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K R Stenmark

Publications and source records attributed to K R Stenmark.

At least 55 records · Page 3Linked to original sources
PubMed1995

Role of angiotensin-converting enzyme and angiotensin II in development of hypoxic pulmonary hypertension.

Although angiotensin converting enzyme (ACE) inhibitors are known to attenuate the development of hypoxic pulmonary hypertension in rats, the precise mechanism of this protective effect remains unknown. Thus we utilized specific angiotensin II (ANG II)-receptor antagonists to investigate whether ANG II is involved directly in the hemodynamic and structural changes of pulmonary hypertension, and we tested whether the protective effects of ACE inhibition can be attributed partly to potentiation of bradykinin. During 14 days of hypobaric hypoxia, rats received, via intraperitoneal osmotic minipumps, either 1) the ACE inhibitor captopril, 2) captopril plus the bradykinin B2-receptor antagonist CP-0597, 3) the ANG II type 1 receptor antagonist losartan, 4) the ANG II type 2 receptor antagonist PD-123319, or 5) saline. At 14 days, mean pulmonary arterial pressure (MPAP) was reduced (P < 0.05) in hypoxic rats treated with captopril (26.6 +/- 0.8 mmHg) or losartan (24.4 +/- 1.0 mmHg) compared with saline (32.0 +/- 1.4 mmHg) but was unaffected by PD-123319 (29.5 +/- 1.7 mmHg). Right ventricular hypertrophy was reduced in hypoxic rats treated with captopril or losartan compared with saline-treated rats. Morphometry showed less medial thickening and peripheral muscularization of small pulmonary arteries in hypoxic animals treated with captopril or losartan. Coadministration of CP-0597 did not reverse the protective effects of captopril on pulmonary vascular remodeling. These results suggest a novel role for endogenous ANG II, acting through the type 1 receptor, in the vascular remodeling associated with hypoxic pulmonary hypertension. The beneficial effects of ACE inhibition in this model can be attributed to reduced ANG II production rather than potentiation of bradykinin.

Angiotensin II↗
PubMed1995

Enhanced growth of fetal and neonatal pulmonary artery adventitial fibroblasts is dependent on protein kinase C.

The earliest and most striking proliferative changes in the neonatal pulmonary arterial wall occur in the adventitia where the fibroblast resides. The protein kinase C (PKC) pathway is developmentally regulated and important in vascular cell growth. We tested the hypothesis that developmental differences in growth of pulmonary artery adventitial fibroblasts would be detectable in vitro and dependent on PKC. Fibroblasts were isolated from bovine fetal, neonatal, and adult pulmonary arteries. Growth was measured by [3H]thymidine incorporation and cell counts. Under serum-stimulated conditions, fetal and neonatal pulmonary artery fibroblasts grew faster and reached higher plateau densities than adult cells. Increased growth of fetal cells in vitro was dependent on time of harvest during fetal life (early > late). Under quiescent conditions, fetal and neonatal fibroblasts had increased DNA synthesis compared with adult cells in response to the PKC agonist phorbol 12-myristate 13-acetate. To test whether the developmental differences in fibroblast growth were dependent on PKC, three different inhibitor strategies were used (dihydrosphingosine, phorbol-ester-induced downregulation, and heparin). Fetal and neonatal fibroblasts were more susceptible than adult cells to each antagonist strategy. Finally, we measured whole cellular PKC catalytic activity and found it correlated with growth and susceptibility to PKC inhibition (i.e., fetal PKC activity > neonatal > adult). We conclude that PKC-dependent developmental differences in growth of pulmonary artery fibroblasts are detectable in vitro and that the enhanced growth capacity of fetal and neonatal cells may contribute to the dramatic adventitial thickening seen in vivo after hypoxic exposure in the neonatal calf.

Animals↗
PubMed1995

Hypoxia selectively induces proliferation in a specific subpopulation of smooth muscle cells in the bovine neonatal pulmonary arterial media.

Medial thickening of the pulmonary arterial wall, secondary to smooth muscle cell (SMC) hyperplasia, is commonly observed in neonatal hypoxic pulmonary hypertension. Because recent studies have demonstrated the existence of multiple phenotypically distinct SMC populations within the arterial media, we hypothesized that these SMC subpopulations would differ in their proliferative responses to hypoxic pulmonary hypertension and thus contribute in selective ways to the vascular remodeling process. Expression of meta-vinculin, a muscle-specific cytoskeletal protein, has been shown to reliably distinguish two unique SMC subpopulations within the bovine pulmonary arterial media. Therefore, to assess the proliferative responses of phenotypically distinct SMC subpopulations in the setting of neonatal pulmonary hypertension, we performed double immunofluorescence staining on pulmonary artery cryosections from control and hypertensive calves with antibodies against meta-vinculin and the proliferation-associated nuclear antigen, Ki-67. We found that, although neonatal pulmonary hypertension caused significant increases in overall cell replication, proliferation occurred almost exclusively in one, the meta-vinculin-negative SMC population, but not the other SMC population expressing meta-vinculin. We also examined fetal pulmonary arteries, where proliferative rates were high and meta-vinculin expression again reliably distinguished two SMC subpopulations. In contrast to the hypertensive neonate, we found in the fetus that the relative proliferative rates of both SMC subpopulations were equal, thus suggesting the existence of different mechanisms controlling proliferation and expression of cytoskeletal proteins in the fetus and neonate. We conclude that phenotypically distinct SMC populations in the bovine arterial media exhibit specific and selective proliferative responses to neonatal pulmonary hypertension. Distinct SMC subpopulations may, thus, contribute in unique ways to vascular homeostasis under both normal and pathologic conditions.

Animals↗
PubMed1995

Angiotensin converting enzyme expression is increased in small pulmonary arteries of rats with hypoxia-induced pulmonary hypertension.

Previous studies suggest that while lung angiotensin converting enzyme (ACE) activity is reduced during chronic hypoxia, inhibitors of ACE attenuate hypoxic pulmonary hypertension. In an attempt to explain this paradox we investigated the possibility that whole lung ACE activity may not reflect local pulmonary vascular ACE expression. The experimental approach combined in vivo hemodynamic studies in control and chronically hypoxic rats, measurement of whole lung ACE activity, and evaluation of local pulmonary vascular ACE expression by in situ hybridization and immunohistochemistry. Total lung ACE activity was reduced to 50% of control activity by 5 d of hypoxia and remained low for the duration of the study. Immunohistochemistry showed a marked reduction of ACE staining in alveolar capillary endothelium. However, an increase in ACE staining was observed in the walls of small newly muscularized pulmonary arteries at the level of alveolar ducts and walls. In situ hybridization studies showed increased signal for ACE mRNA in the same vessels. Inhibition of ACE by captopril during chronic hypoxia attenuated pulmonary hypertension and markedly reduced distal muscularization of small pulmonary arteries. In addition, we demonstrated marked longitudinal variation in ACE expression along the normal pulmonary vasculature with the highest levels found in small muscular arteries associated with terminal and respiratory bronchioles. We conclude that local ACE expression is increased in the walls of small pulmonary arteries during the development of hypoxic pulmonary hypertension, despite a generalized reduction in alveolar capillary ACE expression, and we speculate that local arteriolar ACE may play a role in the vascular remodeling associated with pulmonary hypertension.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1994

Enhanced growth capacity of neonatal pulmonary artery smooth muscle cells in vitro: dependence on cell size, time from birth, insulin-like growth factor I, and auto-activation of protein kinase C.

Based on the unique susceptibility of the neonatal pulmonary circulation to hypoxia-induced structural alteration in vivo, we hypothesized that pulmonary artery (PA) smooth muscle cells (SMC) from the neonate would demonstrate enhanced growth capacity in vitro compared to adult cells. To test this hypothesis, matched neonatal and adult bovine SMC were tested for differences in size, serum-stimulated proliferation, susceptibility to senescence, resistance to serum withdrawal, autocrine growth capacity, and responsiveness to a locally important growth factor (insulin-like growth factor I; IGF-I) and an activator of protein kinase C (PKC) (phorbol 12-myristate 13-acetate; PMA). Neonatal PA SMC were smaller, grew faster, reached a higher plateau density, and were less susceptible to senescence. They were more resistant to serum withdrawal, had spontaneous autocrine growth capacity, and were more responsive to IGF-I, PMA, and the combination. Acquisition of increased growth factor responsiveness occurred between d5 and d14 after birth. Increased neonatal growth to IGF-I was associated with reduced IGF-I binding activity, implicating a post-receptor mechanism in enhanced responsiveness. Increased membrane-bound PKC catalytic activity was found in serum-deprived neonatal SMC. This basal increase was equal to that stimulated by 1 nM PMA in adult SMC, a pretreatment that caused these cells to become as responsive to IGF-I as untreated neonatal ones. We conclude that neonatal bovine PA SMC have marked enhancement of growth capacity in vitro, the acquisition of which is dependent on time from birth and is associated with auto-activation of PKC, These increased growth properties detected in vitro may contribute to the striking hyperplasia of neonatal PA SMC found in vivo following hypoxic exposure.

Aging↗
PubMed1994

Multiple phenotypically distinct smooth muscle cell populations exist in the adult and developing bovine pulmonary arterial media in vivo.

Different smooth muscle cell (SMC) functions may require different cell phenotypes. Because the main pulmonary artery performs diverse functions, we hypothesized that it would contain heterogeneous SMC populations. If the hypothesis were confirmed, we wished to determine the developmental origin of the different populations. Using specific antibodies, we analyzed the expression of smooth muscle (SM) contractile and cytoskeletal proteins (alpha-SM-actin, SM myosin, calponin, desmin, and meta-vinculin) in the main pulmonary artery of fetal (60 to 270 days of gestation), neonatal, and adult animals. We demonstrated the existence of a complex, site-specific heterogeneity in the structure and cellular composition of the pulmonary arterial wall. We found that at least four cell/SMC phenotypes, based on immunobiochemical characteristics, cell morphology, and elastic lamellae arrangement pattern, were simultaneously expressed within the mature arterial media. Further, we were able to assess phenotypic alterations in each of the four identified cell populations during development. We found that each cell population within the arterial media expressed alpha-SM-actin at least at certain stages of development, thus demonstrating its smooth muscle identity. However, each cell population progressed along different developmental pathways, suggesting the existence of multiple and distinct cell lineages. A novel anti-metavinculin antibody described in this study reliably distinguished one SMC population from the others during all the developmental stages analyzed. We conclude that the pulmonary arterial media is indeed composed of multiple phenotypically distinct cell/SMC populations with unique lineages. We speculate that these distinct cell populations may serve different functions within the arterial media and may also respond in unique ways to pathophysiological stimuli.

Age Factors↗
PubMed1994

Eicosanoids decrease with successful extracorporeal membrane oxygenation therapy in neonatal pulmonary hypertension.

Elevated concentrations of eicosanoids have been reported in bronchoalveolar lavage fluid (BALF) and blood of infants with persistent pulmonary hypertension (PPHN), thereby indicating their potential role in its pathophysiology. Extracorporeal membrane oxygenation (ECMO) has improved the outcome in selected infants with PPHN. We hypothesized that ECMO, by alleviating lung injury, would be associated with decreased eicosanoid production and clinical improvement. Twenty-two newborns with PPHN treated with either ECMO or conventional means were studied. Concentrations of TxB2, 6-keto-PGF1 alpha, PGD2, PGE2, LTB4, and LTE4 were serially measured in BALF. Elevated concentrations of all eicosanoids measured were observed in all infants with PPHN at the initiation of ECMO. Eicosanoid concentrations decreased in all infants with a good clinical outcome after ECMO, but they remained elevated in those with a poor outcome. In patients with less severe PPHN, not requiring ECMO, lower concentrations of eicosanoids were observed at initiation of therapy. Eicosanoid levels increased or did not change over the course of conventional treatment. We conclude that eicosanoids are present in high concentrations in infants with PPHN. Iatrogenic factors, including oxygen and barotrauma, appear to correlate with their concentrations. Removal of these factors is associated with decreased production of mediators and clinical improvement.

Acute Disease↗
PubMed1994

Persistence of the fetal pattern of tropoelastin gene expression in severe neonatal bovine pulmonary hypertension.

Neonatal hypoxic pulmonary hypertension causes increases and spatial changes in tropoelastin expression in pulmonary arteries. However, it is not clear if this is due to recruitment of quiescent smooth muscle cells (SMC) into an elastin-producing phenotype or persistence of the fetal pattern of tropoelastin gene expression. We evaluated the distribution and relative concentration of tropoelastin mRNA in intralobar pulmonary arteries from late gestation fetuses and in animals exposed to hypobaric hypoxia (430 mmHg) from birth for 1, 3, 7, or 14 d, as well as in age-matched and adult room air-breathing controls. In situ hybridization demonstrated that tropoelastin mRNA was distributed throughout the entire radius of the pulmonary vessel wall in the fetus and newborn calf. By 15 d of age, only cells in the inner third of the media expressed tropoelastin mRNA, and by adulthood no tropoelastin mRNA was detected in the vessel wall. These findings demonstrated that tropoelastin expression shuts off in a spatially specific pattern, moving from the abluminal to the luminal side of the medial in the neonatal pulmonary artery when pressures and resistance are falling. In the aorta of 15-d-old calves, tropoelastin mRNA expression was seen equally throughout the media, indicating tissue-specific regulation of elastin in the neonatal period. In contrast, intralobar pulmonary arteries from calves exposed to hypoxia, which prevented the normal postnatal decline in pulmonary artery pressure, maintained the fetal pattern and levels of tropoelastin mRNA expression at all time points. Thus, rather than causing a recruitment of SMC into an elastin-producing phenotype, neonatal pulmonary hypertension caused a persistence of the fetal pattern of tropoelastin expression in medial SMC. Cell-free translation showed that the same tropoelastin isoforms were made by mRNA from control and hypertensive calves and, unlike the ligamentum nuchae, did not change during the transition from fetal to neonatal life. We conclude that pulmonary hypertension in the neonate perturbs the normal postpartum repression of tropoelastin expression resulting in a persistence of the fetal spacial and isoform patterns of tropoelastin gene expression.

Animals↗
PubMed1994

Persistence, re-expression, and induction of pulmonary arterial fibronectin, tropoelastin, and type I procollagen mRNA expression in neonatal hypoxic pulmonary hypertension.

Changes in the structure and function of muscular pulmonary arteries are crucial for normal adaptation to extrauterine life and rapid changes in matrix protein gene expression are likely necessary for this adaptation. We hypothesized that pathological stimuli imposed at the time of birth would alter developmental changes in matrix protein gene expression thereby affecting the normal post-uterine changes in pulmonary hemodynamics. We used in situ hybridization to examine the normal developmental expression of three extracellular matrix protein mRNAs, fibronectin, tropoelastin, and alpha 1 (I) procollagen, in muscular pulmonary arteries of both fetal and neonatal calves and assessed the impact of severe hypoxia-induced pulmonary hypertension on their expression. Morphometric techniques were used to assess whether changes in matrix protein mRNA levels were related to changes in matrix fiber accumulation. Exposure to chronic hypoxia postnatally resulted in the persistence, reexpression, and induction of fibronectin, tropoelastin, and alpha 1 (I) procollagen mRNAs, respectively, in muscular pulmonary arteries. In each case the hybridization signal was localized primarily to the adventitial layer of the vessel. Morphometric analysis showed that the increased hybridization signals seen correlated with an increase in both vascular elastin and collagen fiber volumes in the adventitial layer. We conclude that the change in expression of matrix genes in the pulmonary artery wall during exposure to chronic hypoxia is an important adaptive response to changes in hemodynamic factors and/or oxygen tension. The unchecked increase in matrix protein expression seen likely contributes to the pathological pulmonary arterial structural remodeling and loss of vasoreactivity that occurs during the development of severe neonatal pulmonary hypertension.

Animals↗
PubMed1993

Progressive loss of vasodilator responsive component of pulmonary hypertension in neonatal calves exposed to 4,570 m.

Severe neonatal pulmonary hypertension (PH) may have both reversible (vasoconstrictive) and "fixed" (vasodilator unresponsive) components. To assess when and to what degree vasodilator unresponsive PH developed in the neonate, pulmonary arterial pressures (PAP) and cardiac outputs (CO) were measured, and total pulmonary resistances (TPR) were calculated in neonatal calves exposed to chronic hypoxia (CH) (barometric pressure of 430 mmHg = 4,570 m) for 1, 3, 7, and 14 days under both normoxic (barometric pressure of 640 mmHg = 1,500 m) and hypoxic conditions with and without an infusion of the vasodilator acetylcholine (ACh). Studies were done at 4 h and at 2, 4, 8, and 15 days of life in both control and CH animals. The fixed component of PH was defined as that PAP or TPR above the control baseline value which remained in CH animals after an infusion ACh at 1,500 m. Small pulmonary arteries were also examined histologically in an attempt to correlate relative changes in the reversible and fixed elements of PH with alterations in vessel structure. Chronic exposure to 4,570 m altitude prevented the normal postnatal fall in PAP and TPR observed in control animals. Instead, PAP, TPR, and the structure of small pulmonary arteries initially remained similar to those of the 4-h-old newborn. By 7 days exposure to 4,570 m, a significant element of fixed PH developed, which increased dramatically between the 7- and 14-day exposure periods and appeared to correlate with a narrowed pulmonary artery lumen and increased medial and adventitial thickness.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine↗
PubMed1993

Functional and structural adaptation of the yak pulmonary circulation to residence at high altitude.

The high-altitude (HA) native yak (Bos grunniens) has successfully adapted to chronic hypoxia (CH) despite being in the same genus as domestic cows, which are known for their great hypoxic pulmonary vasoconstrictor responses (HPVRs), muscular pulmonary arteries, and development of severe pulmonary hypertension on exposure to CH. To determine possible mechanisms by which the pulmonary circulation may adapt to CH, yak pulmonary vascular reactivity to both vasoconstrictor and vasodilator stimuli and yak pulmonary artery structure were assessed. Hypoxia caused a small but significant HPVR, and norepinephrine infusion caused a greater rise in pulmonary arterial pressure (Ppa) than did hypoxia. Acetylcholine, an endothelium-dependent vasodilator, had no effect on Ppa but lowered pulmonary resistance (Rp) by causing an increase in cardiac output. Sodium nitroprusside, an endothelium-independent vasodilator, decreased both Ppa and Rp significantly. Yak small pulmonary arteries had a 4.1 +/- 0.1% medial thickness, with vessels < or = 100 microns devoid of smooth muscle. Yak pulmonary artery endothelial cells were much longer, wider, and rounder in appearance than those of domestic cows. Thus the yak has successfully adapted to HA conditions by maintaining both a blunted HPVR and thin-walled pulmonary vessels. Differences in both endothelial cell morphology and response to acetylcholine between the yak and those reported in the domestic cow suggest the adaptation to HA may include changes not only in the amount of pulmonary vascular smooth muscle but in endothelial cell function and structure as well.

Acclimatization↗
PubMed1992

Changes in lung eicosanoid content during normal and abnormal transition in perinatal lambs.

To study the potential contribution of eicosanoids in maintaining high vascular tone in utero or in modulating resistance during the normal or abnormal transition of the pulmonary circulation, we performed serial measurements of hemodynamic parameters and lung eicosanoid content in perinatal sheep with and without pulmonary hypertension. Prostacyclin (6-keto-PGF1 alpha), thromboxane (TxB2), and leukotriene contents were measured in fetal lung liquid (FLL), bronchoalveolar lavage fluid (BALF), and lung tissue samples. Leukotriene content was barely detectable above background in FLL samples from 11 late-gestation fetuses, and lung leukotriene content in fetal lung was one-third of that measured in maternal lung (P less than 0.01). Tissue samples from serial lung biopsies obtained before and after cesarean-section delivery of late-gestation lambs demonstrated increased lung prostacyclin content after delivery (P less than 0.04), but no changes in total leukotriene or thromboxane contents were found. In an experimental model of perinatal pulmonary hypertension, prostanoid and leukotriene content of FLL obtained immediately before delivery were not different from an age-matched nonhypertensive control group. Leukotriene content in BALF and lung tissue obtained 2 h after delivery was not increased in the hypertensive group. TxB2, but not 6-keto-PGF1 alpha, content was higher in lung tissue from the hypertensive group (P less than 0.02). Thus lung leukotriene content did not decrease from fetal values after cesarean-section delivery, and the lipoxygenase pathway was not significantly activated with delivery after chronic intrauterine pulmonary hypertension.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Pulmonary vascular impedance and wave reflections in the hypoxic calf.

The alterations in pulsatile hemodynamics that occur during hypoxic pulmonary vasoconstriction have not been well characterized. Changes in oscillatory hemodynamics, however, may affect right ventricular-pulmonary vascular coupling and the dissipation of energy within the lung vasculature. To better define hypoxic pulsatile hemodynamics, we measured main pulmonary artery proximal and distal micromanometric pressures and ultrasonic flow in four open-chest calves during progressive hypoxia. Main pulmonary artery impedance and pressure transmission spectra were calculated using spectral analysis methods. Measured pressure and flow signals were separated in the time domain into forward and backward components. Hypoxia increased pulmonary blood pressure and resistance and produced multiple modifications in the impedance and pressure transmission spectra that indicated increased wave reflections and elasticity. The impedance and apparent phase velocity first-harmonic values were increased in amplitude, and the pressure transmission modulus plot showed an increased peak value. In addition, the impedance modulus plot demonstrated a rightward shift and increased oscillation in the mid- to high-frequency range. The time domain analysis also confirmed increased wave reflections and elasticity. Hypoxia produced large backward-traveling (reflected) pressure and flow waves. The initial portions of these waves arrived at the heart during systole, producing characteristic changes in the measured pressure and flow waveforms. With prolonged hypoxia, main pulmonary artery pulse wave velocity increased by 30%. Thus, hypoxia is associated with complex alterations in pulmonary artery elasticity and wave reflections that act to increase the oscillatory afterload of the right ventricle.

Animals↗
PubMed1992

Insulin-like growth factor I and pulmonary hypertension induced by continuous air embolization in sheep.

Chronic pulmonary hypertension is associated with arterial structural remodeling. Insulin-like growth factor I (IGF-I) has been proposed as one of the mediators of vascular change because of its ability to stimulate proliferation in, and elastin production by, cultured vascular smooth muscle cells. We have shown previously that 12 days of continuous air embolization into the pulmonary arterial circulation of sheep results in the functional and structural changes of chronic pulmonary hypertension. In the present study, measurements of IGF-I (by radioimmunoassay) and IGF-I binding protein activity in sheep lung lymph and plasma were made before and during the 12 days of air embolization in six sheep. Two untreated animals served as controls. Baseline lung lymph contained 23.5 +/- 3.6 ng/ml (mean +/- SEM) of IGF-I, and there was a slight increase to 36.7 +/- 9.8 on day 3, but by day 6 levels were back to baseline. The flux of IGF-I from the lung (concentration times lymph flow) increased significantly by day 2 embolization and remained elevated through day 12 (baseline = 37.2 +/- 11.1 ng/15 min; day 2 = 237.7 +/- 55.8; day 5 = 190.2 +/- 53.4; day 6 = 82.6 +/- 21.9; day 12 = 78.7 +/- 12.5). IGF-I binding protein activity was also present in lung lymph at baseline (29.6 +/- 3.0%) and was unchanged during air embolization. Plasma levels of IGF-I and plasma binding protein activity remained at baseline throughout the 12 days of embolization (71.51 +/- 34.48 ng/ml and 36.4 +/- 3.5%, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Cellular adaptation during chronic neonatal hypoxic pulmonary hypertension.

Newborn animals develop more severe hypoxic pulmonary hypertension than do adults, their vascular changes are greater, and both the hypertension and vascular changes occur more rapidly. We hypothesize that this differential developmentally controlled response may arise from either a difference in the type or quantity of endogenously secreted mediators in response to a given injury or a difference in the replicative and/or matrix-producing response of the vascular cells to physical or chemical stimuli. We investigated the effect of chronic hypoxia (14 days) on the proliferative and matrix-producing phenotype of the neonatal (14-day-old) pulmonary artery smooth muscle cell (SMC) and examined the heterogeneity and potential mechanisms responsible for this response. In situ hybridization studies demonstrated a remarkable change in the distribution of cells hybridizing with a tropoelastin cRNA probe after 14 days of hypoxia. Studies also demonstrated a population of SMC that did not hybridize with the elastin or collagen probes, indicating that the pulmonary artery contains SMC of multiple phenotypes and that the response to hypoxic and hemodynamic stress is not uniform for the various types. Bromodeoxyuridine labeling experiments indicated a large increase in DNA synthesis in hypertensive vessels, which, again, was not uniform either across or along the arterial wall. In vitro experiments with neonatal SMC suggested that hypoxia alone could not be responsible for the proliferative or matrix changes.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Neonatal calves develop airflow limitation due to chronic hypobaric hypoxia.

Neonates and infants presenting with pulmonary hypertension and chronic hypoxia often exhibit airway obstruction. To investigate this association, we utilized a system in which neonatal calves are exposed to chronic hypobaric hypoxia and develop severe pulmonary hypertension. For the present study, one of each pair of six age-matched pairs of neonatal calves was continuously exposed to hypobaric hypoxia at 4,500 m (CH); the other remained at 1,500 m. At 2 wk of age, mean pulmonary arterial pressure (MPAP), dynamic lung compliance (Cdyn), resistance (RL), and static respiratory system compliance (Crs) were measured at 4,500 m in both CH and control calves exposed acutely to hypoxia (C). These measurements were repeated after cumulative administrations of nebulized methacholine (MCh). Tissues were removed for histological examination and assessment of bronchial ring contractility to MCh and KCl. After 2 wk of hypobaric hypoxia, MPAP (C 35 +/- 1.7 vs. CH 120 +/- 7 mmHg, P less than 0.001) and RL (C 2.64 +/- 0.16 vs CH 4.99 +/- 0.47 cmH2O.l-1s, P less than 0.001) increased. Cdyn (C 0.100 +/- 0.01 vs. CH 0.082 +/- 0.007 l/cmH2O) and Crs (CH 0.46 +/- 0.003 vs. C 0.59 +/- 0.009 l/cmH2O) were not significantly different. Compared with airways of C calves, airways of CH animals did not exhibit in vivo or in vitro MCh hyperresponsiveness; however, in vitro contractility to KCl of airways from CH animals was significantly increased. Histologically, airways from the CH calves showed increases in airway fibrous tissue and smooth muscle.(ABSTRACT TRUNCATED AT 250 WORDS)

Airway Resistance↗
PubMed1991

Alteration of the pulsatile load in the high-altitude calf model of pulmonary hypertension.

We compared main pulmonary arterial elasticity and global pulmonary arterial compliance in control and high-altitude (HA) calves to determine whether 1) changes in pulmonary arterial elasticity are contributing to an increase in the oscillatory load of the right ventricle in this model of pulmonary hypertension and 2) measured changes in stiffness of the HA calves' arterial wall are the result of both an increase in pressure and an alteration of the material properties of the HA calves' arterial wall. Newborn calves were placed at 4,300 m simulated altitude for 14 days, and control calves were kept at 1,500 m. The HA calves were then reacclimatized to 1,500 m for 24 h so that baseline pressures of the two groups were similar. Open-chest main pulmonary arterial and right ventricular micromanometric pressures, ultrasonic main pulmonary arterial diameter, and green dye flow were measured under baseline conditions and then under moderate and severely hypoxic conditions to make measurements at both baseline and increased pulmonary pressures. At elevated pressures, the pressure-diameter relationship was noted to be nonlinear, and a characteristic late systolic peaking of the right ventricular pressure waveform was seen. The Peterson pressure-strain modulus, pulse wave velocity, characteristic impedance, and global compliance (3 element windkessel) were calculated. The calculated variables were all shown to be pressure dependent, and no intrinsic differences in stiffness were seen between the control and HA animals when mean pressure was taken into account. Pulmonary arterial histology demonstrated, however, a characteristic increase in wall thickness in the HA animals. Thus, in this model of pulmonary hypertension, major changes in elasticity and pulsatile load are primarily due to an increase in pulmonary pressure. The structural changes present in the HA calves' arterial wall did not separately produce any measurable changes in arterial distensibility or the oscillatory load.

Altitude↗