two variables (r = -0.24). Because the mechanism of these physiological changes is unclear, the following experiments were performed to determine whether they were due to the release of vasoactive chemical mediators. We measured arterial and venous plasma histamine, a mediator released systemically in IgE-mediated anaphylactic reactions, but found no changes in histamine levels. Furthermore, pretreatment with both H1 and H2 blockers (diphenhydramine and cimetidine), agents that blocked histamine-induced hypotension, did not prevent hyperosmolar vasodilation. Also, indomethacin (a cyclooxygenase pathway inhibitor of prostaglandin synthesis) did not affect hyperosmolar vasodilation or the fall in systemic vascular resistance. Therefore, hyperosmolar vasodilation is not caused by the systemic release of histamine or by the effects of prostaglandins. The mechanism of these reactions is unknown, but it may be due to direct local effects of hyperosmolar solutions on vascular smooth muscle, perhaps mediated by local fluid and electrolyte shifts.

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Positive-pressure ventilation with positive end-expiratory pressure (PEEP) has been associated with elevation of left ventricular filling pressure for a stable or reduced cardiac output. To exclude the possibility that right ventricular distension due to increased pulmonary vascular resistance decreases left ventricular compliance (ventricular interdependence), we studied the effect of PEEP on left ventricular function in open-chest right-heart-bypassed dogs. A rightward shift of the left ventricular function curve was caused by 15 cmH2O PEEP without a change in the aortic pressure-flow relationship. The pericardial pressure, however, was found to exceed atmospheric pressure on 15 cmH2O even with the chest widely opened. This increase in the pressure surrounding the heart accounted for the increase in left ventricular filling pressure. We postulate, therefore, that the elevation in left ventricular filling pressure found with PEEP is due in part, if not entirely, to mechanical interaction of the heart and lungs by direct compression or pericardial traction.

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Left ventricular stroke volume decreases during inspiratory efforts whether lung volume is actually increasing as in normal inspiration or whether it remains constant as in a Mueller Maneuver (M.M.). Explanations have included phase lag between lung volume changes and left ventricular volume changes during inspiration as well as increased capacity of pulmonary vessels due to inflation. The capacitance changes could not be used to explain stroke volume (SV) fall in Mueller Maneuvers where lung volume is constant. The increased negative pleural pressure may be responsible for increases in right heart volume due to increased venous return. This mechanism has also been suggested as one of the causes of the fall in left ventricular stroke volume by ventricular interdependence due to changes in left ventricular pressure/volume (P/V) relations, i.e., compliance. In all these explanations a decrease in left ventricular diastolic filling and decreased diastolic pressure is assumed. The fact that decreases in pleural pressure may also act like an increase in left ventricular afterload and impede outflow, thereby decreasing stroke volume, has not been generally considered. We found that left ventricular stroke volume can still decrease without a decrease in left ventricular filling and even when increases in venous return have been prevented (right-heart bypass, i.e., constant pulmonary inflow). Thus the fall in stroke volume during inspiratory effort appears to be caused by a variety of factors, among which increased left ventricular afterload must be considered of primary importance. In addition, decreased left ventricular diastolic compliance due to increased right ventricular (RV) volume also has to be considered (interdependence).

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