Disodium cromoglycate attenuates hypoxia induced enlargement of end-expiratory lung volume in rats

Mechanism responsible for the enlargement of end-expiratory lung volume (EELV) induced by chronic hypoxia remains unclear. The fact that the increase in EELV persists after return to normoxia suggests involvement of morphological changes. Because hypoxia has been also shown to activate lung mast cells, we speculated that they could play in the mechanism increasing EELV similar role as in vessel remodeling in hypoxic pulmonary hypertension (HPH). We, therefore, tested an effect of mast cells degranulation blocker disodium cromoglycate (DSCG) on hypoxia induced EELV enlargement. Ventilatory parameters, EELV and right to left heart weight ratio (RV/LV+S) were measured in male Wistar rats. The experimental group (H+DSCG) was exposed to 3 weeks of normobaric hypoxia and treated with DSCG during the first four days of hypoxia, control group was exposed to hypoxia only (H), two others were kept in normoxia as non-treated (N) and treated (N+DSCG) groups. DSCG treatment significantly attenuated the EELV enlargement (H+DSCG = 6.1+/-0.8; H = 9.2+/-0.9; ml +/-SE) together with the increase in minute ventilation (H + DSCG = 190+/-8; H = 273 +/- 10; ml/min +/- SE) and RV/LV + S (H + DSCG = 0.39 +/- 0.03; H = 0.50 +/- 0.06).     

Doppler tissue imaging in assessment of pulmonary hypertension-induced right ventricle dysfunction

We aimed to assess the accuracy of Doppler tissue imaging (DTI) in detecting right ventricle (RV) dysfunction and electromechanical coupling alteration following pulmonary hypertension (PHT) in rat. PHT was induced by chronic hypoxia exposure (hypoxic PHT) or monocrotaline treatment (monocrotaline PHT). In both PHT models, we observed transparietal RV pressure increase and remodeling, including hypertrophy and dilation. Conventional echocardiography provided evidence for pulmonary outflow impairment with midsystolic notch and acceleration time decrease in PHT groups (21.7 +/- 1.6 and 13.2 +/- 2.9 ms in hypoxic and monocrotaline PHT groups vs. 28.1 +/- 1.0 ms in control). RV shortening fraction was decreased in the monocrotaline PHT group compared with the hypoxic PHT and control groups. Combining conventional Doppler and DTI was more helpful to detect RV diastolic dysfunction in the monocrotaline PHT group (E/Ea ratio = 17.0 +/- 1.4) compared with the hypoxic PHT and control groups (11.5 +/- 0.7 and 10.2 +/- 0.4, respectively). Tei index measured using DTI highlighted global RV dysfunction in the monocrotaline PHT group (1.36 +/- 0.24 vs. 0.92 +/- 0.05 and 0.86 +/- 0.05 in the hypoxic PHT and control groups, respectively). Q-Sm time measured from the onset of Q wave to the onset of DTI Sm wave was increased in both PHT groups. PHT-induced electromechanical coupling alteration was confirmed by in vitro activation-contraction delay measurements on isolated RV papillary muscle, and both Q-Sm time and activation-contraction delay were correlated with PHT severity. We demonstrated that Q-Sm time measured in DTI was an easily and convenient index to detect early RV electromechanical coupling alteration in both moderate and severe PHT.     

Alterations in atrial and plasma atrial natriuretic factor (ANF) content during development of hypoxia-induced pulmonary hypertension in the rat

Distension of the atrial wall has been proposed as a signal for the increased release of atrial natriuretic factor (ANF) from atrial myocytes in response to perceived volume overload. To determine whether pressure changes resulting from hypertension in the pulmonary circulation may stimulate release of ANF, rats were exposed to chronic hypobaric hypoxia for 3 or 21 days and the ANF concentration in the atria and plasma were determined by specific radioimmunoassay. Exposure to chronic hypoxia resulted in significant increases in hematocrit at both 3 (p less than 0.025) and 21 days (p less than 0.005) and in the development of right ventricular hypertrophy (RVH) expressed as the ratio of the weight of the right ventricle to the weight of the left ventricle and septum (RV/LV+S) at both 3 (RV/LV+S = 0.278 +/- 0.005) and 21 days (RV/LV+S = 0.536 +/- 0.021). After 21 days, left atrial (LA) ANF content was significantly increased in hypoxic rats compared to controls (508 +/- 70 ng/mg tissue vs 302 +/- 37 ng/mg), while right atrial (RA) ANF content was significantly reduced (440 +/- 45 vs 601 +/- 58 ng/mg). At this time, plasma ANF concentration was significantly elevated compared to controls (238 +/- 107 pg/ml vs 101 +/- 10 pg/ml). These results suggest that the development of pulmonary hypertension following chronic hypobaric exposure induces altered atrial ANF content and increased plasma ANF concentration as a result of altered distension of the atrial wall.     

Exposure of neonatal rats to carbon monoxide alters cardiac adaptation to aortic constriction.

We tested the hypothesis that a 32-day exposure of newborn rats to 500 ppm carbon monoxide (CO) would alter the adaptive response of the heart to aortic constriction in adulthood. At 110 days of age aortic constriction or sham operations were performed, and hearts were studied 28 days later. Aortic constriction increased left ventricular (LV) mass by 40% over the control value of 611 +/- 27 mg; this adaptive response was not altered by CO exposure. Aortic constriction and CO exposure increased right ventricular (RV) mass by 10 and 11%, respectively, over the control value of 185 +/- 10 mg. The effects of both experimental procedures on RV mass were additive (23%). Peak LV pressure development (dP/dtmax) in vitro increased 29% after aortic constriction in the nonexposed rats. CO exposure blunted the increase in peak LV systolic pressure due to aortic constriction. Maximum positive and negative dP/dtmax decreased by 19% after aortic constriction and were unaffected by CO exposure. The percentage of alpha-myosin heavy chain (MHC) in the ventricles was 94 +/- 2% in the control group and was decreased to 81 +/- 3% by aortic constriction. In contrast, the percentage of alpha-MHC was 87 +/- 2% for CO-exposed rats and was not significantly altered after aortic constriction. In vitro coronary flow was increased 18% in hearts of adult rats exposed to CO as neonates. Exposure of neonatal rats to CO induced chronic adaptations in the myocardium, some of which became evident in adulthood only when hearts were challenged by aortic constriction.     

Hypercapnia does not affect functional residual capacity enlargement induced by chronic hypoxia

To determine whether changes in partial pressure of CO2 participate in mechanism enlarging the lung functional residual capacity (FRC) during chronic hypoxia, we measured FRC and ventilation in rats exposed either to poikilocapnic (group H, F(I)O2 0.1, F(I)CO2 <0.01) or hypercapnic (group H+CO2, F(I)O2 0.1, F(I)CO2 0.04-0.05) hypoxia for the three weeks and in the controls (group C) breathing air. At the end of exposure a body plethysmograph was used to measure ventilatory parameters (V'(E), f(R), V(T)) and FRC during air breathing and acute hypoxia (10 % O2 in N2). The exposure to hypoxia for three weeks increased FRC measured during air breathing in both experimental groups (H: 3.0+/-0.1 ml, H+CO2: 3.1+/-0.2 ml, C: 1.8+/-0.2 ml). During the following acute hypoxia, we observed a significant increase of FRC in the controls (3.2+/-0.2 ml) and in both experimental groups (H: 3.5+/-0.2 ml, H+CO2: 3.6+/-0.2 ml). Because chronic hypoxia combined with chronic hypercapnia and chronic poikilocapnic hypoxia induced the same increase of FRC, we conclude that hypercapnia did not participate in the FRC enlargement during chronic hypoxia.     

Chronic hypoxia induces nonreversible right ventricle dysfunction and dysplasia in rats

The purpose of this study was to evaluate the reversibility of right ventricular (RV) remodelling after pulmonary artery hypertension (PAHT) secondary to 3 wk of hypobaric hypoxia. A group of 10 adult male Wistar rats were studied and were the following: control normoxic (C), after 3 wk of chronic hypoxia (CH), and after 3 wk of exposure to hypoxia followed by 3 wk of normoxia recovery (N-RE). Mean pulmonary artery pressure was 11 +/- 2 mmHg in the C group, 35 +/- 2 mmHg in the CH group, and 14 +/- 3 mmHg in the N-RE group. RV function was assessed by echocardiography. In the CH group, the pulmonary flow measured in Doppler mode depicted a midsystolic notch and a decrease of the pulmonary acceleration time compared with control [17 +/- 1 vs. 34 +/- 1 ms (n = 10), respectively; P < 0.05]. RV thickening measured in M-mode was apparent in the CH group compared with the control group [2.84 +/- 0.40 vs. 1.73 +/- 0.26 mm (n = 10), P < 0.05]. In the N-RE group, the RV wall was significantly thinner compared with the CH group [1.56 +/- 0.08 vs. 1.73 +/- 0.26 mm (n = 10), P < 0.05]. The calculated RV diameter shortness fraction was not different between the CH group and C group (34 +/- 4.2% vs. 36 +/- 2.8%) but decreased in the N-RE group [20 +/- 2.4% (n = 10), P < 0.01]. The E-to-A wave ratio on the tricuspid Doppler inflow was significantly lower in the CH group and N-RE group compared with the C group [0.70 +/- 0.8 and 0.72 +/- 0.1 vs. 0.88 +/- 0.2 (n = 10), respectively; P < 0.05]. In the isolated perfused heart using the Langendorff method, RV compliance was increased in the CH group and decreased in the N-RE group. In the N-RE group, fibrous bands with metaplasia were observed on histological sections of the RV free wall. We conclude that PAHT induces nonreversible RV dysfunction with dysplasia.     

Heart and lung alterations in neonatal rats exposed to CO or high altitude.

We wished to determine whether cardiac changes produced by CO are related to the development of pulmonary hypertension and whether they are specific for CO or also occur with high-altitude exposure. Newborn male Sprague-Dawley rats were exposed to 500 ppm CO for 32 days (CO) at Detroit, MI or to 11,500-ft simulated altitude at Fort Collins, CO (barometric pressure 495 Torr; 11K); ambient air controls were maintained at Detroit (657 ft, 200 m; AIR) and at Fort Collins (5,000 ft, 1,524 m; 5K). Rats were maintained at Fort Collins after 34 days of age. Hematocrit was elevated to a greater extent in the CO than in the 11K group 2 days postexposure; however, no differences existed 40, 76, or 112 days postexposure. Right ventricle (RV) and left ventricle plus septum (LV + S) mass in CO rats were increased 38.0 and 37.4%, respectively, relative to the AIR group 2 days after CO exposure; RV and LV + S in the 11K group were increased 55.7 and 9.3%, respectively, relative to the 5K group. Cardiac hypertrophy declined in the CO and 11K groups postexposure but remained significant for the RV, reaching 20.7% above the AIR group (CO) and 29.7% above the 5K group (11K) at 145 days of age. By use of an in vitro preparation, pulmonary vascular resistance (PVR) and pulmonary arterial pressure were significantly increased immediately after altitude but not after CO exposure and remained elevated in adulthood after altitude exposure. PVR was correlated with hematocrit in altitude- but not in CO-exposed rats.(ABSTRACT TRUNCATED AT 250 WORDS)     

The impact of endurance exercise training on left ventricular systolic mechanics

Although exercise training-induced changes in left ventricular (LV) structure are well characterized, adaptive functional changes are incompletely understood. Detailed echocardiographic assessment of LV systolic function was performed on 20 competitive rowers (10 males and 10 females) before and after endurance exercise training (EET; 90 days, 10.7 +/- 1.1 h/wk). Structural changes included LV dilation (end-diastolic volume = 128 +/- 25 vs. 144 +/- 28 ml, P < 0.001), right ventricular (RV) dilation (end-diastolic area = 2,850 +/- 550 vs. 3,260 +/- 530 mm2, P < 0.001), and LV hypertrophy (mass = 227 +/- 51 vs. 256 +/- 56 g, P < 0.001). Although LV ejection fraction was unchanged (62 +/- 3% vs. 60 +/- 3%, P = not significant), all direct measures of LV systolic function were altered. Peak systolic tissue velocities increased significantly (basal lateral S'Delta = 0.9 +/- 0.6 cm/s, P = 0.004; and basal septal S'Delta = 0.8 +/- 0.4 cm/s, P = 0.008). Radial strain increased similarly in all segments, whereas longitudinal strain increased with a base-to-apex gradient. In contrast, circumferential strain (CS) increased in the LV free wall but decreased in regions adjacent to the RV. Reductions in septal CS correlated strongly with changes in RV structure (DeltaRV end-diastolic area vs. DeltaLV septal CS; r2 = 0.898, P < 0.001) and function (Deltapeak RV systolic velocity vs. DeltaLV septal CS, r2 = 0.697, P < 0.001). EET leads to significant changes in LV systolic function with regional heterogeneity that may be secondary to concomitant RV adaptation. These changes are not detected by conventional measurements such as ejection fraction.     

Rapamycin attenuates hypoxia-induced pulmonary vascular remodeling and right ventricular hypertrophy in mice

Background

Chronic hypoxia induces pulmonary arterial hypertension (PAH). Smooth muscle cell (SMC) proliferation and hypertrophy are important contributors to the remodeling that occurs in chronic hypoxic pulmonary vasculature. We hypothesized that rapamycin (RAPA), a potent cell cycle inhibitor, prevents pulmonary hypertension in chronic hypoxic mice.

Methods

Mice were held either at normoxia (N; 21% O₂) or at hypobaric hypoxia (H; 0.5 atm; ~10% O₂). RAPA-treated animals (3 mg/kg*d, i.p.) were compared to animals injected with vehicle alone. Proliferative activity within the pulmonary arteries was quantified by staining for Ki67 (positive nuclei/vessel) and media area was quantified by computer-aided planimetry after immune-labeling for α-smooth muscle actin (pixel/vessel). The ratio of right ventricle to left ventricle plus septum (RV/[LV+S]) was used to determine right ventricular hypertrophy.

Results

Proliferative activity increased by 34% at day 4 in mice held under H (median: 0.38) compared to N (median: 0.28, p = 0.028) which was completely blocked by RAPA (median HO+RAPA: 0.23, p = 0.003). H-induced proliferation had leveled off within 3 weeks. At this time point media area had, however, increased by 53% from 91 (N) to 139 (H, p < 0.001) which was prevented by RAPA (H+RAPA: 102; p < 0.001). RV/[LV+S] ratio which had risen from 0.17 (N) to 0.26 (H, p < 0.001) was attenuated in the H+RAPA group (0.22, p = 0.041). For a therapeutic approach animals were exposed to H for 21 days followed by 21 days in H ± RAPA. Forty two days of H resulted in a media area of 129 (N: 83) which was significantly attenuated in RAPA-treated mice (H+RAPA: 92). RV/[LV+S] ratios supported prevention of PH (N 0.13; H 0.27; H+RAPA 0.17). RAPA treatment of N mice did not influence any parameter examined.

Conclusion

Therapy with rapamycin may represent a new strategy for the treatment of pulmonary hypertension.     

Synergistic effects of ANP and sildenafil on cGMP levels and amelioration of acute hypoxic pulmonary hypertension

We hypothesized that the phosphodiesterase 5 inhibitor, sildenafil, and the guanosine cyclase stimulator, atrial natriuretic peptide (ANP), would act synergistically to increase cGMP levels and blunt hypoxic pulmonary hypertension in rats, because these compounds act via different mechanisms to increase the intracellular second messenger. Acute hypoxia: Adult Sprague-Dawley rats were gavaged with sildenafil (1 mg/ kg) or vehicle and exposed to acute hypoxia with and without ANP (10(-8)-10(-5) M ). Sildenafil decreased systemic blood pressure (103 +/- 10 vs. 87 +/- 6 mm Hg, P < 0.001) and blunted the hypoxia-induced increase in right ventricular systolic pressure (RVSP; percent increase 73.7% +/- 9.4% in sildenafil-treated rats vs. 117.2% +/- 21.1% in vehicle-treated rats, P = 0.03). Also, ANP and sildenafil had synergistic effects on blunting the hypoxia-induced increase in RVSP (P < 0.001) and on rising plasma cGMP levels (P < 0.05). Chronic hypoxia: Other rats were exposed to prolonged hypoxia (3 weeks, 0.5 atm) after subcutaneous implantation of a sustained-release pellet containing lower (2.5 mg), or higher (25 mg) doses of sildenafil, or placebo. Higher-dose, but not lower-dose sildenafil blunted the chronic hypoxia-induced increase in RVSP (P = 0.006). RVSP and plasma sildenafil levels were inversely correlated in hypoxic rats (r(2) = 0.68, P = 0.044). Lung cGMP levels were increased by both chronic hypoxia and sildenafil, with the greatest increase achieved by the combination. Plasma and right ventricular (RV) cGMP levels were increased by hypoxia, but sildenafil had no effect. RV hypertrophy and pulmonary artery muscularization were also unaffected by sildenafil. In conclusion, sildenafil and ANP have synergistic effects on the blunting of hypoxia-induced pulmonary vasoconstriction. During chronic hypoxia, sildenafil normalizes RVSP, but in the doses used, sildenafil has no effect on RV hypertrophy or pulmonary vascular remodeling.     

Cardiac atrophy after bed rest and spaceflight.

Cardiac muscle adapts well to changes in loading conditions. For example, left ventricular (LV) hypertrophy may be induced physiologically (via exercise training) or pathologically (via hypertension or valvular heart disease). If hypertension is treated, LV hypertrophy regresses, suggesting a sensitivity to LV work. However, whether physical inactivity in nonathletic populations causes adaptive changes in LV mass or even frank atrophy is not clear. We exposed previously sedentary men to 6 (n = 5) and 12 (n = 3) wk of horizontal bed rest. LV and right ventricular (RV) mass and end-diastolic volume were measured using cine magnetic resonance imaging (MRI) at 2, 6, and 12 wk of bed rest; five healthy men were also studied before and after at least 6 wk of routine daily activities as controls. In addition, four astronauts were exposed to the complete elimination of hydrostatic gradients during a spaceflight of 10 days. During bed rest, LV mass decreased by 8.0 +/- 2.2% (P = 0.005) after 6 wk with an additional atrophy of 7.6 +/- 2.3% in the subjects who remained in bed for 12 wk; there was no change in LV mass for the control subjects (153.0 +/- 12.2 vs. 153.4 +/- 12.1 g, P = 0.81). Mean wall thickness decreased (4 +/- 2.5%, P = 0.01) after 6 wk of bed rest associated with the decrease in LV mass, suggesting a physiological remodeling with respect to altered load. LV end-diastolic volume decreased by 14 +/- 1.7% (P = 0.002) after 2 wk of bed rest and changed minimally thereafter. After 6 wk of bed rest, RV free wall mass decreased by 10 +/- 2.7% (P = 0.06) and RV end-diastolic volume by 16 +/- 7.9% (P = 0.06). After spaceflight, LV mass decreased by 12 +/- 6.9% (P = 0.07). In conclusion, cardiac atrophy occurs during prolonged (6 wk) horizontal bed rest and may also occur after short-term spaceflight. We suggest that cardiac atrophy is due to a physiological adaptation to reduced myocardial load and work in real or simulated microgravity and demonstrates the plasticity of cardiac muscle under different loading conditions.     

Cardioprotective and vasomotor effects of HO activity during acute and chronic hypoxia

Prolonged hypoxia leads to the development of pulmonary hypertension. Recent reports have suggested enhancement of heme oxygenase (HO), the major source of intracellular carbon monoxide (CO), prevents hypoxia-induced pulmonary hypertension and vascular remodeling in rats. Therefore, we hypothesized that inhibition of HO activity by tin protoporphyrin (SnPP) would exacerbate the development of pulmonary hypertension. Rats were injected weekly with either saline or SnPP (50 micromol/kg) and exposed to hypobaric hypoxia or room air for 5 wk. Pulmonary and carotid arteries were catheterized, and animals were allowed to recover for 48 h. Pulmonary and systemic pressures, along with cardiac output, were recorded during room air and acute 10% O2 breathing in conscious rats. No difference was detected in pulmonary artery pressure between saline- and SnPP-treated animals in either normoxic or hypoxic groups. However, blockade of HO activity altered both systemic and pulmonary vasoreactivity to acute hypoxic challenge. Despite no change in baseline pulmonary artery pressure, all rats treated with SnPP had decreased ratio of right ventricular (RV) weight to left ventricular (LV) plus septal (S) weight (RV/LV + S) compared with saline-treated animals. Echocardiograms suggested dilatation of the RV and decreased RV function in hypoxic SnPP-treated rats. Together these data suggest that inhibition of HO activity and CO production does not exacerbate pulmonary hypertension, but rather that HO and CO may be involved in mediating pulmonary and systemic vasoreactivity to acute hypoxia and hypoxia-induced RV function.     

Training-specific changes in cardiac structure and function: a prospective and longitudinal assessment of competitive athletes.

This prospective, longitudinal study examined the effects of participation in team-based exercise training on cardiac structure and function. Competitive endurance athletes (EA, n = 40) and strength athletes (SA, n = 24) were studied with echocardiography at baseline and after 90 days of team training. Left ventricular (LV) mass increased by 11% in EA (116 +/- 18 vs. 130 +/- 19 g/m(2); P < 0.001) and by 12% in SA (115 +/- 14 vs. 132 +/- 11 g/m(2); P < 0.001; P value for the compared Delta = NS). EA experienced LV dilation (end-diastolic volume: 66.6 +/- 10.0 vs. 74.7 +/- 9.8 ml/m(2), Delta = 8.0 +/- 4.2 ml/m(2); P < 0.001), enhanced diastolic function (lateral E': 10.9 +/- 0.8 vs. 12.4 +/- 0.9 cm/s, P < 0.001), and biatrial enlargement, while SA experience LV hypertrophy (posterior wall: 4.5 +/- 0.5 vs. 5.2 +/- 0.5 mm/m(2), P < 0.001) and diminished diastolic function (E' basal lateral LV: 11.6 +/- 1.3 vs. 10.2 +/- 1.4 cm/s, P < 0.001). Further, EA experienced right ventricular (RV) dilation (end-diastolic area: 1,460 +/- 220 vs. 1,650 +/- 200 mm/m(2), P < 0.001) coupled with enhanced systolic and diastolic function (E' basal RV: 10.3 +/- 1.5 vs. 11.4 +/- 1.7 cm/s, P < 0.001), while SA had no change in RV parameters. We conclude that participation in 90 days of competitive athletics produces significant training-specific changes in cardiac structure and function. EA develop biventricular dilation with enhanced diastolic function, while SA develop isolated, concentric left ventricular hypertrophy with diminished diastolic relaxation.     

Characterization of right ventricular function after monocrotaline-induced pulmonary hypertension in the intact rat

We characterized hemodynamics and systolic and diastolic right ventricular (RV) function in relation to structural changes in the rat model of monocrotaline (MCT)-induced pulmonary hypertension. Rats were treated with MCT at 30 mg/kg body wt (MCT30, n = 15) and 80 mg/kg body wt (MCT80, n = 16) to induce compensated RV hypertrophy and RV failure, respectively. Saline-treated rats served as control (Cont, n = 13). After 4 wk, a pressure-conductance catheter was introduced into the RV to assess pressure-volume relations. Subsequently, rats were killed, hearts and lungs were rapidly dissected, and RV, left ventricle (LV), and interventricular septum (IVS) were weighed and analyzed histochemically. RV-to-(LV + IVS) weight ratio was 0.29 +/- 0.05 in Cont, 0.35 +/- 0.05 in MCT30, and 0.49 +/- 0.10 in MCT80 (P < 0.001 vs. Cont and MCT30) rats, confirming MCT-induced RV hypertrophy. RV ejection fraction was 49 +/- 6% in Cont, 40 +/- 12% in MCT30 (P < 0.05 vs. Cont), and 26 +/- 6% in MCT80 (P < 0.05 vs. Cont and MCT30) rats. In MCT30 rats, cardiac output was maintained, but RV volumes and filling pressures were significantly increased compared with Cont (all P < 0.05), indicating RV remodeling. In MCT80 rats, RV systolic pressure, volumes, and peak wall stress were further increased, and cardiac output was significantly decreased (all P < 0.05). However, RV end-systolic and end-diastolic stiffness were unchanged, consistent with the absence of interstitial fibrosis. MCT-induced pressure overload was associated with a dose-dependent development of RV hypertrophy. The most pronounced response to MCT was an overload-dependent increase of RV end-systolic and end-diastolic volumes, even under nonfailing conditions.     

Effects of hypergravity on the distributions of lung ventilation and perfusion in sitting humans assessed with a simple two-step maneuver.

Increased gravity impairs pulmonary distributions of ventilation and perfusion. We sought to develop a method for rapid, simultaneous, and noninvasive assessments of ventilation and perfusion distributions during a short-duration hypergravity exposure. Nine sitting subjects were exposed to one, two, and three times normal gravity (1, 2, and 3 G) in the head-to-feet direction and performed a rebreathing and a single-breath washout maneuver with a gas mixture containing C(2)H(2), O(2), and Ar. Expirograms were analyzed for cardiogenic oscillations (COS) and for phase IV amplitude to analyze inhomogeneities in ventilation (Ar) and perfusion [CO(2)-to-Ar ratio (CO(2)/Ar)] distribution, respectively. COS were normalized for changes in stroke volume. COS for Ar increased from 1-G control to 128 +/- 6% (mean +/- SE) at 2 G (P = 0.02 for 1 vs. 2 G) and 165 +/- 13% at 3 G (P = 0.002 for 2 vs. 3 G). Corresponding values for CO(2)/Ar were 135 +/- 12% (P = 0.04) and 146 +/- 13%. Phase IV amplitude for Ar increased to 193 +/- 39% (P = 0.008) at 2 G and 229 +/- 51% at 3 G compared with 1 G. Corresponding values for CO(2)/Ar were 188 +/- 29% (P = 0.02) and 219 +/- 18%. We conclude that not only large-scale ventilation and perfusion inhomogeneities, as reflected by phase IV amplitude, but also smaller-scale inhomogeneities, as reflected by the ratio of COS to stroke volume, increase with hypergravity. Except for small-scale ventilation distribution, most of the impairments observed at 3 G had been attained at 2 G. For some of the parameters and gravity levels, previous comparable data support the present simplified method.     

Expression of mitochondrial regulatory genes parallels respiratory capacity and contractile function in a rat model of hypoxia-induced right ventricular hypertrophy

Chronic hypobaric hypoxia (CHH) increases load on the right ventricle (RV) resulting in RV hypertrophy. We hypothesized that CHH elicits distinct responses, i.e., the hypertrophied RV, unlike the left ventricle (LV), displaying enhanced mitochondrial respiratory and contractile function. Wistar rats were exposed to 4 weeks CHH (11% O(2)) versus normoxic controls. RV/body weight ratio increased (P < 0.001 vs. control) while RV systolic and developed pressures were higher. However, LV systolic and developed pressures were significantly reduced. Mitochondrial O(2) consumption was sustained in the hypertrophied RV, ADP/O increased (P < 0.01 vs. control) and proton leak significantly decreased. Conversely, LV mitochondrial O(2) consumption was attenuated (P < 0.05 vs. control) and proton leak significantly increased. In parallel, expression of mitochondrial regulators was upregulated in the hypertrophied RV but not the LV. Our data show that the hypertrophied RV induces expression of mitochondrial regulatory genes linking respiratory capacity and enhanced efficiency to sustained contractile function.     

Alveolar hypoxia induces left ventricular diastolic dysfunction and reduces phosphorylation of phospholamban in mice

Chronic obstructive pulmonary disease (COPD) may lead to pulmonary hypertension (PH) and reduced function of the right ventricle (RV). However, COPD patients may also develop left ventricular (LV) diastolic dysfunction. We hypothesized that alveolar hypoxia induces LV diastolic dysfunction and changes in proteins governing Ca(2+) removal from cytosol during diastole. Mice exposed to 10% oxygen for 1, 2, or 4 wk were compared with controls. Cardiac hemodynamics were assessed with Doppler echocardiography and a microtransducer catheter under general anesthesia. The pulmonary artery blood flow acceleration time was shorter and RV pressure was higher after 4 wk of hypoxia compared with controls (both P < 0.05). In the RV and LV, 4 wk of hypoxia induced a prolongation of the time constant of isovolumic pressure decay (51% RV, 43% LV) and a reduction in the maximum rate of decline in pressure compared with control (42% RV, 42% LV, all P < 0.05), indicating impaired relaxation and diastolic dysfunction. Alveolar hypoxia induced a 38%, 47%, and 27% reduction in Ser16-phosphorylated phospholamban (PLB) in the RV after 1, 2, and 4 wk of hypoxia, respectively, and at the same time points, Ser16-phosphorylated PLB in the LV was downregulated by 32%, 34%, and 25% (all P < 0.05). The amounts of PLB and sarco(endo)plasmic reticulum Ca(2+) ATPase (SERCA2a) were not changed. In conclusion, chronic alveolar hypoxia induces hypophosphorylation of PLB at Ser16, which might be a mechanism for impaired relaxation and diastolic dysfunction in both the RV and LV.     

低氧性肺动脉高压小鼠肺组织apoE蛋白表达的变化及其意义

目的：观察低氧性肺动脉高压小鼠肺组织中载脂蛋白E（apoE）蛋白表达的变化,以探讨低氧性肺动脉高压形成过程中apoE蛋白表达的变化及可能的意义。方法：SPF级雄性野生型（WT）C57BL/6小鼠和雄性apoE基因敲除（apoE-KO）小鼠各20只,各随机再分为2组（n=10）：常氧组和低氧组,共4组。常压连续低氧3周（9%~11% O₂,23 h/d）复制慢性低氧性肺动脉高压模型,采用右心导管法测定小鼠右心室压（RVSP）,计算右心室与左心室加室间隔重量比RV/（LV+S）,ELISA法检测血浆中高密度脂蛋白（HDL）、低密度脂蛋白（LDL）和总胆固醇（TC）的含量;Western blot法检测肺组织中apoE和过氧化物酶体增殖物激活受体γ（PPARγ）蛋白的表达。结果：①低氧组WT小鼠RVSP、RV/（LV+S）分别较常氧组高68%和59%（P均<0.05）,血浆中HDL含量及HDL/LDL比值分别较常氧组低17%和40%（P均<0.05）,同时肺、肝组织中apoE及肺组织中PPARγ的蛋白表达分别较常氧组下调48%、52%和37%（P均<0.05）,RVSP与apoE及PPARγ蛋白表达均呈显著负相关（P均<0.01）;②低氧组apoE-KO小鼠RVSP、RV/（LV+S）较常氧组分别高96%和86%（P均<0.05）,低氧组apoE-KO小鼠RVSP和RV/（LV+S）较低氧组WT小鼠分别高29%和24%（P均<0.05）。结论：小鼠低氧性肺动脉高压的形成与肺组织中apoE蛋白表达下调有关。     

Triiodothyronine concomitantly inhibits calcium overload and postischemic myocardial stunning in diabetic rats.

Acute effects of triiodothyronine (T3) on postischemic myocardial stunning and intracellular Ca2+ contents were studied in the isolated working hearts of streptozotocin-induced diabetic rats and age-matched controls. After two weeks of diabetes, serum T3 and T4 levels were decreased to 62.5% and 33.9% of control values. Basal preischemic cardiac performance did not differ between diabetic and control rats. In contrast, during reperfusion after 20-min ischemia, diabetic rats exhibited an impaired recovery of heart rate (at 30-min reperfusion 57.5% of baseline vs. control 88.5%), left ventricular (LV) systolic pressure (44.1% vs. 89.5%), and cardiac work (23.1% vs. 66.0%). When 1 and 100 nM T3 was added before ischemia, heart rate was recovered to 77.2% and 81.8% of baseline, LV systolic pressure to 68.3% and 81.9%, and cardiac work to 50.8% and 59.0%, respectively. Diabetic rat hearts showed a higher Ca2+ content in the basal state and a further increase after reperfusion (4.96+/-1.17 vs. control 3.78+/-0.48 micromol/g, p<0.01). In diabetic hearts, H+ release was decreased after reperfusion (5.24+/-2.21 vs. 8.70+/-1.41 mmol/min/g, p<0.05). T3 administration caused a decrease in the postischemic Ca2+ accumulation (lnM T3 4.66+/-0.41 and 100 nM T3 3.58+/-0.36) and recovered the H+ release (lnM T3 16.2+/-3.9 and 100 nM T3 11.6+/-0.9). T3 did not alter myocardial O2 consumption. Results suggest that diabetic rat hearts are vulnerable to postischemic stunning, and T3 protects the myocardial stunning possibly via inhibiting Ca2+ overload.     

Differential effects of left ventricular pacing sites in an acute canine model of contraction dyssynchrony

The goal of the present study was to assess the effects of left ventricular (LV) pacing sites (apex vs. free wall) on radial synchrony and global LV performance in a canine model of contraction dyssynchrony. Ultrasound tissue Doppler imaging and hemodynamic (LV pressure-volume) data were collected in seven anesthetized, opened-chest dogs. Right atrial (RA) pacing served as the control, and contraction dyssynchrony was created by simultaneous RA and right ventricular (RV) pacing to induce a left bundle-branch block-like contraction pattern. Cardiac resynchronization therapy (CRT) was implemented by adding simultaneous LV pacing to the RV pacing mode at either the LV apex (CRTa) or free wall (CRTf). A new index of synchrony was developed via pair-wise cross-correlation analysis of tissue Doppler radial strain from six midmyocardial cross-sectional regions, with a value of 15 indicating perfect synchrony. Compared with RA pacing, RV pacing significantly decreased radial synchrony (11.1 +/- 0.8 vs. 4.8 +/- 1.2, P < 0.01) and global LV performance (cardiac output: 2.0 +/- 0.3 vs. 1.4 +/- 0.1 l/min and stroke work: 137 +/- 22 vs. 60 +/- 14 mJ, P < 0.05). Although both CRTa and CRTf significantly improved radial synchrony, only CRTa markedly improved global function (cardiac output: 2.1 +/- 0.2 l/min and stroke work: 113 +/- 13 mJ, P < 0.01 vs. RV pacing). Furthermore, CRTa decreased LV end-systolic volume compared with RV pacing without any change in LV end-systolic pressure, indicating an augmented global LV contractile state. Thus, LV apical pacing appears to be a superior pacing site in the context of CRT. The dissociation between changes in synchrony and global LV performance with CRTf suggests that regional analysis from a single plane may not be sufficient to adequately characterize contraction synchrony.