Increase In Ppa Research Articles

Abstract 16270: Pulse Pressure Amplification Contributes to the Exaggerated Peripheral Blood Pressure Response to Exercise in Patients With HFpEF

Background: Patients with suspected heart failure and preserved ejection fraction (HFpEF) undergo invasive (right heart catheterization) cardiopulmonary exercise testing (iCPET) to confirm diagnosis. During iCPET peripheral arterial blood pressure (BP) is measured using a brachial cuff or radial arterial catheter. Notably, peripheral BP is typically higher than central BP and this difference is assessed by measuring pulse pressure amplification (PPA; peripheral - central PP; PP = systolic BP [SBP] - diastolic BP). The effect of PPA on the assessment of (exaggerated) exercise BP in HFpEF is unknown. Methods: 20 patients with HFpEF (75% Female; age: 69±7 years, BMI: 38±7 kg/m 2 ) were studied at rest and during submaximal and maximal cycling exercise. We measured radial BP (arterial catheterization) and derived ascending aortic BP using a transfer function applied to radial arterial waveforms (SphygmoCor). Pulse pressure amplification was assessed as radial-aortic pulse pressure. Data were compared with one-way and two-way (Site*Exercise Stage) ANOVA. Results: The increase in radial PP with exercise was greater than aortic PP (Site*Stage P<0.001; Figure A); thus, PPA increased with exercise (ANOVA, P =0.001; Figure B). The increase in PPA was due to a greater increase in radial compared to aortic SBP (Site*Stage P=0.002; Figure C). The change in diastolic pressure was not different between sites (Figure D). Increases in PPA accounted for ~30% of the increase in radial SBP. The incidence of exaggerated exercise SBP (Male: >210 mmHg; Female: >190 mmHg) was higher in the radial artery compared to aorta (95 vs 40 %, χ2<0.001). Conclusion: Peak exercise SBP was ~50 mmHg greater in the radial artery compared to aorta. The marked overestimation of central BP during exercise when measuring peripheral BP leads to misguided interpretation of BP responses to exercise, the magnitude of afterload and has implications for the assessment of ventricular-arterial coupling.

Levosimendan reduces segmental pulmonary vascular resistancein isolated perfused rat lungs and relaxes human pulmonary vessels.

IntroductionLevosimendan is approved for acute heart failure. Within this context, pulmonary hypertension represents a frequent co-morbidity. Hence, the effects of levosimendan on segmental pulmonary vascular resistance (PVR) are relevant. So far, this issue has been not studied. Beyond that the relaxant effects of levosimendan in human pulmonary vessel are unknown. We addressed these topics in rats’ isolated perfused lungs (IPL) and human precision-cut lung slices (PCLS).Material and methodsIn IPL, levosimendan (10 μM) was perfused in untreated and endothelin-1 pre-contracted lungs. The pulmonary arterial pressure (PPA) was continuously recorded and the capillary pressure (Pcap) was determined by the double-occlusion method. Thereafter, segmental PVR, expressed as precapillary (Rpre) and postcapillary resistance (Rpost) and PVR were calculated. Human PCLS were prepared from patients undergoing lobectomy. Levosimendan-induced relaxation was studied in naïve and endothelin-1 pre-contracted PAs and PVs. In endothelin-1 pre-contracted PAs, the role of K+-channels was studied by inhibition of KATP-channels (glibenclamide), BKCa2+-channels (iberiotoxin) and Kv-channels (4-aminopyridine). All changes of the vascular tone were measured by videomicroscopy. In addition, the increase of cAMP/GMP due to levosimendan was measured by ELISA.ResultsLevosimendan did not relax untreated lungs or naïve PAs and PVs. In IPL, levosimendan attenuated the endothelin-1 induced increase of PPA, PVR, Rpre and Rpost. In human PCLS, levosimendan relaxed pre-contracted PAs or PVs to 137% or 127%, respectively. In pre-contracted PAs, the relaxant effect of levosimendan was reduced, if KATP- and Kv-channels were inhibited. Further, levosimendan increased cGMP in PAs/PVs, but cAMP only in PVs.DiscussionLevosimendan reduces rats’ segmental PVR and relaxes human PAs or PVs, if the pulmonary vascular tone is enhanced by endothelin-1. Regarding levosimendan-induced relaxation, the activation of KATP- and Kv-channels is of impact, as well as the formation of cAMP and cGMP. In conclusion, our results suggest that levosimendan improves pulmonary haemodynamics, if PVR is increased as it is the case in pulmonary hypertension.

Effect of Increased Blood Flow on Pulmonary Circulation Before and During High Altitude Acclimatization.

Pulmonary artery catheter determined that systolic Ppa (mean ± SEM) was increased from 20 ± 1 at SL to 27 ± 2 mmHg at HA3 (p < 0.01). Echocardiography assessed that systolic Ppa remained equally increased throughout acclimatization (26 ± 2, 25 ± 2, 25 ± 2, and 24 ± 2 mmHg at HA1-HA4; p = 0.93) and returned to baseline upon return (17 ± 2, 18 ± 1 mmHg at SL, SL2; p = 0.3). The same was shown for PVR. Right heart function remained unaffected. Thigh cuff release maneuvers at SL and HA3 resulted in similar increase in cardiac output (2.5 ± 0.5 and 2.2 ± 0.4 L/min; p = 0.61) without affecting mean Ppa. Prolonged altitude exposure leads to a persistent increase in Ppa and PVR without affecting right heart function and is fully reversible within 1 week after return to SL. The thigh cuff release maneuver-induced increase in cardiac output suggests a preserved ability of pulmonary circulation to cope with sudden remarkable increase in pulmonary blood flow throughout acclimatization.

All physical activity may not be associated with a lower likelihood of adolescent smoking uptake

ObjectiveResearch has documented that physical activity is associated with a lower risk of adolescent smoking uptake, yet it is unclear whether this relationship exists for all types of physical activity. We sought to determine whether certain types of physical activity are associated with a decreased or an increased risk of adolescent smoking uptake. MethodsIn this longitudinal cohort study, adolescents (n=1356) were surveyed every six months for four years (age 14–18years old). Smoking and physical activity were measured at each of the eight time-points. Physical activity that was negatively associated with smoking across the eight waves was considered positive physical activities (i.e., PPA; linked to not smoking such as racquet sports, running, and swimming laps). Physical activity that was positively associated with smoking across the eight waves were considered negative physical activities (i.e., NPA; linked to smoking such as skating, walking, bicycling, sport fighting, and competitive wrestling). ResultsAssociative Processes Latent Growth Curve Modeling revealed that each 30-minute increase in NPA per week at baseline was associated with a 4-fold increased odds of smoking progression (OR=4.10, 95% CI=2.14, 7.83). By contrast, each 30-minute increase in PPA at baseline was associated with a 51% decrease in the odds of smoking progression (OR=.49, 95% CI=.25, .93). ConclusionsThe type of physical activity that an adolescent engages appears to be important for the uptake of cigarette smoking among adolescents. These associative relationships warrant consideration in interventions to increase overall physical activity and those promoting physical activity to prevent smoking uptake.

Non-invasively measured aortic wave reflection and pulse pressure amplification are related to the severity of coronary artery disease

BackgroundAugmentation index (AIx) and pulse pressure amplification (PPA, here the aortic/brachial pulse pressure ratio) are an age-related emerging risk factor for cardiovascular disease. However, it has not been clearly shown that AIx and PPA predict a high risk of coronary artery disease (CAD). ObjectivesThe aim of the study was to investigate the association between non-invasively measured aortic wave reflection (AWR) and PPA and CAD. MethodsThe study group consisted of 80 patients who were admitted to our institute for elective coronary angiography. We non-invasively measured augmentation pressure (AP), AIx, and PPA using radial applanation tonometry. ResultsWhen the extent of CAD was divided by no or minimal CAD, 1- or 2- and 3-vessel disease (VD), there was a significant association between the extent of CAD and AIx and PPA in patients aged <65 years, but not in patients aged ≥65 years. In multivariate regression analysis after controlling the traditional risk factors, the odds ratio of having 3VD was significant in patients aged <65 years: 2.15 (1.04–4.44; p=0.039) per 5% increase of AIx and 2.02 (1.15–3.55; p=0.015) per 0.05 increase of PPA, but not in patients aged ≥65 years. The severity of CAD expressed as a Gensini score showed a significant correlation with AP, AIx, and PPA in patients aged <65 years, but not in patients aged ≥65 years. ConclusionIncreasing of non-invasively measured AWR and PPA is related to the severity of CAD, particularly in younger patients up to 65 years of age.

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.

The relationship between pulmonary hemodynamics and chest X-ray findings in patients with sequelae of pulmonary tuberculosis

For better understanding of pathophysiological aspects of tuberculosis sequelae, we investigated the relationship between pulmonary hemodynamics and chest X-ray findings. One hundred and seven patients with sequelae of pulmonary tuberculosis were examined by the right cardiac catheterization, and pulmonary hemodynamic values were measured and calculated. Chest X-ray findings were defined and classified into the following five items. The items were emphysematous change; fibrosis, bronchiectasis and/or cavity (hereafter abbreviated as "fibrosis"); pulmonary resection and/or atelectasis; pleural thickening; and thoracoplasty. The extent of each finding was defined. We tried to describe chest X-ray findings by applying and categorizing these classifications and the extent to each case. First, we tried to estimate the grade of pulmonary hypertension by categorized X-ray findings. Further, we analyzed what kinds of findings were most influential on the increase of pulmonary artery mean pressure (PPA) and pulmonary arteriolar resistance (PAR). Secondly, we investigated whether PPA, cardiac index (CI) and PAR changed before and after oxygen administration. Thirdly, we analyzed what kind of X-ray findings most affected pulmonary hemodynamics under 100% oxygen administration for 10 minutes. The results were as follows: (1) Out of 107 cases, it was possible to predict PPA by categorized chest X-ray findings in 75 cases by Hayashi's first method of quantification, one of multivariative analyses. "Pleural thickening" was the most influential finding on the increase of PPA. "Fibrosis" was the most influential on the increase of PAR. (2) The values of PPA, CI and PAR decreased more after 100% oxygen administration than under room air breathing. Therefore, PAR was used as the index to estimate pulmonary hemodynamics under the condition of oxygen administration. (3) It was possible to measure PAR under oxygen administration (PARO2) in 72 cases. "Emphysematous change" was the most influential X-ray finding on the increase of PARO2. From these results, it was thought that pulmonary circulatory disorder in patients with tuberculosis sequelae was caused by the combination of various chest X-ray findings with the different extent. It was possible to predict pulmonary hypertension to a certain degree from categorized chest X-ray findings. It was suggested that "emphysematous change" less related to hypoxic pulmonary vasoconstriction than "fibrosis" and "pleural thickening" from the results of comparison among the partial correlation coefficients, which were associated with the increase of PAR under room air breathing and oxygen administration.(ABSTRACT TRUNCATED AT 400 WORDS)

Iodine‐123 metaiodobenzylguanidine scintigraphic assessment of pulmonary vascular status in patients with chronic obstructive pulmonary disease

Lung uptake of iodine-123 metaiodobenzylguanidine (¹²³I-MIBG) is used as an indicator of pulmonary endothelial function. Decreased lung uptake of ¹²³I-MIBG has been demonstrated in patients with COPD as compared with normal subjects. The present study was performed to examine the relationship between lung uptake of ¹²³I-MIBG and pulmonary artery pressure (Ppa) at rest and during exercise, in patients with COPD. ¹²³I-MIBG scintigraphy was performed in 19 patients with COPD. Anterior planar images were acquired 15 min after the injection of ¹²³I-MIBG, and the total lung to upper mediastinum ratio (LMR) was calculated for both lungs. Right heart catheters were used to monitor Ppa continuously at rest and during exercise. Exercise was performed on an electrically braked bicycle ergometer at a constant workload of 25 W for 3 min. In COPD patients the LMR were not correlated with the pulmonary function parameters measured before exercise, including FEV₁, PaO₂, DL(CO), or Ppa at rest. However, the percentage increase in Ppa during exercise was significantly correlated with LMR. Evaluation of the kinetics of lung uptake of ¹²³I-MIBG may be a novel scintigraphic tool for the assessment of exercise-induced pulmonary hypertension in patients with COPD.

Reduced Pulmonary Vascular Reactivity after Cold Exposure to Acute Hypoxia: A Role of Nitric Oxide (NO)

Exposure to high altitude causes pulmonary hypertension and alterations in pulmonary vascular reactivity. Among the environmental factors, cold exposure has been suggested to be involved in the development of pulmonary hypertension. However, little information is available about pulmonary vascular reactivity after cold exposure. We examined whether cold exposure can cause changes in pulmonary vascular reactivity to acute hypoxia and the possible participation of endogenous nitric oxide. We measured mean systemic (Psa) and pulmonary artery pressures (Ppa) in conscious rats after 1-week cold exposure (3.5 +/- 1.0 degrees C). Subsequently, we investigated hypoxic pulmonary vasoconstriction (HPV) with and without endogenous NO inhibition using N(G)-nitro-L-arginine methyl ester (3 mg/kg) or 7-nitroindazole (1 mg/kg). Cold exposure for 1 week caused a small but significant increase in Ppa, but not in Psa. Neither Ppa nor Psa showed significant changes after both NO inhibitions in rats exposed to cold. However, cold exposure caused a blunted HPV and an increase in plasma nitrite-nitrate concentration compared with rats kept in a neutral environment (24.0 +/- 1.0 degrees C). In addition, NO inhibition by N(G)-nitro-L-arginine methyl ester partially restored the blunted HPV in rats exposed to cold, but not 7-nitroindazole, a selective inhibitor of neuronal NO synthase. We concluded that cold exposure alters pulmonary vascular reactivity to acute hypoxia, and augmented endothelial NO bioactivity plays a counterregulatory role in response to acute hypoxia during cold exposure in rats.

Systemic Inflammation in Patients With COPD and Pulmonary Hypertension

COPD is a systemic disorder that is associated with increases of inflammatory proteins in systemic circulation. However, no data on the potential role of systemic inflammation in pulmonary hypertension secondary to COPD are available. Therefore, our aim was to investigate the degree of systemic inflammation reflected by circulatory levels of C-reactive protein (CRP), tumor-necrosis factor (TNF)-alpha, and interleukin (IL)-6 in COPD patients with and without pulmonary hypertension. Cross-sectional study. University hospital, tertiary referral setting. In 43 consecutive patients with COPD (mean [+/- SD] age, 65.0 +/- 10.5 years; mean FEV(1), 46.2 +/- 18.1% predicted), lung function was assessed using body plethysmography; pulmonary artery pressure (Ppa) levels were measured by echocardiography. Serum TNF-alpha and IL-6 levels were assessed by enzyme-linked immunosorbent assay, and high-sensitivity serum CRP levels were measured by chemiluminescent immunoassay. Pulmonary hypertension was present in 19 patients and was absent in 24 patients. In patients with pulmonary hypertension, serum CRP and TNF-alpha levels were significantly higher than in those patients without hypertension (median, 3.6 mg/L [25th to 75th percentile, 1.4 to 13.0 mg/L] vs 1.8 mg/L [25th to 75th percentile, 0.8 to 2.8 mg/L; p = 0.034]; and median, 4.2 pg/mL [25th to 75th percentile, 3.4 to 10.9 pg/mL] vs 3.1 pg/mL [25th to 75th percentile, 2.1 to 4.2 pg/mL]; p = 0.042, respectively). No differences were seen in serum IL-6 (median, 10.4 pg/mL [25th to 75th percentile, 8.8 to 12.2 pg/mL] vs 10.5 pg/mL [25th to 75th percentile, 9.4 to 39.1 pg/mL]; p = 0.651) between the groups. In multiple linear regression analysis, the following two variables were independent predictors of systolic Ppa (R(2) = 0.373): Pao(2) (p = 0.011); and log-transformed serum CRP level (p = 0.044). We conclude that increases in Ppa in patients with COPD are associated with higher serum levels of CRP and TNF-alpha, raising the possibility of a pathogenetic role for low-grade systemic inflammation in the pathogenesis of pulmonary hypertension in COPD patients.

Fullerene derivative attenuates ischemia-reperfusion-induced lung injury

Reactive oxygen species are the major contributing factors to lung ischemia-reperfusion (IR) injury. In this study, we tested whether a water soluble antioxidant fullerene derivative [C 60(ONO 2) 7 ± 2] attenuates IR lung injury. Young Wistar rats were divided into two groups: control and C 60(ONO 2) 7 ± 2. Under ventilation with 95% air-5% CO 2 gas mixture and a 2.5 cm H 2O end-expiratory pressure, the isolated lungs were perfused with a physiological solution. The experimental protocol included three periods: baseline (10 min), ischemia (45 min) and reperfusion (60 min, ventilated with 95% O 2-5% CO 2 gas mixture). Before and after ischemia, we measured pulmonary arterial pressure (Ppa), pulmonary venous pressure and lung weight (W). Then, pulmonary capillary pressure and filtration coefficient (K fc) were calculated. Ischemia caused increases in Ppa, W and K fc in the control group. For most cases, the above ischemia-induced increases were attenuated by the C 60(ONO 2) 7 ± 2 pretreatment. Our results suggest that the antioxidant C 60(ONO 2) 7 ± 2 attenuates IR-induced lung injury.

Benefits of Oxygen on Exercise Performance and Pulmonary Hemodynamics in Patients With COPD With Mild Hypoxemia

To clarify the effects of oxygen on exercise performance and pulmonary hemodynamics during exercise in patients with COPD with mild hypoxemia at rest. Seventy-five male patients with stable COPD ("pink puffer" type), accompanied by mild hypoxemia (> 60 mm Hg) at rest and with mild (percentage of predicted FEV1 [%FEV1] > 50%, n = 16), moderate (%FEV1 > 35% to < or = 50%, n = 25), and severe (%FEV1 < or =35%, n = 34) airflow obstruction were recruited from an outpatient clinic. A 6-min walking distance (6MD) test was administered to 75 patients, and the pulmonary hemodynamics of 43 subjects were determined during exercise on a supine bicycle ergometer at 25 W and breathing compressed air and oxygen at 2 L/min. Supplemental oxygen resulted in a significant increase in 6MD, except for patients with mild airflow obstruction and mild desaturation. This increase in 6MD produced by oxygen was greater as the restriction of the airflow was more severe, and correlated negatively with %FEV1, but not with PaO2 at rest or exercise hypoxemia. Pulmonary artery pressure (Ppa) and pulmonary artery occlusion pressure (Pop) increased with exercise, while the rates of increase in both types of pressure were significantly higher for severe COPD than for mild COPD and moderate COPD. Oxygen inhalation significantly reduced the increases in Ppa and Pop during exercise in patients with moderate-to-severe COPD, and the effect of oxygen on the increase in Pop correlated positively with airtrapping (vital capacity - FVC). These findings suggest that supplemental oxygen benefits patients with COPD with moderate-to-severe airflow obstruction and mild hypoxemia at rest, as reflected in improvement in exercise performance and pulmonary hypertension during exercise.

ACTIVATION OF EGF RECEPTORS MEDIATES PULMONARY VASOCONSTRICTION INDUCED BY RESIDUAL OIL FLY ASH

Residual oil fly ash (ROFA)is a constituent of pollutant particles that can producelung injury and activate protein tyrosine phosphorylation cascade. In this study, we determined whether or not protein tyrosine phosphorylation caused lung injury, and if so, identified critical tyrosine phosphorylated proteins that mediated the injury. ROFA was instilled intratracheally into perfused rabbit lungs and injury responses, including increase in pulmonary artery pressure (Ppa), lung weight gain, as well as release of interleukin (IL)-1 β, IL-6, IL-8, and nitrite/nitrate were measured. ROFA increased Ppa and IL-1 β, but inhibited nitrite/nitrate accumulation. Vanadyl sulfate at concentration equivalent to the amount of vanadium detected in the perfusate of ROFA-treated lungs induced similar changes. ROFAenhanced tyrosine phosphorylation of lung proteins, including a 170-kDa protein, likely the epidermal growth factor (EGF)receptor, as shown by immunoprecipitation. Pretreatment with genistein, a tyrosine kinase inhibitor, blocked the increase in Ppa and tyrosine phosphorylation of the 170-kDa protein. Intravascular administration of human EGF increased Ppa, and pretreatment with PD153035, an EGF receptor-specific tyrosine kinase inhibitor, attenuated ROFA-induced pulmonary vasoconstriction. These results indicate that tyrosine phosphorylation of EGF receptors in the lung, possibly as a result of inhibition of protein tyrosine phosphatases, mediates constriction of pulmonary vessels induced by ROFA.

Reactive oxygen species and substance P in monocrotaline-induced pulmonary hypertension.

We attempted to evaluate whether the antioxidants 1,3-dimethyl-2-thiourea (DMTU) and hexa(sulfobutyl)fullerenes (FC(4)S) attenuate monocrotaline (MCT)-induced pulmonary hypertension (PH) by lowering lung substance P (SP) in Wistar rats. Sixty-three rats weighing 297 +/- 8 g were divided into six groups: control; MCT; capsaicin + MCT; MCT + DMTU-1; MCT + DMTU-2; and MCT + FC(4)S. Three weeks before the functional study, saline was injected into each control rat, whereas each MCT rat received 60 mg/kg sc MCT. Rats in the third group received capsaicin pretreatment followed by MCT. A 3-day injection of DMTU was performed during the early (DMTU-1) or the late (DMTU-2) post-MCT period. For the last group, each MCT-treated rat received a daily FC(4)S injection until the commencement of the functional study. Compared to the control group, MCT caused significant increases in pulmonary arterial pressure (Ppa), right ventricular hypertropy, pulmonary arterial medial thickness, lung SP level, and luminol-enhanced chemiluminescence counts in bronchoalveolar lavage. Both capsaicin and antioxidants significantly attenuated the above MCT-induced alterations. SP-induced acute increase in Ppa was exaggerated in MCT-treated rats. These results suggest that oxygen radicals play an important role in MCT-induced PH via elevating lung SP level.

Inhibition of hypoxic pulmonary vasoconstriction by carbon monoxide in dogs.

We tested the hypothesis that carbon monoxide might participate in the modulation of hypoxic pulmonary vasoconstriction (HPV) by prostacyclin (PGI2) and nitric oxide. Prospective, interventional study. University laboratory. Nineteen intact anesthetized mongrel dogs. Right heart catheterization for the measurements of mean pulmonary artery pressure (Ppa), left atrial pressure estimated from occluded Ppa (Ppao), pulmonary capillary pressure (Pcp) calculated from the Ppa decay curve after balloon occlusion, and cardiac output (Q); inferior vena cava balloon for the control of Q by manipulation of venous return; ventilation in hyperoxia (fraction of inspired O2, 0.4) or in hypoxia (Fio2, 0.1); inhibition of cyclooxygenase by indomethacin (Indo); inhibition of nitric oxide synthase by NG-nitro-l-arginine (L-NA); inhibition of heme oxygenase by mesoporphyrin IX (SnMP); inhalation of nitric oxide (20 ppm); and inhalation of carbon monoxide (100 ppm). The first seven dogs were weak responders to hypoxia as assessed by a hypoxia-induced increase in the gradient between Ppa and Ppao, measured at one level of Q kept constant, by an average of only 2 mm Hg (p = NS). This HPV was markedly increased by the combined administration of Indo and L-NA. A further enhancement of HPV was observed after the addition of SnMP, leading to severe pulmonary hypertension with an average increase in Ppa to 39 mm Hg. Inhaled nitric oxide inhibited HPV only after the combined administration of Indo, L-NA, and SnMP. Inhaled carbon monoxide had no effect. The next 12 dogs were stronger responders to hypoxia, as assessed by a hypoxia-induced increase in the gradient between Ppa and Ppao, measured at several levels of Q, by an average of 3 mm Hg (p <.05). This HPV was of the same magnitude after administration of placebo (n = 6) or SnMP (n = 6). Addition of Indo enhanced HPV to the same extent in the placebo and in the SnMP groups. Addition of L-NA induced a further enhancement of HPV, which was, however, greater in the SnMP group. There was a slight increase in the capillary-venous segment relative to the arterial segment in hypoxic conditions, but the partitioning of pulmonary vascular resistance was otherwise unaffected by nitric oxide, carbon monoxide, or PGI2. Endogenous carbon monoxide modulates canine HPV only in the absence of nitric oxide. The vasodilation mediated by nitric oxide, PGI2, or carbon monoxide is essentially distributed between proximal and distal sites proportionally to the degree of constriction produced during hypoxia.

Neural and local effects of hypoxia on cardiovascular responses to obstructive apnea.

Obstructive sleep apnea (OSA) acutely increases systemic (Psa) and pulmonary (Ppa) arterial pressures and decreases ventricular stroke volume (SV). In this study, we used a canine model of OSA (n = 6) to examine the role of hypoxia and the autonomic nervous system (ANS) in mediating these cardiovascular responses. Hyperoxia (40% oxygen) completely blocked any increase in Ppa in response to obstructive apnea but only attenuated the increase in Psa. In contrast, after blockade of the ANS (20 mg/kg iv hexamethonium), obstructive apnea produced a decrease in Psa (-5.9 mmHg; P < 0.05) but no change in Ppa, and the fall in SV was abolished. Both the fall in Psa and the rise in Ppa that persisted after ANS blockade were abolished when apneas were induced during hyperoxia. We conclude that 1) hypoxia can account for all of the Ppa and the majority of the Psa response to obstructive apnea, 2) the ANS increases Psa but not Ppa in obstructive apnea, 3) the local effects of hypoxia associated with obstructive apnea cause vasodilation in the systemic vasculature and vasoconstriction in the pulmonary vasculature, and 4) a rise in Psa acts as an afterload to the heart and decreases SV over the course of the apnea.

Low-dose systemic phosphodiesterase inhibitors amplify the pulmonary vasodilatory response to inhaled prostacyclin in experimental pulmonary hypertension.

Inhalation of aerosolized prostaglandin I(2) (PGI(2)) causes selective pulmonary vasodilation, but the effect rapidly levels off after termination of nebulization. In experimental pulmonary hypertension in intact rabbits, provoked by continuous infusion of the stable thromboxane mimetic U46619, the impact of intravenous phosphodiesterase (PDE) inhibitors on pulmonary and systemic hemodynamics was investigated in the absence and the presence of aerosolized PGI(2). We employed the monoselective inhibitors motapizone (PDE 3), rolipram (PDE 4), and zaprinast (PDE 5), as well as the dual-selective blockers zardaverine and tolafentrine (both PDE 3/4). All PDE inhibitors dose-dependently reduced the pulmonary artery pressure (Ppa), with doses for an approximately 20% decrease in pulmonary vascular resistance being 5 microgram/kg for motapizone, 25 microgram/kg for rolipram, 500 microgram/kg for zardaverine, 1 mg/kg for zaprinast, and 1 mg/kg for tolafentrine. Additive efficacy was noted when combining the monoselective 3 plus 4, 3 plus 5, and 4 plus 5 inhibitors. In parallel with the pulmonary vasorelaxant effect, all PDE inhibitors caused a decrease in systemic arterial pressure and an increase in cardiac output. Nebulized PGI(2) (56 ng/kg. min) reduced the U46619-evoked increase in Ppa by approximately 30%. This vasorelaxant effect was fully lost within 10 min after termination of PGI(2) nebulization. Coapplication of subthreshold doses of intravenous PDE inhibitors, which per se did not affect pulmonary and systemic hemodynamics, resulted in a marked prolongation of the post-PGI(2) decrease in Ppa for all blockers (motapizone at 2.2 microgram/kg, rolipram at 5.5 microgram/kg, zaprinast at 100 microgram/kg). The most effective agents, zardaverine (50 microgram/kg) and tolafentrine (100 microgram/kg), augmented the maximum Ppa drop during nebulization by approximately 30-50% and prolonged the post-PGI(2) pulmonary vasodilation to > 30 min, without affecting systemic arterial pressure and arterial oxygenation. We conclude that subthreshold systemic doses of monoselective PDE 3, 4, and 5 inhibitors and in particular dual-selective PDE 3/4 inhibitors cause significant amplification of the pulmonary vasodilatory response to inhaled PGI(2), while limiting the hypotensive effect to the pulmonary circulation. Combining nebulized PGI(2) with low-dose systemic PDE inhibitors may thus offer a therapeutic strategy to achieve selective pulmonary vasodilation in acute and chronic pulmonary hypertension.

Effect of inhaled nitric oxide on experimentally induced pulmonary hypertension in neonatal foals

Abstract Objective To evaluate the efficacy of inhaled nitric oxide (NO) in anesthetized healthy newborn foals with experimentally induced pulmonary hypertension. Animals Five 1- to 3-day-old foals. Procedure Anesthesia was induced and maintained with propofol, and foals were intubated and mechanically ventilated. Systemic pressure and pulmonary arterial pressure (PPA) were recorded every 30 seconds. Hypertension was induced via a hypoxic gas mixture or chemical vasoconstriction, using the thromboxane mimetic U46619. Nitric oxide was added at a concentration of 80 parts per million (ppm) for 6 minutes under baseline conditions and during pulmonary hypertension-induced alveolar hypoxia (inspired oxygen concentration = 0.08). Nitric oxide (20, 40, 80, and 160 ppm) was evaluated during U46619-induced hypertension. Samples for determination of arterial blood gas tensions were collected before and after each NO treatment. Results Inhaled NO (approx 80 ppm) did not have an effect on baseline variables. Infusion of U46619 (0.35 ± 0.04 μg/kg of body weight/min) or alveolar hypoxia resulted in increased PPA and decreased arterial oxygenation (Pao2) and hemoglobin saturation (HbSat). The increase in PPA was attenuated, in a dose-dependent manner, by NO during U46619 infusion and reversed by NO during induced hypoxemia. The Pao2 and HbSat were significantly improved at all NO doses during U44619 infusion but not during alveolar hypoxia. For all inhaled NO concentrations, nitrogen dioxide and methoglobin values were &lt; 5 ppm and 3%, respectively. Conclusions and Clinical Relevance Nitric oxide is a potent, selective vasodilator of the pulmonary circulation in healthy newborn foals. Inhaled NO may have value as a therapeutic agent in foals with pulmonary hypertension. (Am J Vet Res 1999;60:1207–1212)

Role of Nitric Oxide Synthase and Cyclooxygenase in Pulmonary Vascular Control in Isolated Perfused Lungs of Ferrets, Rats and Rabbits

Dilator products of nitric oxide synthase (NOS) and cyclooxygenase (COX) may contribute to the low normal pulmonary artery pressure (Ppa). In isolated perfused lungs of ferrets, rabbits and rats we investigated this hypothesis by blockade of NOS with L-NAME (L-nitro-arginine methyl ester) and COX with meclofenamate. There were species differences. Inhibition of either enzyme caused little rise in Ppa in ferrets and rats but inhibition of both enzymes caused huge increases in Ppa. We suggest this might be due to intracellular connections between the excitatory pathways for NOS and COX dilators, such that inhibition of one enzyme leads to activation of the other. Impairment of these endothelial-based enzymes in pulmonary vascular disease might lead to severe pulmonary hypertension. By contrast, in rabbits, comparable doses of L-NAME lead to large rises in Ppa which were reversed rather than amplified by COX blockade. NO seems to protect against some pressor/oedema forming product of COX in this species.

Effect of dehydroepiandrosterone on hypoxic pulmonary vasoconstriction: a Ca(2+)-activated K(+)-channel opener.

In the present study, we investigated the effects of the naturally occurring hormone dehydroepiandrosterone (DHEA) on hypoxic pulmonary vasoconstriction (HPVC) in isolated ferret lungs and on K+ currents in isolated and cultured ferret pulmonary arterial smooth muscle cells (FPSMCs). Severe alveolar hypoxia (3% O2-5% CO2-92% N2) caused an initial increase in pulmonary arterial pressure (Ppa) that was followed by a reversal in pulmonary hypertension. Maintaining alveolar hypoxia caused a sustained secondary increase in Ppa. Pretreating the lungs with the K(+)-channel inhibitor tetraethylammonium (TEA) caused a small increase in baseline Ppa, potentiated HPVC, and prevented the reversal of HPVC during the sustained alveolar hypoxia. Treating the lungs with DHEA caused a near-complete reversal of HPVC in control lungs and in lungs that were pretreated with TEA. DHEA also reversed the KCl-induced increase in Ppa. In FPSMCs, DHEA caused an adenosine 3',5'-cyclic monophosphate- and guanosine 3',5'-cyclic monophosphate-independent increase in activity of the Ca(2+)-activated K+ (KCa) current. In a cell-attached configuration, DHEA caused a mean shift of -22 mV in the voltage-dependent activation of the KCa channel. We conclude that DHEA is a novel KCa-channel opener of the pulmonary vasculature.