Pulmonary Vascular Pressure-flow Relationship Research Articles

Effects of body position on exercise capacity and pulmonary vascular pressure-flow relationships.

There has been revival of interest in exercise testing of the pulmonary circulation for the diagnosis of pulmonary vascular disease, but there still is uncertainty about body position and the most relevant measurements. Doppler echocardiography pulmonary hemodynamic measurements were performed at progressively increased workloads in 26 healthy adult volunteers in supine, semirecumbent, and upright positions that were randomly assigned at 24-h intervals. Mean pulmonary artery pressure (mPAP) was estimated from the maximum tricuspid regurgitation jet velocity. Cardiac output was calculated from the left ventricular outflow velocity-time integral. Pulmonary vascular distensibility α-index, the percent change of vessel diameter per millimeter mercury of mPAP, was calculated from multipoint mPAP-cardiac output plots. Body position did not affect maximum oxygen uptake (Vo2max), maximum respiratory exchange ratio, ventilatory equivalent for carbon dioxide, or slope of mPAP-cardiac output relationships, which was on average of 1.5 ± 0.4 mmHg·l-1·min-1 Maximum mPAP, cardiac output, and total pulmonary vascular resistance were, respectively, 34 ± 4 mmHg, 18 ± 3 l/min, and 1.9 ± 0.3 Wood units. However, the semirecumbent position was associated with a 10% decrease in maximum workload. Furthermore, cardiac output-workload or cardiac output-Vo2 relationships were nonlinear and variable. These results suggest that body position does not affect maximum exercise testing of the pulmonary circulation when results are expressed as mPAP-cardiac output or maximum total pulmonary vascular resistance. Maximum workload is decreased in semirecumbent compared with upright exercise. Workload or Vo2 cannot reliably be used as surrogates for cardiac output.

Physiology of the Pulmonary Circulation and the Right Heart

The pulmonary circulation is a high-flow and low-pressure circuit. The functional state of the pulmonary circulation is defined by pulmonary vascular pressure-flow relationships conforming to distensible vessel models with a correction for hematocrit. The product of pulmonary arterial compliance and resistance is constant, but with a slight decrease as a result of increased pulsatile hydraulic load in the presence of increased venous pressure or proximal pulmonary arterial obstruction. An increase in left atrial pressure is transmitted upstream with a ratio ≥1 for mean pulmonary artery pressure and ≤1 the diastolic pulmonary pressure. Therefore, the diastolic pressure gradient is more appropriate than the transpulmonary pressure gradient to identify pulmonary vascular disease in left heart conditions. Exercise is associated with a decrease in pulmonary vascular resistance and an increase in pulmonary arterial compliance. Right ventricular function is coupled to the pulmonary circulation with an optimal ratio of end-systolic to arterial elastances of 1.5-2.

Pulmonary hypertension and the right ventricle in hypoxia

Hypoxia causes pulmonary vasoconstriction. Regional hypoxic vasoconstriction improves the matching of perfusion to alveolar ventilation. Global hypoxic vasoconstriction increases right ventricular afterload. The hypoxic pulmonary pressor response is universal in mammals and in birds, but with considerable interspecies and interindividual variability. Chronic hypoxia induces pulmonary hypertension in proportion to initial vasoconstriction. Prolonged hypoxic exposure is also associated with an increase in red blood cell mass, which aggravates pulmonary hypertension by an increase in blood viscosity. Hypoxic pulmonary hypertension in humans is usually mild to moderate, but pulmonary vascular pressure-flow relationships are steep, which corresponds to a substantial afterload on the right ventricle during exercise. A partial recovery of 10-25% of the hypoxia-induced decrease in maximal oxygen uptake has been reported with intake-specific pulmonary vasodilating interventions. Hypoxia has been reported to decrease myocardial fibre contractility in vitro. However, the acutely hypoxic right ventricle remains able to preserve the coupling of its contractility to increased afterload in intact animals. Echocardiographic studies of the right ventricle in healthy hypoxic human subjects show altered diastolic function, but systolic function that is preserved or even increased acutely and slightly depressed chronically. These findings are more pronounced in patients with chronic mountain sickness. Their clinical significance remains incompletely understood. Almost no imaging studies of right ventricular function have been reported in a minority of subjects who develop severe pulmonary hypertension and clinical right ventricular failure in hypoxia. No imaging studies of right ventricular function during hypoxic exercise in normal subjects are yet available. Thus, while it is plausible that the right ventricle limits exercise capacity in hypoxia, this still needs to be firmly established.

Pulmonary circulation at exercise.

The pulmonary circulation is a high-flow and low-pressure circuit, with an average resistance of 1 mmHg/min/L in young adults, increasing to 2.5 mmHg/min/L over four to six decades of life. Pulmonary vascular mechanics at exercise are best described by distensible models. Exercise does not appear to affect the time constant of the pulmonary circulation or the longitudinal distribution of resistances. Very high flows are associated with high capillary pressures, up to a 20 to 25 mmHg threshold associated with interstitial lung edema and altered ventilation/perfusion relationships. Pulmonary artery pressures of 40 to 50 mmHg, which can be achieved at maximal exercise, may correspond to the extreme of tolerable right ventricular afterload. Distension of capillaries that decrease resistance may be of adaptative value during exercise, but this is limited by hypoxemia from altered diffusion/perfusion relationships. Exercise in hypoxia is associated with higher pulmonary vascular pressures and lower maximal cardiac output, with increased likelihood of right ventricular function limitation and altered gas exchange by interstitial lung edema. Pharmacological interventions aimed at the reduction of pulmonary vascular tone have little effect on pulmonary vascular pressure-flow relationships in normoxia, but may decrease resistance in hypoxia, unloading the right ventricle and thereby improving exercise capacity. Exercise in patients with pulmonary hypertension is associated with sharp increases in pulmonary artery pressure and a right ventricular limitation of aerobic capacity. Exercise stress testing to determine multipoint pulmonary vascular pressures-flow relationships may uncover early stage pulmonary vascular disease.

Characterization of the Isolated, Ventilated, and Instrumented Mouse Lung Perfused with Pulsatile Flow

The isolated, ventilated and instrumented mouse lung preparation allows steady and pulsatile pulmonary vascular pressure-flow relationships to be measured with independent control over pulmonary arterial flow rate, flow rate waveform, airway pressure and left atrial pressure. Pulmonary vascular resistance is calculated based on multi-point, steady pressure-flow curves; pulmonary vascular impedance is calculated from pulsatile pressure-flow curves obtained at a range of frequencies. As now recognized clinically, impedance is a superior measure of right ventricular afterload than resistance because it includes the effects of vascular compliance, which are not negligible, especially in the pulmonary circulation. Three important metrics of impedance--the zero hertz impedance Z(0;), the characteristic impedance Z(C;), and the index of wave reflection R(W;)--provide insight into distal arterial cross-sectional area available for flow, proximal arterial stiffness and the upstream-downstream impedance mismatch, respectively. All results obtained in isolated, ventilated and perfused lungs are independent of sympathetic nervous system tone, volume status and the effects of anesthesia. We have used this technique to quantify the impact of pulmonary emboli and chronic hypoxia on resistance and impedance, and to differentiate between sites of action (i.e., proximal vs. distal) of vasoactive agents and disease using the pressure dependency of Z(C;). Furthermore, when these techniques are used with the lungs of genetically engineered strains of mice, the effects of molecular-level defects on pulmonary vascular structure and function can be determined.

Effects of ketamine on hypoxic pulmonary vasoconstriction in the isolated perfused lungs of endotoxaemic mice

During sepsis and endotoxaemia, hypoxic pulmonary vasoconstriction (HPV) is impaired. Sedation of septic patients in ICUs is performed with various anaesthetics, most of which have pulmonary dilatory properties. Ketamine is a sympathetic nervous system-activating anaesthetic that preserves cardiovascular stability. The effects of ketamine on the pulmonary vasculature and HPV during sepsis have not been characterized yet. Therefore, isolated lungs of mice were perfused with ketamine (0, 0.1, 1.0, and 10 mg kg(-1) body weight min) 18 h following intraperitoneal injection of lipopolysaccharide (LPS); untreated mouse groups served as controls (n = 7 per group, respectively). Pulmonary artery pressure (PAP) and pressure-flow curves during normoxic (FiO(2) = 0.21) and hypoxic (FiO(2) = 0.01) ventilation were obtained. HPV was reduced in endotoxaemic animals when compared with controls (means +/- SD; DeltaPAP control 103 +/- 28% vs. LPS 23 +/- 25%, P < 0.05). Ketamine caused a dose-dependent reduction of HPV in the lungs of control (DeltaPAP 0 mg kg(-1) min(-1) ketamine 103 +/- 28% vs. 10 mg kg(-1) min(-1) ketamine 28 +/- 21%, P < 0.05) and septic animals (DeltaPAP 0 mg kg(-1) min(-1) ketamine 23 +/- 25% vs. 10 mg kg(-1) min(-1) ketamine 0 +/- 4%, P < 0.05). Analysis of pressure-flow curves revealed that ketamine partly reversed the endotoxin-induced changes in basal pulmonary vascular wall properties rather than interfering with the HPV response itself. Ketamine modified baseline pulmonary vascular properties, resulting in a reduced HPV responsiveness in untreated mice. Further, ketamine counteracted the LPS-induced changes in pulmonary vascular pressure-flow relationships, but did not affect impaired HPV in this murine endotoxaemia model.

Letter by Naeije and Mélot Regarding Article, “Exercise-Induced Pulmonary Arterial Hypertension”

HomeCirculationVol. 120, No. 23Letter by Naeije and Mélot Regarding Article, “Exercise-Induced Pulmonary Arterial Hypertension” Free AccessLetterPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessLetterPDF/EPUBLetter by Naeije and Mélot Regarding Article, “Exercise-Induced Pulmonary Arterial Hypertension” Robert Naeije, MD, PhD and Christian Mélot, MD, PhD Robert NaeijeRobert Naeije Erasme Hospital, Free University of Brussels, Brussels, Belgium Search for more papers by this author and Christian MélotChristian Mélot Erasme Hospital, Free University of Brussels, Brussels, Belgium Search for more papers by this author Originally published8 Dec 2009https://doi.org/10.1161/CIRCULATIONAHA.108.846287Circulation. 2009;120:e283To the Editor:In a recent issue of Circulation, Tolle et al reported on exercise-induced pulmonary arterial hypertension (PAH) as a well-circumscribed syndrome with clinical cardiopulmonary exercise testing and hemodynamic criteria.1 The authors are to be commended for this article, which is original and clinically relevant. However, we were intrigued by the presentation of their results as log-log plots of mean pulmonary arterial pressure (PAP) as a function of predicted oxygen consumption (V̇o2).According to the authors, the logPAP-logV̇o2 relationship normally shows an inflection point with increased slope above the anaerobic threshold (“takeoff pattern”), in contrast to a “plateau pattern” identified in exercise-induced PAH and in established PAH. Because V̇o2 and cardiac output are tightly correlated, accounting for “highly concordant” PAP versus cardiac output (Q) and PAP versus V̇o2 log-log plots, the authors explain these patterns by exercise-induced pulmonary vasoconstriction in normal subjects but not in patients with pulmonary vascular disease.Until now, pulmonary vascular pressure-flow relationships have always been reported to be best described by a linear approximation.2,3 However, when flow was increased by exercise, negative extrapolated pressure intercepts were observed in some studies in patients with heart failure and/or pulmonary vascular diseases.4,5 A disproportionate increase in pulmonary artery pressure at exercise may be explained by an increased pulmonary vascular resistance or an increased filling pressure of the left heart. In the article by Tolle et al, there was no increase in either pulmonary vascular resistance or pulmonary capillary wedge pressure at the highest level of exercise in either normal controls or PAH patients.Therefore, we do not see any explanation for “takeoff” and “plateau” patterns of PAP versus V̇o2 log-log plots. Could it be an artifact related to an excessive manipulation of data in the presentation of the results? Although this is not clearly stated in the Methods, we assume that the reason to present results as log-log plots was that the distributions of the variables of interest tested negative for normality. The reason for V̇o2 presented as a percentage predicted or V̇o2 instead of Q is more difficult to understand.It would be interesting to see the results shown as PAP versus Q, which is probably the most appropriate way to describe the functional state of the pulmonary circulation. On these real source data, one would be curious to see some statistical comparison between the slopes of the double linear regression, with power regression analysis to confirm the results obtained by double linear regression (with a slope coefficient <1 for the plateau pattern and >1 for the takeoff pattern).In our opinion, the article by Tolle et al is convincing about the notion of exercise-induced PAH as a clinically relevant syndrome but less so about the nonlinearity of pulmonary vascular pressure-flow relationships at exercise.DisclosuresNone. References 1 Tolle JJ, Waxman AB, Van Horn TL, Pappagianopoulos PP, Systrom DM. Exercise-induced pulmonary arterial hypertension. Circulation. 2008; 118: 2183–2189.LinkGoogle Scholar2 Reeves JT, Dempsey JA, Grover RF. Pulmonary circulation during exercise. In: Weir EK, Reeves JT, eds. Pulmonary Vascular Physiology and Physiopathology. New York, NY: Dekker; 1989: 107–133.Google Scholar3 Naeije R. Pulmonary vascular function. In: Peacock AJ, Rubin LJ, eds. Pulmonary Circulation. Diseases and Their Treatment. 2nd ed. London, UK: Arnold; 2004: 3–13.Google Scholar4 Abdel Kafi S, Mélot C, Vachiéry JL, Brimioulle S, Naeije R. Partitioning of pulmonary vascular resistance in primary pulmonary hypertension. J Am Coll Cardiol. 1998; 31: 1372–1376.CrossrefMedlineGoogle Scholar5 Janicki JS, Weber KT, Likoff MJ, Fishman AP. The pressure-flow response of the pulmonary circulation in patients with heart failure and pulmonary vascular disease. Circulation. 1985; 72: 1270–1278.CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetails December 8, 2009Vol 120, Issue 23 Advertisement Article InformationMetrics https://doi.org/10.1161/CIRCULATIONAHA.108.846287PMID: 19996021 Originally publishedDecember 8, 2009 PDF download Advertisement SubjectsExercise TestingPulmonary Hypertension

Role of endogenous nitric oxide in endotoxin-induced alteration of hypoxic pulmonary vasoconstriction in mice

Pulmonary vasoconstriction in response to alveolar hypoxia (HPV) is frequently impaired in patients with sepsis or acute respiratory distress syndrome or in animal models of endotoxemia. Pulmonary vasodilation due to overproduction of nitric oxide (NO) by NO synthase 2 (NOS2) may be responsible for this impaired HPV after administration of endotoxin (LPS). We investigated the effects of acute nonspecific (N(G)-nitro-L-arginine methyl ester, L-NAME) and NOS2-specific [L-N6-(1-iminoethyl)lysine, L-NIL] NOS inhibition and congenital deficiency of NOS2 on impaired HPV during endotoxemia. The pulmonary vasoconstrictor response and pulmonary vascular pressure-flow (P-Q) relationship during normoxia and hypoxia were studied in isolated, perfused, and ventilated lungs from LPS-pretreated and untreated wild-type and NOS2-deficient mice with and without L-NAME or L-NIL added to the perfusate. Compared with lungs from untreated mice, lungs from LPS-challenged wild-type mice constricted less in response to hypoxia (69 +/- 17 vs. 3 +/- 7%, respectively, P < 0.001). Perfusion with L-NAME or L-NIL restored this blunted HPV response only in part. In contrast, LPS administration did not impair the vasoconstrictor response to hypoxia in NOS2-deficient mice. Analysis of the pulmonary vascular P-Q relationship suggested that the HPV response may consist of different components that are specifically NOS isoform modulated in untreated and LPS-treated mice. These results demonstrate in a murine model of endotoxemia that NOS2-derived NO production is critical for LPS-mediated development of impaired HPV. Furthermore, impaired HPV during endotoxemia may be at least in part mediated by mechanisms other than simply pulmonary vasodilation by NOS2-derived NO overproduction.

Propofol Attenuates Prostacyclin-induced Pulmonary Vasorelaxation in U46619 Preconstricted Dog

Background: The goal of our study was to investigate the effects of propofol anesthesia on the pulmonary vascular response to prostacyclin during U46619 precontraction in dogs. Methods: Eight mongrel dogs were anesthetized and instrumented to measure the left pulmonary vascular pressure-flow relation, by loosely positioning a hydraulic occluder around the right main pulmonary artery and placing an electromagnetic flow probe around the left main pulmonary artery. During slowly occlusion of the right main pulmonary artery, the pressure-flow plots were measured in the left main pulmonary artery in the control and propofol-anesthetized (5.0 mg/kg plus 0.5 mg/kg/min intravenously) states at baseline, after preconstriction with the U46619, and during the cumulative intravenous administration of prostacyclin. Results: Propofol had no effect on the baseline pressure-flow relation versus the control state. A lower (P

Effects of halothane and enflurane anesthesia on sympathetic beta-adrenoreceptor-mediated pulmonary vasodilation in chronically instrumented dogs.

The authors previously reported that the pulmonary vasodilator response to the sympathetic beta-adrenoreceptor agonist isoproterenol is potentiated during isoflurane anesthesia compared with the conscious state. In the present in vivo study, the authors tested the hypothesis that halothane and enflurane anesthesia also enhance sympathetic beta adrenoreceptor-mediated pulmonary vasodilation. The authors also used the membrane-permeable analog of cyclic adenosine monophosphate (cAMP), dibutyryl cAMP, to help delineate the site in the signaling pathway for an anesthesia-induced effect on beta adrenoreceptor-mediated pulmonary vasodilation. Mongrel dogs were chronically instrumented to measure the left pulmonary vascular pressure-flow (LPQ) relationship. LPQ plots were measured on separate days in the conscious, halothane-, and enflurane-anesthetized states at baseline, after preconstriction with the thromboxane analog U46619, and during the cumulative intravenous administration of isoproterenol. LPQ plots were also measured in conscious, halothane-, and isoflurane-anesthetized dogs after U46619 preconstriction and during the cumulative intravenous administration of dibutyryl cAMP. Compared with the conscious state, neither halothane nor enflurane had an effect on the baseline LPQ relationship. The magnitude of the pulmonary vasodilator response to isoproterenol was potentiated during halothane anesthesia but unchanged during enflurane anesthesia. The pulmonary vasodilator response to dibutyryl cAMP was not altered during either halothane or isoflurane anesthesia compared with the conscious state. These results indicate that inhalational anesthetic agents can exert differential effects on the pulmonary vasodilator response to sympathetic beta-adrenoreceptor activation. The potentiated vasodilator response observed during halothane and isoflurane anesthesia is the result of effects proximal to cAMP accumulation in the beta-adrenoreceptor signaling pathway.

Propofol selectively attenuates endothelium-dependent pulmonary vasodilation in chronically instrumented dogs.

The objective was to investigate the effects of propofol anesthesia on the pulmonary vascular response to endothelium-dependent and -independent vasodilators, compared with the responses measured in the conscious state. Twenty-six conditioned, male, mongrel dogs were instrumented long-term to measure the left pulmonary vascular pressure-flow relation. Pressure-flow plots were measured on separate days in conscious and propofol-anesthetized (5.0 mg/kg plus 0.5 mg. kg-1. min-1 intravenously) dogs at baseline, after preconstriction with the thromboxane mimetic U46619, and during the cumulative intravenous administration of endothelium-dependent (acetylcholine and bradykinin) and -independent (proline-nitric oxide) vasodilators. Propofol had no effect on the baseline pressure-flow relation compared with the conscious state. A lower (P < 0.05) dose of U46619 was necessary to achieve the same degree of preconstriction during propofol anesthesia. The pulmonary vasodilator responses to bradykinin and proline-nitric oxide were similar in the conscious and propofol-anesthetized states. In contrast, the pulmonary vasodilator response to acetylcholine was markedly attenuated (P < 0.01) during propofol anesthesia. The intralipid vehicle for propofol had no effect on the acetylcholine dose-response relation. These results suggest that propofol causes a specific defect in the signal transduction pathway for acetylcholine-induced pulmonary vasodilation. This defect involves the endothelial and not the vascular smooth muscle component of the response.

Pulmonary vasoregulation by endothelin in conscious dogs after left lung transplantation.

We tested the hypothesis that regulation of the pulmonary circulation by endogenous endothelin (ET) during normoxia and hypoxia was altered in conscious dogs 1 mo after left lung autotransplantation (LLA). Sham-operated control and post-LLA dogs were chronically instrumented to measure the left pulmonary vascular pressure-flow (LP-Q) relationship. LP-Q plots were generated on separate days during normoxia and hypoxia (arterial PO(2) approximately 50 Torr) in the intact condition, after selective ET(A)-receptor inhibition (BQ-485), and after combined ET(A+B)-receptor inhibition (bosentan). Although LLA resulted in a chronic increase in pulmonary vascular resistance, the ET-receptor antagonists had no effect on the LP-Q relationship during normoxia in either group. The magnitude of hypoxic pulmonary vasoconstriction (HPV) was flow dependent in both groups, and the HPV response was potentiated post-LLA compared with control. ET(A)-receptor inhibition attenuated the HPV response to the same extent in both groups. ET(A+B)-receptor inhibition attenuated the HPV response to a greater extent than did ET(A)-receptor inhibition alone, and this effect was greater post-LLA compared with control. Plasma ET-1 concentration only increased during hypoxia in the LLA group. These results indicate that ET does not regulate the baseline LP-Q relationship in either group. Both ET(A)- and ET(B)-receptor activation mediate a component of HPV in conscious dogs, and the vasoconstrictor influence of ET(B)-receptor activation is enhanced post-LLA.

Inhibition of cyclooxygenase and nitric oxide synthase in hypoxic vasoconstriction and oleic acid-induced lung injury.

Cyclooxygenase (COX) products and nitric oxide (NO) inhibit hypoxic pulmonary vasoconstriction (HPV), and their release could contribute to alterations in gas exchange in lung injury. We tested the hypothesis that combined blockade of COX and NO synthase (NOS) could further increase HPV and better protect gas exchange in lung injury than could blockade of either COX or NOS alone. We determined pulmonary vascular pressure-flow relationships in pentobarbital-anesthetized and ventilated dogs submitted to hypoxic challenges before and after administration of solvent (n = 4), indomethacin alone (2 mg/kg intravenously, n = 8), Nomega-nitro-L-arginine (L-NA) alone (10 mg/kg intravenoulsy, n = 8), indomethacin followed by L-NA (n = 8), and L-NA followed by indomethacin (n = 8). All of the dogs so treated then received oleic acid (0.06 ml/kg intravenously) to induce lung injury. Blood flow was manipulated by establishing a femoral arteriovenous bypass or by inflating an inferior vena caval balloon. Gas exchange was evaluated by measuring arterial PO2 and intrapulmonary shunt (using the inert gas sulfur hexafluoride) at identical cardiac outputs. The magnitude of HPV was not affected by solvent. Indomethacin and L-NA given separately enhanced HPV. L-NA added to indomethacin further enhanced HPV, as did indomethacin added to L-NA. After oleic acid-induced lung injury, gas exchange deteriorated less in dogs pretreated with indomethacin than in dogs pretreated with solvent or with L-NA alone. These results suggest that in pentobarbital-anesthetized dogs: (1) the magnitude of HPV is limited by the corelease of COX metabolites and of NO; and (2) inhibition of COX, but not of NOS, attenuates the deterioration of gas exchange in oleic acid-induced lung injury.

Effects of isoflurane anesthesia on pulmonary vascular response to K+ ATP channel activation and circulatory hypotension in chronically instrumented dogs.

The objective of this study was to evaluate the effects of isoflurane anesthesia on the pulmonary vascular responses to exogenous adenosine triphosphate-sensitive potassium (K+ ATP) channel activation and circulatory hypotension compared with responses measured in the conscious state. In addition, the extent to which K+ ATP channel inhibition modulates the pulmonary vascular response to circulatory hypotension in conscious and isoflurane-anesthetized dogs was assessed. Fifteen conditioned, male mongrel dogs were fitted with instruments for long-term monitoring to measure the left pulmonary vascular pressure-flow relation. The dose-response relation to the K+ ATP channel agonist, lemakalim, and the pulmonary vascular response to circulatory hypotension were assessed in conscious and isoflurane-anesthetized (approximately 1.2 minimum alveolar concentration) dogs. The effect of the selective K+ ATP channel antagonist, glibenclamide, on the pulmonary vascular response to hypotension was also assessed in conscious and isoflurane-anesthetized dogs. Isoflurane had no effect on the baseline pulmonary circulation, but it attenuated (P<0.05) the pulmonary vasodilator response to lemakalim. Reducing the mean systemic arterial pressure to approximately 50 mm Hg resulted in pulmonary vasoconstriction (P<0.05) in the conscious state, and this response was attenuated (P<0.05) during isoflurane. Glibenclamide had no effect on the baseline pulmonary circulation, but it potentiated (P<0.05) the pulmonary vasoconstrictor response to hypotension in conscious and isoflurane-anesthetized dogs. These results indicate that K+ ATP-mediated pulmonary vasodilation and the pulmonary vasoconstrictor response to hypotension are attenuated during isoflurane anesthesia. Endogenous K+ ATP channel activation modulates the pulmonary vasoconstrictor response to hypotension in the conscious state, and this effect is preserved during isoflurane anesthesia.

PROPOFOL ANESTHESIA RESULTS IN PROFOUND PULMONARY VASOCONSTRICTION IN CHRONICALLY-INSTRUMENTED DOGS FOLLOWING LEFT LUNG AUTOTRANSPLANTATION

S546 Introduction: Left lung autotransplantation (LLA) results in a chronic increase in pulmonary vascular resistance. [1] The effects of propofol anesthesia on the pulmonary circulation are controversial. In normal dogs, propofol can induce profound pulmonary vasoconstriction in the setting of acutely elevated vasomotor tone. [2] In this study, we investigated the effects of propofol anesthesia on the left pulmonary vascular pressure-flow (LPQ) relationship in chronically-instrumented dogs with elevated vasomotor tone resulting from LLA. Methods: We utilized 8 dogs that had undergone LLA 3 to 7 weeks earlier. LPQ plots were generated by continuously measuring the pulmonary vascular pressure gradient (PAP-LAP) and left pulmonary flow (LQ) during gradual ([similar]1 min) inflation of a hydraulic occuder implanted around the right pulmonary artery. In protocol 1, LPQ plots were measured in the conscious state and during the cumulative intravenous administration of propofol anesthesia (5 mg/kg bolus plus 0.25, 0.5, 1.0 mg[center dot]kg-1 [center dot]min-1 maintenance dose). In protocol 2, LPQ plots were obtained in the conscious state, following preconstriction with the thromboxane analog, U46619 ([similar]0.2 [micro sign]g[center dot]kg-1 [center dot]min-1, iv), to acutely increase pulmonary vasomotor tone, and during propofol anesthesia as described in protocol 1. Two-way ANOVA was used to assess the effects of propofol on the LPQ relationship. Values are means +/- SEM. Results: LLA resulted in a chronic increase (p < 0.01) in pulmonary vascular resistance. Compared to the conscious state, propofol anesthesia had no effect on the baseline LPQ relationship post-LLA (Figure 1). In contrast, when pulmonary vasomotor tone was acutely increased (p < 0.01) with U46619, propofol resulted in marked dose-dependent pulmonary vasoconstriction (Figure 1).Figure 1Discussion: Despite the chronic increase in pulmonary vasomotor tone post-LLA, propofol did not exert a vasodilator influence on the baseline pulmonary circulation post-LLA. However, in the setting of acutely elevated vasomotor tone, propofol induced profound dose-dependent pulmonary vasoconstriction post-LLA.

Halothane and Enflurane Attenuate Pulmonary Vasodilation Mediated by Adenosine Triphosphate-sensitive Potassium Channels Compared to the Conscious State

Adenosine triphosphate (ATP)-sensitive potassium (k+ATP) channels play an important role in pulmonary vasoregulation. However, the effects of volatile anesthetics on k+ATP channel-mediated pulmonary vasoregulation have not been elucidated. The purpose of the present study was to investigate the effects of halothane and enflurane anesthesia on the pulmonary vasodilator response to the selective k+ATP channel agonist lemakalim (BRJ38227) compared with that measured in the conscious state. The authors also investigated the extent to which endogenous neurohumoral vasoconstrictor mechanisms modulate the vasodilator response to k+ATP channel activation. Nineteen conditioned, male mongrel dogs were chronically instrumented to measure the left pulmonary vascular pressure-flow (LPQ) relationship. LPQ plots were generated by continuously measuring the pulmonary vascular pressure gradient (pulmonary arterial pressure-left atrial pressure) and left pulmonary blood flow during gradula (approximately 1 min) inflation of a hydraulic occluder implanted around the right main pulmonary artery. After preconstriction with the thromboxane analog, U46619 (9,11-dideoxy-11 alpha, 9 alpha-epoxymethano-prostaglandin F2 alpha), the pulmonary vascular dose-response relationship for the k+ATP agonist lemakalim was assessed in the conscious and halothane-anesthetized states and also in the conscious and enflurane-anesthetized states. This protocol was repeated in conscious and halothane-anesthetized dogs after combined neurohumoral block with antagonists of sympathetic alpha 1 adrenoreceptors, arginine vasopressin V1-receptors, and angiotensin II receptors. The effect of the k+ATP antagonist glybenclamide on the baseline LPQ relationship and on the lemakalim dose-response relationship also was assessed in conscious dogs. Compared with the conscious state, halothane, enflurane and glybenclamide had no net effect on the baseline LPQ relationship. In contrast, halothane and enflurane attenuated (P < 0.05) the pulmonary vasodilator response to lemakalim compared with the conscious state. Glybenclamide also caused a rightward shift (P < 0.05) in the lemakalim dose-response relationship. Combined neurohumoral block did not modulate the vasodilator response to lemakalim in the conscious state. The halothane-induced attenuation of the vasodilator response to lemakalim was apparent after combined neurohumoral block. These results indicate that halothane and enflurane act to reduce the magnitude of K+ATP channel-mediated pulmonary vasodilation. Reflex pulmonary vasoconstriction resulting from K+ATP mediated systematic hypotension does not alter the magnitude of the pulmonary vasodilator response to lemakalim nor is it responsible for the attenuated response to K+ATP channel activation during halothane anesthesia.

Pulmonary vascular effects of isoflurane anesthesia after left lung autotransplantation in chronically instrumented dogs.

Single lung transplantation has become a viable therapy for treatment of end-stage pulmonary disease. We previously observed that left lung autotransplantation (LLA) results in a chronic increase in pulmonary vascular resistance and enhanced pulmonary vascular reactivity to sympathetic alpha adrenoreceptor activation. The effects of inhalational anesthetics on the pulmonary circulation after lung transplantation have not been investigated. In the current study, the authors tested the hypothesis that isoflurane anesthesia, known to cause systemic vasodilation, would exert a vasodilator influence on the baseline pulmonary circulation after LLA. In addition, they tested the hypothesis that isoflurane anesthesia, known to attenuate the systemic vasoconstrictor response to sympathetic alpha adrenoreceptor agonists, would reduce the magnitude of the pulmonary vasoconstrictor response to sympathetic alpha adrenoreceptor activation after LLA. Left pulmonary vascular pressure-flow (LPQ) plots were generated in chronically instrumented dogs by measuring the pulmonary vascular pressure gradient (pulmonary arterial pressure-left atrial pressure) and left pulmonary blood flow during inflation of a hydraulic occluder implanted around the right main pulmonary artery. Left pulmonary vascular pressure-flow plots were generated in 8 dogs 2-5 weeks after LLA in the conscious and isoflurane-anesthetized states at baseline, after beta adrenoreceptor block with propranolol, and during the cumulative administration of the alpha agonist, phenylephrine. Left pulmonary vascular pressure-flow plots also were generated in eight conscious, sham-operated control dogs at baseline, after beta block, and during phenylephrine administration. Compared with conscious control dogs, LLA resulted in a leftward shift (P < 0.01) in the baseline left pulmonary vascular pressure-flow relation, indicating chronic pulmonary vasoconstriction. Despite the enhanced level of pulmonary vasomotor tone after LLA, isoflurane did not exert a vasodilator influence on the baseline left pulmonary vascular pressure-flow relation. The pulmonary vasoconstrictor response to phenylephrine was enhanced (P < 0.01) after LLA compared with the response measured in conscious control dogs. The magnitude of the pulmonary vasoconstrictor response to phenylephrine after LLA was not attenuated during isoflurane anesthesia. Isoflurane anesthesia does not exert a vasodilator influence on the pulmonary circulation in the setting of increased pulmonary vascular resistance after LLA. In addition, in contrast to previous studies of the systemic circulation, isoflurane does not attenuate the enhanced pulmonary vasoconstrictor response to sympathetic alpha adrenoreceptor activation after LLA.

Chronic infusion of nitric oxide in experimental pulmonary hypertension: pulmonary pressure-flow analysis.

Inhaled-nitric oxide (NO) is a selective pulmonary vasodilator in short-term clinical studies. Use of NO inhalation in chronic pulmonary hypertension is complicated by potential problems with ambulatory NO delivery. We hypothesized that long-term infusion of NO solution into the central venous circulation, which did not suffer from this drawback, might reduce chronic pulmonary hypertension. Saturated NO solution was infused in chronically hypoxic rats by implantable minipumps at a rate which was effective in reducing acute hypoxic vasoconstriction in isolated, Krebs' albumin perfused lungs (2.5 microL.h-1). Pulmonary haemo dynamics and the pressure-flow relationship were studied after 4 weeks of infusion. NO was still present in the minipumps at the end of the infusion period. Despite causing methaemoglobinaemia, NO infusion did not significantly attenuate pulmonary arterial pressure, pulmonary vascular resistance, right ventricular hypertrophy, or the parameters of the pulmonary vascular pressure-flow relationship. Pressure-flow curves, analysed with the nonlinear, distensible vessel model, indicated increased near-zero pressure resistance (Ro) in chronic hypoxia. The tendency of chronic NO infusion to reduce Ro did not reach statistical significance. Long-term infusion of nitric oxide solution is technically feasible but does not effectively reverse chronic pulmonary hypertension. The failure of infused NO to reduce pulmonary hypertension is explained by the fact that the inactivation of NO by haemoglobin is much faster than anticipated.

Effect of nitric oxide on the pulmonary vascular pressure-flow relationship in a canine model of thrombolytic pulmonary hypertension

Effect of nitric oxide on the pulmonary vascular pressure-flow relationship in a canine model of thrombolytic pulmonary hypertension

Thoracotomy increases peripheral airway tone and reactivity.

Our goal was to investigate the extent to which thoracotomy for chronic vascular instrumentation alters peripheral airway tone and reactivity. Using the wedged bronchoscope technique to measure peripheral airway resistance (RP), pentobarbital-fentanyl anesthetized, ventilated dogs were studied before and (16 +/- 2 d) after a left thoracotomy for chronic implantation of instrumentation to measure the left pulmonary vascular pressure-flow relationship. A map of the airways was constructed as bronchoscopes were advanced and wedged in the middle lobes of both the left and right lung. This allowed us to measure RP in the same sublobar region of the left and right lung both pre- and postoperatively. At the time of postoperative experimentation, all dogs appeared fully recovered from the surgical procedure. Compared with preoperative values, baseline RP (cm H2O.ml-1.s-1) was selectively increased (p < 0.03) postoperatively in the left (0.41 +/- 0.07 versus 1.27 +/- 0.36) but not in the right (0.29 +/- 0.06 versus 0.35 +/- 0.07) lung. Peripheral airway responses to acetylcholine, histamine, hypocapnia, and dry air challenges were all increased (p < 0.05) in both magnitude and duration in the left but not the right lung postoperatively. Total lung volume (helium dilution technique) was decreased (p < 0.01) by 10 +/- 3% postoperatively. However, similar reductions in lung volume were observed in the left and right lung. These results indicate that left thoracotomy for chronic instrumentation selectively increases left lung peripheral airway tone and reactivity, but has no effect on the right lung.