Peripheral chemoreceptor modulation of the pulmonary vasculature in the cat.

The present study was undertaken to determine whether stimulation of the carotid and aortic bodies (cb and ab) could affect the pulmonary vasculature. Our hypothesis was that each promoted vasodilation and thus could modulate the pulmonary vasoconstrictor response to hypoxia. The experimental design of the first set of experiments took advantage of the facts that 1) the ab, but not the cb, increases its neural output in response to CO, whereas both respond to a decreased arterial PO2 (hypoxic hypoxia, HH) and 2) the aortic nerves in cats are easily transected. Hence, both cb and ab sent neural activity to the brain stem when the intact cat was exposed to 10% O2 in N2. Only the ab sent information during CO hypoxia (COH intact). Only the cb did so during HH in the cat in which the aortic nerves had been transected, removing the aortic body (HH abr); neither ab nor cb did so during COH abr. Fifteen anesthetized paralyzed artificially ventilated cats were fit with catheters in the femoral artery and vein, right and left atria, left ventricle, and pulmonary artery and with an aortic flow probe. In the HH intact and HH abr conditions, there was a significant rise in cardiac output, whereas pulmonary arterial pressure (Ppa) rose initially but then leveled off while cardiac output continued to rise. During the 15-min exposure to HH, pulmonary vascular resistance [PVR = (Ppa - Pla)/cardiac output, where Pla is left atrial pressure] rose initially and then decreased significantly at 2-3 min. In response to COH, PVR showed only a significant decrease. In the second set of experiments, seven cats were instrumented as above and had loops placed in the common carotid arteries for selectively perfusing the cbs. In response to a brief infusion of venous blood mixed with 0.3-0.5 micrograms NaCN, which selectively stimulated only the cb, aortic flow remained relatively constant while heart rate and Ppa - alveolar pressure difference decreased significantly; so also did PVR. These data are consistent with the hypothesis that stimulation of the ab and cb singly or together can provoke a significant pulmonary vasodilation in the anesthetized paralyzed artificially ventilated cat.     

Noninvasive assessment of pulmonary arterial hypertension by MR phase-mapping method.

We describe a magnetic resonance (MR) imaging method that emphasizes pressure wave velocity to noninvasively assess pulmonary arterial hypertension. Both the blood flow and the corresponding vessel cross-sectional area (CSA) were measured by MR phase mapping in the main pulmonary artery (MPA) in 15 patients. MPA pressures were also measured, in the same patients, by right-side heart catheterization. Two significant relationships were established: 1) between the pressure wave velocity in the MPA and the mean pressure in the MPA (Ppa) writing pressure wave velocity = 9.25 Ppa - 202.51 (r = 0.82) and 2) between the ratio of pressure wave velocity to the systolic blood velocity peak in the MPA (R) and the mean pressure in the MPA writing R = 0.68 Ppa - 4.33 (r = 0.89). Using these relationships, we estimated two pressure values to frame the actual Ppa value in each patient from the present series with a reasonable reliability percentage (87%).     

Blind identification of the aortic pressure waveform from multiple peripheral artery pressure waveforms

We have developed a new technique to estimate the clinically relevant aortic pressure waveform from multiple, less invasively measured peripheral artery pressure waveforms. The technique is based on multichannel blind system identification in which two or more measured outputs (peripheral artery pressure waveforms) of a single-input, multi-output system (arterial tree) are mathematically analyzed so as to reconstruct the common unobserved input (aortic pressure waveform) to within an arbitrary scale factor. The technique then invokes Poiseuille's law to calibrate the reconstructed waveform to absolute pressure. Consequently, in contrast to previous related efforts, the technique does not utilize a generalized transfer function or any training data and is therefore entirely patient and time specific. To demonstrate proof of concept, we have evaluated the technique with respect to four swine in which peripheral artery pressure waveforms from the femoral and radial arteries and a reference aortic pressure waveform from the descending thoracic aorta were simultaneously measured during diverse hemodynamic interventions. We report that the technique reliably estimated the entire aortic pressure waveform with an overall root mean squared error (RMSE) of 4.6 mmHg. For comparison, the average overall RMSE between the peripheral artery pressure and reference aortic pressure waveforms was 8.6 mmHg. Thus the technique reduced the RMSE by 47%. As a result, the technique also provided similar improvements in the estimation of systolic pressure, pulse pressure, and the ejection interval. With further successful testing, the technique may ultimately be employed for more precise monitoring and titration of therapy in, for example, critically ill and hypertension patients.     

Effects of sildenafil on hypoxic pulmonary vascular function in dogs.

Sildenafil has been shown to be an effective treatment of pulmonary arterial hypertension and is believed to present with pulmonary selectivity. This study was designed to determine the site of action of sildenafil compared with inhaled nitric oxide (NO) and intravenous sodium nitroprusside (SNP), known as selective and nonselective pulmonary vasodilators, respectively. Inhaled NO (40 ppm), and maximum tolerated doses of intravenous SNP and sildenafil, (5 microg x kg(-1) x min(-1) and 0.1 mg x kg(-1) x h(-1)), respectively, were administered to eight dogs ventilated in hypoxia. Pulmonary vascular resistance (PVR) was evaluated by pulmonary arterial pressure (Ppa) minus left atrial pressure (Pla) vs. flow curves, and partitioned into arterial and venous segments by the occlusion method. Right ventricular hydraulic load was defined by pulmonary arterial characteristic impedance (Zc) and elastance (Ea) calculations. Right ventricular arterial coupling was estimated by the ratio of end-systolic elastance (Ees) to Ea. Decreasing the inspired oxygen fraction from 0.4 to 0.1 increased Ppa - Pla at a standardized flow of 3 l x min(-1) x m(-2) from 6 +/- 1 to 18 +/- 1 mmHg (mean +/- SE). Ppa - Pla was decreased to 9 +/- 1 by inhaled NO, 14 +/- 1 by SNP, and 14 +/- 1 mmHg by sildenafil. The partition of PVR, Zc, Ea, and Ees/Ea was not affected by the three interventions. Inhaled NO did not affect systemic arterial pressure, which was similarly decreased by sildenafil and SNP, from 115 +/- 4 to 101 +/- 4 and 98 +/- 5 mmHg, respectively. We conclude that inhaled NO inhibits hypoxic pulmonary vasoconstriction more effectively than sildenafil or SNP, and sildenafil shows no more selectivity for the pulmonary circulation than SNP.     

A computed method for noninvasive MRI assessment of pulmonary arterial hypertension.

The present method enables the noninvasive assessment of mean pulmonary arterial pressure from magnetic resonance phase mapping by computing both physical and biophysical parameters. The physical parameters include the mean blood flow velocity over the cross-sectional area of the main pulmonary artery (MPA) at the systolic peak and the maximal systolic MPA cross-sectional area value, whereas the biophysical parameters are related to each patient, such as height, weight, and heart rate. These parameters have been measured in a series of 31 patients undergoing right-side heart catheterization, and the computed mean pulmonary arterial pressure value (Ppa(Comp)) has been compared with the mean pressure value obtained from catheterization (Ppa(Cat)) in each patient. A significant correlation was found that did not differ from the identity line Ppa(Comp) = Ppa(Cat) (r = 0.92). The mean and maximal absolute differences between Ppa(Comp) and Ppa(Cat) were 5.4 and 11.9 mmHg, respectively. The method was also applied to compute the MPA systolic and diastolic pressures in the same patient series. We conclude that this computed method, which combines physical (whoever the patient) and biophysical parameters (related to each patient), improves the accuracy of MRI to noninvasively estimate pulmonary arterial pressures.     

Optimal control aspects of left ventricular ejection dynamics

A model of the ejecting left ventricle is developed in which ventricular elastance as a function of time is optimized with respect to a simple performance index selected on an energetic basis. The model correctly predicts a number of well known experimental findings concerning the effects of preload and afterload conditions and varying system parameters on left ventricular pressure and elastance waveforms and on the ejection period. The results characterize ventricular systolic elastance as dependent on both end-diastolic volume and mean aortic pressure.     

Role of rib cage elastance in the coupling between the abdominal muscles and the lung.

The abdominal muscles expand the rib cage when they contract alone. This expansion opposes the deflation of the lung and may be viewed as pressure dissipation. The hypothesis was raised, therefore, that alterations in rib cage elastance should affect the lung deflating action of these muscles. To test this hypothesis and evaluate the quantitative importance of this effect, we measured the changes in airway opening pressure (Pao), abdominal pressure (Pab), and rib cage transverse diameter during isolated stimulation of the transversus abdominis muscle in anesthetized dogs, first with the rib cage intact and then after rib cage elastance was increased by clamping the ribs and the sternum. Stimulation produced increases in Pao, Pab, and rib cage diameter in both conditions. With the ribs and sternum clamped, however, the change in Pab was unchanged but the change in Pao was increased by 77% (P < 0.001). In a second experiment, the transversus abdominis was stimulated before and after rib cage elastance was reduced by removing the bony ribs 3-8. Although the change in Pab after removal of the the ribs was still unchanged, the change in Pao was reduced by 62% (P < 0.001). These observations, supported by a model analysis, indicate that rib cage elastance is a major determinant of the mechanical coupling between the abdominal muscles and the lung. In fact, in the dog, the effects of rib cage elastance and Pab on the lung-deflating action of the abdominal muscles are of the same order of magnitude.     

Analysis of bronchovascular downstream blood pressure changes in exercising sheep

The relative roles of neural and pressure gradient factors, causing a fall or maintenance of bronchial blood flow in exercising sheep, are unknown. These were examined in sheep prepared under thiopentone/isoflurane general anaesthesia with a pulsed Doppler probe mounted on the bronchial artery, and aortic pressure (Pa) catheter in superficial cervical artery. After recovery, Swan-Ganz catheters were inserted under local anaesthesia into the pulmonary artery. Bronchial flow and conductance (Qbr, Cbr), and pressure gradients (Pg; i.e. aortic minus right atrial, Pg_RAP; pulmonary artery, Pg_Ppa; and, left atrial (wedge) Pg_LAP) were derived from continuous records, after switching between downstream sites during and after moderately severe treadmill exercise (3.8 km.h(-1), for 1.7 min, 6 min recovery). The protocol was repeated after combined alpha1,alpha2-adrenoceptor/cholinoceptor blockade using phentolamine methanesulfonate and methscopolamine bromide. Bronchial flow fell in both receptor intact (INT) and (BL) blocked state. Pa rose in INT, but downstream pressures rose only 3.7 (RAP), 2.8 (Ppa) and 2.0 (LAP) mmHg (P for each < 0.05) in both INT and BL. Pg_RAP and Pg_Ppa did not rise, but Pg_LAP rose 4.0 mmHg (P < 0.05). In BL, Pa fell, as did Pg_RAP (7.0 mmHg, P < 0.05), Pg_Ppa (8.9 mmHg, P < 0.001), but Pg_LAP did not change. Thus, downstream pressures change by small amounts, and pressure gradients to RAP and Ppa sites do not change during moderately severe exercise in normal sheep. The fall in Qbr in INT is due to neural factors, but in BL is due to a fall in Pg. The relative rise in Pg_LAP in both INT and BL favours redistribution within total Qbr to the pulmonary capillary/vein/left atrium site.     

Response of pulmonary veins to increased intracranial pressure and pulmonary air embolization

Brain compression with subdural air causes pulmonary hypertension and noncardiogenic pulmonary edema (A. B. Malik, J. Appl. Physiol.: Respirat. Environ. Exercise Physiol. 42: 335-343, 1977). To see whether air emboli to the lungs rather than brain compression caused these findings, anesthetized dogs received intravenous air infusions, subdural air infusions, or brain compression from balloons inflated in the subdural space. Subdural air and intravenous air resulted in similar vascular responses. Pulmonary artery pressure (Ppa) increased 160% (P less than 0.01) and pulmonary venous pressure transiently rose 13 +/- 5 Torr (P less than 0.05) without an increase in left atrial pressure or cardiac output (Q). The end-tidal PCO2 fell 55% (P less than 0.01) and the postmortem weight of the lungs increased 55% (P less than 0.05). Brain compression with a subdural balloon instead of air only caused a 20% rise in Ppa and Q without pulmonary edema. Thus, pulmonary air emboli rather than brain compression accounts for the edema and pulmonary hypertension caused by subdural air. Catheters in pulmonary veins and the left atrium showed that air emboli cause transient pulmonary venous hypertension as well as a reproducible form of noncardiogenic pulmonary endema.     

Compliance of the main pulmonary artery during the ventilatory cycle.

Transmural pulmonary arterial pressure (Ppa), diameter (D), and length (L) of a segment of the main pulmonary artery (MPA) were measured simultaneously in anesthetized open-chest dogs. The instantaneous volume was calculated from D and L. Pulmonary arterial elasticity for diameter (EpD) was calculated as the ratio of the amplitude of Ppa to D oscillation normalized by the mean D. Similar indexes were calculated for L (EpL) and V (Epv). Compliance per unit length was calculated from the dimensions and elasticity of the MPA. Under control conditions with 5 cmH2O positive end-expiratory pressure, EpD, EpL, and Epv at cardiac frequency were 175 +/- 27, 147 +/- 27, and 55 +/- 7 cmH2O, respectively. EpD increased with positive end-expiratory pressure, but EpL decreased and Epv was unaffected. EpD, EpL, Epv, and compliance per unit length were not significantly different between the start of inspiration and the start of expiration. In addition, there were no significant phase differences between the oscillations of Ppa and V at respiratory frequency. We conclude that the previously reported time variation of pulmonary arterial compliance during the ventilatory cycle is not due to time-varying properties of the MPA.     

Effects of pulmonary vascular pressures and flow on airway and parenchymal mechanics in isolated rat lungs.

Changes in pulmonary hemodynamics have been shown to alter the mechanical properties of the lungs, but the exact mechanisms are not clear. We therefore investigated the effects of alterations in pulmonary vascular pressure and flow (Q(p)) on the mechanical properties of the airways and the parenchyma by varying these parameters independently in three groups of isolated perfused normal rat lungs. The pulmonary capillary pressure (Pc(est)), estimated from the pulmonary arterial (Ppa) and left atrial pressure (Pla), was increased at constant Q(p) (n = 7), or Q(p) was changed at Pc(est) = 10 mmHg (n = 7) and at Pc(est) = 20 mmHg (n = 6). In each condition, the airway resistance (Raw) and parenchymal damping (G) and elastance (H) were identified from the low-frequency pulmonary input impedance spectra. The results of measurements made under isogravimetric conditions were analyzed. The changes observed in the mechanical parameters were consistent with an altered Pla: monotonous increases in Raw were observed with increasing Pla, whereas G and H were minimal at Pla of approximately 7-10 mmHg and increased at lower and higher Pla. The results indicate that Pla, and not Ppa or Q(p), is the primary determinant of the mechanical condition of the lungs after acute changes in pulmonary hemodynamics: the parenchymal mechanics are impaired if Pla is lower or higher than physiological, whereas airway narrowing occurs at high Pla.     

Effects of acetazolamide on aerobic exercise capacity and pulmonary hemodynamics at high altitudes.

Aerobic exercise capacity is decreased at altitude because of combined decreases in arterial oxygenation and in cardiac output. Hypoxic pulmonary vasoconstriction could limit cardiac output in hypoxia. We tested the hypothesis that acetazolamide could improve exercise capacity at altitude by an increased arterial oxygenation and an inhibition of hypoxic pulmonary vasoconstriction. Resting and exercise pulmonary artery pressure (Ppa) and flow (Q) (Doppler echocardiography) and exercise capacity (cardiopulmonary exercise test) were determined at sea level, 10 days after arrival on the Bolivian altiplano, at Huayna Potosi (4,700 m), and again after the intake of 250 mg acetazolamide vs. a placebo three times a day for 24 h. Acetazolamide and placebo were administered double-blind and in a random sequence. Altitude shifted Ppa/Q plots to higher pressures and decreased maximum O(2) consumption ((.)Vo(2max)). Acetazolamide had no effect on Ppa/Q plots but increased arterial O(2) saturation at rest from 84 +/- 5 to 90 +/- 3% (P < 0.05) and at exercise from 79 +/- 6 to 83 +/- 4% (P < 0.05), and O(2) consumption at the anaerobic threshold (V-slope method) from 21 +/- 5 to 25 +/- 5 ml.min(-1).kg(-1) (P < 0.01). However, acetazolamide did not affect (.)Vo(2max) (from 31 +/- 6 to 29 +/- 7 ml.kg(-1).min(-1)), and the maximum respiratory exchange ratio decreased from 1.2 +/- 0.06 to 1.05 +/- 0.03 (P < 0.001). We conclude that acetazolamide does not affect maximum exercise capacity or pulmonary hemodynamics at high altitudes. Associated changes in the respiratory exchange ratio may be due to altered CO(2) production kinetics.     

急性低氧下钙阻断剂对左,右心泵功能的影响

在20条麻醉开胸狗上,用RM-6000多道仪同步记录左心室内峰压(LVP)、左室压力变化率(L+dP/dt_(max))、右心室内峰压(RVP)、右室压力变化率(R±dp/dt_(max))、肺动脉压力(P_(Pa))、主动脉血流每搏峰值(Fa)、心率(HR)等各项生理指标,观察钙通道阻断剂Nife-dipine,Diltiazem和Verapamil对左、右心室功能影响。在钙通道阻断剂处理后,左室的LVP,L±dp/dt_(max)下降,而Fa增加;右室的RVF,R±dp/dt_(max)和P_(Pa)均有升高趋势,显示钙通道阻断剂对左、右心泵功能的影响不同。这可能提示左、右心室功能对钙离子的依赖程度不同。在急性低氧状态下,此三种钙阻断剂均使急性低氧引起LVP的增加反应消失,Fa增加明显,Verapamil和Diltiazem有减轻急性低氧引起的RVP和P_(Pa)的增压作用。从这些钙通道阻断剂对左右心泵功能影响的比较来看,Diltiazem比Verapamil和Nifedipine对急性低氧状态下的心泵功能有较好的作用。     

Effects of PEEP on pulmonary hemodynamics in intact dogs with oleic acid pulmonary edema

The effects of positive end-expiratory pressure (PEEP) on the pulmonary circulation were studied in 14 intact anesthetized dogs with oleic acid (OA) lung injury. Transmural (tm) mean pulmonary arterial pressure (Ppa)/cardiac index (Q) plots with transmural left atrial pressure (Pla) kept constant were constructed in seven dogs, and Ppa(tm)/PEEP plots with Q and Pla(tm) kept constant were constructed in seven other dogs. Q was manipulated by using a femoral arteriovenous bypass and a balloon catheter inserted in the inferior vena cava. Pla was manipulated using a balloon catheter placed by thoracotomy in the left atrium. Ppa(tm)/Q plots were essentially linear. Before OA, the linearly extrapolated pressure intercept of the Ppa(tm)/Q relationship approximated Pla(tm). OA (0.09 ml/kg into the right atrium) produced a parallel shift of the Ppa(tm)/Q relationship to higher pressures; i.e., the extrapolated pressure intercept increased while the slope was not modified. After OA, 4 Torr PEEP (5.4 cmH2O) had no effect on the Ppa(tm)/Q relationship and 10 Torr PEEP (13.6 cmH2O) produced a slight, not significant, upward shift of this relationship. Changing PEEP from 0 to 12 Torr (16.3 cmH2O) at constant Q before OA led to an almost linear increase of Ppa(tm) from 14 +/- 1 to 19 +/- 1 mmHg. After OA, Ppa(tm) increased at 0 Torr PEEP but changing PEEP from 0 to 12 Torr did not significantly affect Ppa(tm), which increased from 19 +/- 1 to 20 +/- 1 mmHg. These data suggest that moderate levels of PEEP minimally aggravate the pulmonary hypertension secondary to OA lung injury.     

On an automatic delineator for arterial blood pressure waveforms

Arterial blood pressure waveforms contain rich pathophysiological information; hence receive much attention in cardiovascular health monitoring. To assist computerized analysis, an automatic delineator was proposed for the fiducial points of arterial blood pressure waveforms, namely their onsets, systolic peaks and dicrotic notches. The presented delineator characterizes arterial blood pressure waveforms in a beat-by-beat manner. It firstly seeks the pairs of inflection and zero-crossing points, and then utilizes combinatorial amplitude and interval criteria to select the onset and systolic peak. Once a new beat is settled, the delineator seeks the derivative backward to locate the dicrotic notch in the preceding beat. In a nutshell, the delineator is based on the combinatorial analysis of arterial blood pressure waveforms and their derivatives. Three open databases, with an additional subset database, were utilized for delineator validation and performance evaluation. In terms of beat detection, the delineator achieved an average error rate 1.14%, sensitivity 99.43% and positive predictivity 99.45%. As to dicrotic notch detection, it performed well with an error rate 6.83%, sensitivity 96.53% and positive predictivity 96.64%.     

Mechanism of peptidoleukotriene-induced increases in pulmonary transvascular fluid filtration

We examined the effects of leukotrienes C4 (LTC4) and D4 (LTD4) (1 microgram) on the pulmonary vascular filtration coefficient, a measure of vessel wall conductivity to water, and the alterations in pulmonary vascular resistance (PVR) in isolated-perfused guinea pig lungs. We also assessed whether LTC4 and LTD4 increased the permeability to albumin in cultured monolayers of pulmonary artery endothelial cells. In Ringer-perfused and blood-perfused lungs, LTC4 resulted in increases in pulmonary arterial pressure (Ppa) and the pulmonary capillary pressure (Pcap) measured as the equilibration pressure after simultaneous pulmonary arterial and venous occlusions. Pulmonary venous resistance (Rv) increased to a greater extent than arterial resistance (Ra) in both Ringer-perfused and blood-perused lungs challenged with LTC4. The greater increase in PVR in blood-perfused lungs corresponded with a greater elevation of lung effluent thromboxane B2 (TxB2) concentration. The LTC4-stimulated increase in PVR was prevented by pretreatment with meclofenamate (10(-4) M). LTD4 also induced rapid increases in Ppa and Pcap in both Ringer-perfused and blood-perfused lungs; however, Ppa decreased before stabilizing at a pressure higher than base line. The increases in Rv with LTD4 were greater than Ra. The LTD4-stimulated increases in Ra and Rv also paralleled the elevation in TxB2 concentration. As with LTC4, the increases in Ppa, Pcap, PVR, and TxB2 concentration were greater in blood-perfused than in Ringer-perfused lungs. Pretreatment with meclofenamate reduced the magnitude of the initial increase in Ppa, but did not prevent the response.(ABSTRACT TRUNCATED AT 250 WORDS)     

Modelflow underestimates cardiac output in heat-stressed individuals

An estimation of cardiac output can be obtained from arterial pressure waveforms using the Modelflow method. However, whether the assumptions associated with Modelflow calculations are accurate during whole body heating is unknown. This project tested the hypothesis that cardiac output obtained via Modelflow accurately tracks thermodilution-derived cardiac outputs during whole body heat stress. Acute changes of cardiac output were accomplished via lower-body negative pressure (LBNP) during normothermic and heat-stressed conditions. In nine healthy normotensive subjects, arterial pressure was measured via brachial artery cannulation and the volume-clamp method of the Finometer. Cardiac output was estimated from both pressure waveforms using the Modeflow method. In normothermic conditions, cardiac outputs estimated via Modelflow (arterial cannulation: 6.1 ± 1.0 l/min; Finometer 6.3 ± 1.3 l/min) were similar with cardiac outputs measured by thermodilution (6.4 ± 0.8 l/min). The subsequent reduction in cardiac output during LBNP was also similar among these methods. Whole body heat stress elevated internal temperature from 36.6 ± 0.3 to 37.8 ± 0.4°C and increased cardiac output from 6.4 ± 0.8 to 10.9 ± 2.0 l/min when evaluated with thermodilution (P < 0.001). However, the increase in cardiac output estimated from the Modelflow method for both arterial cannulation (2.3 ± 1.1 l/min) and Finometer (1.5 ± 1.2 l/min) was attenuated compared with thermodilution (4.5 ± 1.4 l/min, both P < 0.01). Finally, the reduction in cardiac output during LBNP while heat stressed was significantly attenuated for both Modelflow methods (cannulation: -1.8 ± 1.2 l/min, Finometer: -1.5 ± 0.9 l/min) compared with thermodilution (-3.8 ± 1.19 l/min). These results demonstrate that the Modelflow method, regardless of Finometer or direct arterial waveforms, underestimates cardiac output during heat stress and during subsequent reductions in cardiac output via LBNP.     

The role of leukotrienes in the late hemodynamic manifestations of group B streptococcal sepsis in piglets

In order to evaluate the role of leukotrienes in group B streptococcal (GBS) sepsis we studied the effect of a leukotriene receptor antagonist, FPL 57231, on the late hemodynamic changes occurring secondary to an infusion of live GBS. Paralyzed, mechanically ventilated piglets received a continuous intravenous infusion of bacteria (5 x 10(7) org/kg/min) while systemic arterial (Psa) and pulmonary artery pressures (Ppa) were measured. To separate the effects of the lipoxygenase products of arachidonic acid from those of the cyclooxygenase by-products, animals in control and treatment groups received indomethacin, a cyclooxygenase blocking agent, 15 min after the infusion of GBS was begun. In addition to GBS and indomethacin, treatment animals received a 30 min infusion of FPL 57231 starting 120 min after the bacterial infusion was begun. All study animals responded to bacteria within 15 min with marked elevation in pulmonary artery pressure (X +/- SD) (12 +/- 3 to 49 +/- 5 mmHg; p less than .01), and a decline in PaO2 (84 +/- 9 to 49 +/- 5 mmHg; p less than .01) and cardiac output (0.29 +/- 0.04 to 0.18 +/- .07 liter/min/kg; p less than .01). These changes were reversed by indomethacin. Subsequent values remained relatively stable until approximately 90 min when a gradual decrease in cardiac output (CO) and PaO2, and an increase in Ppa, and calculated systemic (SVR) and pulmonary (PVR) vascular resistances occurred. After the initial increase in TxB2 and 6-keto-PGF1 alpha, indomethacin treatment resulted in return of these values to baseline with no further increase throughout the study period.(ABSTRACT TRUNCATED AT 250 WORDS)     

Combined inhaled nitric oxide and inhaled prostacyclin during experimental chronic pulmonary hypertension.

Inhaled nitric oxide (NO) and inhaled prostacyclin (PGI2) produce selective reductions in pulmonary vascular resistance (PVR) through differing mechanisms. NO decreases PVR via cGMP, and PGI2 produces pulmonary vasodilation via cAMP. As a general pharmacological principle, two drugs that produce similar effects via different mechanisms should have additive or synergistic effects when combined. We designed this study to investigate whether combined inhaled NO and PGI2 therapy results in additive effects during chronic pulmonary hypertension in the rat. Monocrotaline injected 4 wk before study produced pulmonary hypertension in all animals. Inhaled NO (20 parts/million) reversibly and selectively decreased pulmonary artery pressure (Ppa) with a mean reduction of 18%. Four concentrations of PGI2 were administered via inhalation (5, 10, 20, and 80 microg/ml), both alone and combined with inhaled NO. Inhaled PGI2 alone decreased Ppa in a dose-dependent manner with no change in mean systemic arterial pressure. Combined inhaled NO and PGI2 selectively and significantly decreased Ppa more did than either drug alone. The effects were additive at the lower concentrations of PGI2 (5, 10, and 20 microg/ml). The combination of inhaled NO and inhaled PGI2 may be useful in the management of pulmonary hypertension.