Effects of sprint training on contractility and [Ca(2+)](i) transients in adult rat myocytes.

The effects of 6-8 wk of high-intensity sprint training (HIST) on rat myocyte contractility and intracellular Ca(2+) concentration ([Ca(2+)](i)) transients were investigated. Compared with sedentary (Sed) myocytes, HIST induced a modest (5%) but significant (P < 0.0005) increase in cell length with no changes in cell width. In addition, the percentage of myosin heavy chain alpha-isoenzyme increased significantly (P < 0.02) from 0.566 +/- 0.077% in Sed rats to 0.871 +/- 0.006% in HIST rats. At all three (0.6, 1.8, and 5 mM) extracellular Ca(2+) concentrations ([Ca(2+)](o)) examined, maximal shortening amplitudes and maximal shortening velocities were significantly (P < 0.0001) lower and half-times of relaxation were significantly (P < 0.005) longer in HIST myocytes. HIST myocytes had significantly (P < 0.0001) higher diastolic [Ca(2+)](i) levels. Compared with Sed myocytes, systolic [Ca(2+)](i) levels in HIST myocytes were higher at 0.6 mM [Ca(2+)](o), similar at 1.8 mM [Ca(2+)](o), and lower at 5 mM [Ca(2+)](o). The amplitudes of [Ca(2+)](i) transients were significantly (P < 0.0001) lower in HIST myocytes. Half-times of [Ca(2+)](i) transient decline, an estimate of sarcoplasmic reticulum (SR) Ca(2+) uptake activity, were not different between Sed and HIST myocytes. Compared with Sed hearts, Western blots demonstrated a significant (P < 0.03) threefold decrease in Na(+)/Ca(2+) exchanger, but SR Ca(2+)-ATPase and calsequestrin protein levels were unchanged in HIST hearts. We conclude that HIST effected diminished myocyte contractile function and [Ca(2+)](i) transient amplitudes under the conditions studied. We speculate that downregulation of Na(+)/Ca(2+) exchanger may partly account for the decreased contractility in HIST myocytes.     

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.     

Muscle RING Finger-1 Promotes a Maladaptive Phenotype in Chronic Hypoxia-Induced Right Ventricular Remodeling

Exposure to chronic hypoxia (CH) induces elevated pulmonary artery pressure/resistance, leading to an eventual maladaptive right ventricular hypertrophy (RVH). Muscle RING finger-1 (MuRF1) is a muscle-specific ubiquitin ligase that mediates myocyte atrophy and has been shown to play a role in left ventricular hypertrophy and altered cardiac bioenergetics in pressure overloaded hearts. However, little is known about the contribution of MuRF1 impacting RVH in the setting of CH. Therefore, we hypothesized that MuRF1 deletion would enhance RVH compared to their wild-type littermates, while cardiac-specific overexpression would reduce hypertrophy following CH-induced pulmonary hypertension. We assessed right ventricular systolic pressure (RVSP), right ventricle to left ventricle plus septal weight ratio (RV/LV+S) and hematocrit (Hct) following a 3-wk isobaric CH exposure. Additionally, we conducted dual-isotope SPECT/CT imaging with cardiac function agent ²⁰¹Tl-chloride and cell death agent ^99mTc-annexin V. Predictably, CH induced pulmonary hypertension, measured by increased RVSP, RV/LV+S and Hct in WT mice compared to normoxic WT mice. Normoxic WT and MuRF1-null mice exhibited no significant differences in RVSP, RV/LV+S or Hct. CH-induced increases in RVSP were also similar between WT and MuRF1-null mice; however, RV/LV+S and Hct were significantly elevated in CH-exposed MuRF1-null mice compared to WT. In cardiac-specific MuRF1 overexpressing mice, RV/LV+S increased significantly due to CH exposure, even greater than in WT mice. This remodeling appeared eccentric, maladaptive and led to reduced systemic perfusion. In conclusion, these results are consistent with an atrophic role for MuRF1 regulating the magnitude of right ventricular hypertrophy following CH-induction of pulmonary hypertension.     

Effects of impaired Ca2+ homeostasis on contraction in postinfarction myocytes.

The significance of altered Ca2+ influx and efflux pathways on contractile abnormalities of myocytes isolated from rat hearts 3 wk after myocardial infarction (MI) was investigated by varying extracellular Ca2+ concentration ([Ca2+]o, 0.6-5.0 mM) and pacing frequency (0.1-5.0 Hz). Myocytes isolated from 3-wk MI hearts were significantly longer than those from sham-treated (Sham) hearts (125 +/- 1 vs. 114 +/- 1 micrometer, P < 0.0001). At high [Ca2+]o and low pacing frequency, conditions that preferentially favored Ca2+ influx over efflux, Sham myocytes shortened to a greater extent than 3-wk MI myocytes. Conversely, under conditions that favored Ca2+ efflux (low [Ca2+]o and high pacing frequency), MI myocytes shortened more than Sham myocytes. At intermediate [Ca2+]o and pacing frequencies, differences in steady-state contraction amplitudes between Sham and MI myocytes were no longer significant. Collectively, the interpretation of these data was that Ca2+ influx and efflux pathways were subnormal in MI myocytes and that they contributed to abnormal cellular contractile behavior. Because Na+/Ca2+ exchange activity, but not whole cell Ca2+ current, was depressed in 3-wk MI rat myocytes, our results on steady-state contraction are consistent with, but not proof of, the hypothesis that depressed Na+/Ca2+ exchange accounted for abnormal contractility in MI myocytes. The effects of depressed Na+/Ca2+ exchange on MI myocyte mechanical activity were further evaluated in relaxation from caffeine-induced contractures. Because Ca2+ uptake by sarcoplasmic reticulum was inhibited by caffeine and with the assumption that intracellular Na+ and membrane potential were similar between Sham and MI myocytes, myocyte relaxation from caffeine-induced contracture can be taken as an estimate of Ca2+ extrusion by Na+/Ca2+ exchange. In MI myocytes, in which Na+/Ca2+ exchange activity was depressed, the half time of relaxation (1.54 +/- 0.14 s) was significantly (P < 0.02) prolonged compared with that measured in Sham myocytes (1.10 +/- 0.10 s).     

Endogenous beta3-adrenoreceptor activation contributes to left ventricular and cardiomyocyte dysfunction in heart failure

The objective of the present study was to test the hypothesis that endogenous beta(3)-adrenoreceptor (AR) activation contributes to left ventricular (LV) and cardiomyocyte dysfunction in heart failure (CHF). Stimulation of the beta(3)-AR inhibits cardiac contraction. In the failing myocardium, beta(3)-ARs are upregulated, suggesting that stimulation of beta(3)-ARs may contribute to depressed cardiac performance in CHF. We assessed the functional significance of endogenous beta(3)-AR activation in 10 conscious dogs before and after pacing-induced CHF. Under normal conditions, L-748,337, a specific beta(3)-AR antagonist, produced a mild increase in LV contractile performance assessed by the slope (E(es)) of the LV pressure-volume relation (18%, 6.2 +/- 0.9 vs. 7.3 +/- 1.2 mmHg/ml, P < 0.05) and the improved LV relaxation time constant (tau; 28.4 +/- 1.9 vs. 26.8 +/- 1.0 ms, P < 0.05). After CHF, the plasma norepinephrine concentration increased eightfold, and L-748,337 produced a larger increase in E(es) (34%, 3.8 +/- 0.7 vs. 5.1 +/- 0.8 mmHg/ml, P < 0.05) and a greater decrease in tau (46.4 +/- 4.2 vs. 41.0 +/- 3.9 ms, P < 0.05). Similar responses were observed in isolated myocytes harvested from LV biopsies before and after CHF. In the normal myocyte, L-748,337 did not cause significant changes in contraction or relengthening. In contrast, in CHF myocytes, L-748,337 produced significant increases in contraction (5.8 +/- 0.9 vs. 6.8 +/- 0.9%, P < 0.05) and relengthening (33.5 +/- 4.2 vs. 39.7 +/- 4.0 microm/s, P < 0.05). The L-748,337-induced myocyte response was associated with improved intracellular Ca(2+) concentration regulation. In CHF myocytes, nadolol caused a decrease in contraction and relengthening, and adding isoproterenol to nadolol caused a further depression of myocyte function. Stimulation of beta(3)-AR by endogenous catecholamine contributes to the depression of LV contraction and relaxation in CHF.     

Residual strain in ischemic ventricular myocardium.

Structural remodeling during acute myocardial infarction affects ventricular wall stress and strain. To see whether acute myocardial infarction alters residual stress and strain in the left ventricle (LV), we measured opening angles in rat hearts after 30 minutes of left coronary artery occlusion. The mean opening angle in 18 ischemic hearts (51 +/- 20 deg) was significantly greater than in five sham-operated controls (29 +/- 11 deg, P < 0.05). To determine whether these alterations in residual strain may be associated with strain softening caused by systolic overstretch of the noncontracting ischemic tissue, we also measured opening angles in isolated hearts that had been passively inflated to high LV pressures (120 mmHg). The mean opening angle of the strain-softened hearts was not significantly different from the sham-operated hearts (34 +/- 27 deg, P = 0.74). Mean collagen area fractions in the myocardium were not significantly different between ischemic hearts (0.027 +/- 0.014) and the nonischemic group (0.022 +/- 0.011). Although there were significant differences in opening angles measured with ischemia, they do not appear to be a result of altered extracellular collagen content or softening associated with overstretch. Thus, there is a significant change in residual strain associated with acute ischemia that may be related to changes in collagen fiber structure, myocyte structure, or metabolic state.     

Immunogold labeling study of the distribution of GLUT-1 and GLUT-4 in cardiac tissue following stimulation by insulin or ischemia

Whereas glucose transporter 1 (GLUT-1) is thought to be responsible for basal glucose uptake in cardiac myocytes, little is known about its relative distribution between the different plasma membranes and cell types in the heart. GLUT-4 translocates to the myocyte surface to increase glucose uptake in response to a number of stimuli. The mechanisms underlying ischemia- and insulin-mediated GLUT-4 translocation are known to be different, raising the possibility that the intracellular destinations of GLUT-4 following these stimuli also differ. Using immunogold labeling, we describe the cellular localization of these two transporters and investigate whether insulin and ischemia induce differential translocation of GLUT-4 to different cardiac membranes. Immunogold labeling of GLUT-1 and GLUT-4 was performed on left ventricular sections from isolated hearts following 30 min of either insulin, ischemia, or control perfusion. In control tissue, GLUT-1 was predominantly (76%) localized in the capillary endothelial cells, with only 24% of total cardiac GLUT-1 present in myocytes. GLUT-4 was found predominantly in myocytes, distributed between sarcolemmal and T tubule membranes (1.84 +/- 0.49 and 1.54 +/- 0.33 golds/microm, respectively) and intracellular vesicles (127 +/- 18 golds/microm(2)). Insulin increased T tubule membrane GLUT-4 content (2.8 +/- 0.4 golds/microm, P < 0.05) but had less effect on sarcolemmal GLUT-4 (1.72 +/- 0.53 golds/microm). Ischemia induced greater GLUT-4 translocation to both membrane types (4.25 +/- 0.84 and 4.01 +/- 0.27 golds/microm, respectively P < 0.05). The localization of GLUT-1 suggests a significant role in transporting glucose across the capillary wall before myocyte uptake via GLUT-1 and GLUT-4. We demonstrate independent spatial translocation of GLUT-4 under insulin or ischemic stimulation and propose independent roles for T-tubular and sarcolemmal GLUT-4.     

Importance of fatty acid oxidation in the neonatal pig heart with hypoxia and reoxygenation

We investigated mechanical and metabolic responses in isolated, isovolumically-beating, pig hearts (n = 7), 12 h to 2 days of age; subjected to hypoxia followed by reoxygenation. Hearts were perfused with an erythrocyte-enriched (hematocrit approximately 15%) solution during 3 consecutive 30-min periods: pre-hypoxia, arterial perfusate [O2] = 7.6 +/- 0.2 vol% (PO2 approximately 270 torr); hypoxia, [O2] = 0.6 +/- 0.1 vol% (approximately 10% hemoglobin saturation) and reoxygenation. Prehypoxia parameters averaged: left ventricular peak systolic pressure, 107.1 +/- 2.9 mmHg and end-diastolic pressure, 0.9 +/- 0.3 mmHg; coronary flow, 2.8 +/- 0.2 ml/min per g; myocardial O2 consumption, 59.4 +/- 1.6 microliters/min per g and fatty acid oxidation, 37.1 +/ 1.1 nmol/min per g. Fatty acid oxidation was determined using [14C]palmitate. Early in hypoxia, coronary flow increased 3-4 fold but then decreased. Throughout hypoxia, hearts released lactate yet continued to oxidize fatty acids (45-50% of myocardial O2 consumption). By the end of the hypoxia period, hearts exhibited mechanical failure (peak systolic pressure approximately 55 mmHg and end-diastolic pressure approximately 19 mmHg). After 30 min of reoxygenation, peak systolic pressure recovered to 80.6 +/- 2.6 mmHg and end-diastolic pressure remained elevated at 6.1 +/- 1.9 mmHg. However, fatty acid oxidation rates were 90-95% above pre-hypoxia values. Thus, during 30 min of severe hypoxia neonatal pig hearts exhibited mechanical dysfunction, yet continued to oxidize exogenously supplied fatty acids. Moreover, fatty acid oxidation was enhanced during reoxygenation.     

Voltage-sensitive dye RH421 increases contractility of cardiac muscle.

Voltage-sensitive dyes and imaging techniques have proved to be indispensable tools for use in in vitro electrophysiological studies. To avoid motion artifacts in optical recordings, electromechanical uncouplers such as 2,3-butanedione monoxime (BDM) are required. In this study, we sought to determine whether the voltage-sensitive dye RH421 had an effect on the contractility of heart muscle, either alone or in the presence of BDM. Ventricular contractility was studied in (i) isolated rat myocytes and (ii) Langendorff-perfused rat hearts under control conditions, and during perfusion with RH421 or RH421 + BDM. The following results were obtained. (i) The amplitude of cell shortening increased progressively from 6.24 +/- 0.64 to 9.95 +/- 1.02 microm during 15 min of superfusion with 5 microM RH421 (n = 11), and further increased to 12.54 +/- 0.97 microm during washout. In seven cells first perfused with 15 mM BDM and then with 15 mM BDM + 5 microM RH421, the amplitude of the cell shortening first decreased from 5.17 +/- 0.51 to 0.41 +/- 0.19 microm, then the amplitude increased to 2.63 +/- 0.25 microm. (ii) Left ventricular pressure (LVP) of the heart (n = 7) was reduced by 15 mM BDM from 60.7 +/- 2.5 to 2.8 +/- 0.5 mmHg (1 mmHg = 133.3 Pa). LVP increased to 12.8 +/- 1.1 mmHg during subsequent perfusion with 10 microM RH421 in the presence of BDM and did not change (LVP = 12.4 +/- 2.4 mmHg) during washout of the dye. Therefore, RH421 increased the contractility of rat hearts and isolated myocytes with and without BDM.     

Mechanical function and fatty acid oxidation in the neonatal pig heart with ischemia and reperfusion

We investigated mechanical function and exogenous fatty acid oxidation in neonatal pig hearts subjected to ischemia, followed by reperfusion. Isolated, isovolumically-beating hearts, from pigs 12 h to 2 days of age, were perfused with an erythrocyte-enriched (hematocrit approximately 15%) solution (37 degrees C). All hearts were studied for 30 min. with a perfusion pressure of 60 mmHg (pre-ischemia). One group of hearts (low-flow ischemia, N = 12) was then perfused for 30 min. with a perfusion pressure of approximately 12 mmHg. In the other group (no-flow ischemic arrest, N = 9), the perfusion pressure was zero for 30 min. Following ischemia in both groups, the perfusion pressure was restored to 60 mmHg for 40 min. (reperfusion). Pre-ischemia parameters for all hearts averaged: left ventricular peak systolic pressure, 99.0 +/- 2.0 mmHg; end diastolic pressure, 1.9 +/- 0.2 mmHg; coronary flow, 3.4 +/- 0.1 ml/min per g; myocardial oxygen consumption, 56.6 +/- 1.6 microliter/min per g and fatty acid oxidation, 33.4 +/- 1.4 nmol/min per g. During low-flow ischemia, hearts released lactate, and the corresponding parameters decreased to: 30.7 +/- 0.9 mmHg; 1.2 +/- 0.3 mmHg; 0.8 +/- 0.1 ml/min per g; 26.6 +/- 2.3 microliters/min per g and 12.9 +/- 1.1 nmol/min per g, respectively. Early in reperfusion in both groups, all parameters, except for fatty acid oxidation, exceeded pre-ischemia values, before recovering to near pre-ischemia values. Late in reperfusion, however, rates of fatty acid oxidation exceeded pre-ischemia rates by approximately 60%. Thus, the neonatal pig heart demonstrated similar recovery following 30 min of low-flow ischemia or no-flow ischemic arrest.(ABSTRACT TRUNCATED AT 250 WORDS)     

Improved contractile performance of right ventricle in response to increased RV afterload in newborn lamb

Pulmonary hypertension results in an increased afterload for the right ventricle (RV). To determine the effects of this increased afterload on RV contractile performance, we examined RV performance before and during 4 h of partial balloon occlusion of the pulmonary artery and again after releasing the occlusion in nine newborn lambs. RV contractile performance was quantified by indexes derived from systolic RV pressure-volume relations obtained by a combined pressure-conductance catheter during inflow reduction. An almost twofold increase of end-systolic RV pressure (from 22 to 38 mmHg) was maintained during 4 h. Cardiac output (CO) (0.74 +/- 0.08 l/min) and stroke volume (4.3 +/- 0.4 ml) were maintained, whereas end-diastolic volume (7.9 +/- 1.3 ml) did not change significantly during this period. RV systolic function improved substantially; the end-systolic pressure-volume relation shifted leftward indicated by a significantly decreased volume intercept (up to 70%), together with a slightly increased slope. In this newborn lamb model, maintenance of CO during increased RV afterload is not obtained by an increased end-diastolic volume (Frank-Starling mechanism). Instead, the RV maintains its output by improving contractile performance through homeometric autoregulation.     

Myocardial oxygenation and high-energy phosphate levels during graded coronary hypoperfusion

This study was performed to determine the myocyte PO(2) required to sustain normal high-energy phosphate (HEP) levels in the in vivo heart. In 10 normal dogs, myocyte PO(2) values were calculated from the myocardial deoxymyoglobin resonance (Mb-delta) intensity determined with (1)H-NMR spectroscopy during sequential flow reductions produced by a hydraulic occluder that decreased coronary perfusion pressure to approximately 60, 50, and 40 mmHg and, finally, during total occlusion. Myocardial blood flow was measured with microspheres, and HEP levels were determined with (31)P magnetic resonance spectroscopy. During control conditions, Mb-delta was undetectable. Myocardial blood flow was 1.11 +/- 0.06 ml. min(-1). g(-1) during basal conditions and decreased with sequential graded occlusions to 0.78 +/- 0.05, 0.58 +/- 0.03, and 0.38 +/- 0.04 ml. min(-1). g(-1), respectively; blood flow during total occlusion was 0.07 +/- 0.02 ml. min(-1). g(-1). Reductions of blood flow caused progressive increases of Mb-delta, which were associated with decreases of phosphocreatine (PCr), ATP, and the PCr-to-ATP ratio, as well as progressive increases of the P(i)-to-PCr ratio. There was a strong linear correlation between normalized blood flow and Mb-delta (R(2) = 0.89, P < 0.01). Reductions of HEP and PO(2) were also highly correlated (although nonlinearly); with the assumption that myoglobin was 90% saturated with O(2) during basal conditions and 5% saturated during total coronary occlusion, the intracellular PO(2) values for 20% reductions of PCr and ATP were approximately 4. 4 and approximately 0.9 mmHg, respectively. The data indicate that O(2) availability plays an increasing role in regulation of oxidative phosphorylation when mean intracellular PO(2) values fall below 5 mmHg in the in vivo heart.     

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.     

Decreased left ventricular function, myocarditis, and coronary arteriolar medial thickening following monocrotaline administration in adult rats.

Decreased right as well as left ventricular function can be associated with pulmonary hypertension (PH). Numerous investigations have examined cardiac function following induction of pulmonary hypertension with monocrotaline (MCT) assuming that MCT has no direct cardiac effect. We tested this assumption by examining left ventricular function and histology of isolated and perfused hearts from MCT-treated rats. Experiments were performed on 50 male Sprague-Dawley rats [348 +/- 6 g (SD)]. Thirty-seven rats received MCT (50 mg/kg sc; MCT group) while the remainder did not (Control group). Three weeks later, pulmonary artery pressure was assessed echocardiographically in 20 MCT and 8 Control rats. The hearts were then excised and perfused in the constant pressure Langendorff mode to determine peak left ventricular pressure (LVP), the peak instantaneous rate of pressure increase (+dP/dtmax) and decrease (-dP/dtmax), as well as the rate pressure product (RPP). Histological sections were subsequently examined. Pulmonary artery pressure was higher in the MCT-treated group compared with the Control group [12.9 +/- 6 vs. 51 +/- 35.3 mmHg (P < 0.01)]. Left ventricular systolic function and diastolic relaxation were decreased in the MCT group compared with the Control group (+dP/dtmax 4,178 +/- 388 vs. 2,801 +/- 503 mmHg/s, LVP 115 +/- 11 vs. 83 +/- 14 mmHg, RPP 33,688 +/- 1,910 vs. 23,541 +/- 3,858 beats x min(-1) x mmHg(-1), -dP/dtmax -3,036 +/- 247 vs. -2,091 +/- 389 mmHg/s; P < 0.0001). The impairment of cardiac function was associated with myocarditis and coronary arteriolar medial thickening. Similarly depressed ventricular function and inflammatory infiltration was seen in 12 rats 7 days after MCT administration. Our findings appear unrelated to the degree of PH and indicate a direct cardiotoxic effect of MCT.     

Compression induced by RV pressure overload decreases regional coronary blood flow in anesthetized dogs

Pulmonary artery constriction (PAC), a model of right ventricular (RV) pressure overload, flattens or inverts the septum and may flatten the left ventricular (LV) free wall. Finite element (FE) analysis predicts that such deformations may cause substantial compression. This study tests the hypothesis that deformation-induced myocardial compressive stress impedes coronary blood flow (CBF). Colored microspheres ( approximately 2 x 10(6)) were injected into the left atrium of 13 open-chest, anesthetized dogs under control conditions and during PAC, which decreased the end-diastolic transseptal pressure gradient (LV - RV) from 1.6 +/- 1.3 to -3.4 +/- 1.7 mmHg. Septal and LV deformation was assessed with the use of two-dimensional echocardiography, and by FE analysis, the hydrostatic component of stress was assessed. Postmortem, a 2.5-cm wide, LV equatorial ring was divided into 16 endocardial and epicardial samples. PAC decreased CBF in the FE-predicted compression zones, areas with the greatest compression having the greatest reductions in CBF. During PAC, compression reached a maximum of 25.3 +/- 1.8 mmHg on the (LV) endocardial sides of the RV insertion points, areas that saw CBF decrease from 1.05 +/- 0.08 to 0.68 +/- 0.05 ml.min(-1).g(-1) (P < 0.001), more than 30%. CBF decreased (from 1.08 +/- 0.07 to 0.81 +/- 0.07 ml.min(-1).g(-1); P < 0.001) on the RV side of the midseptum, an area with as much as 16.0 +/- 1.0 mmHg of compression. Overall, average compressions of 10 mmHg decreased CBF by approximately 30%. We conclude that acute RV pressure overload deforms the septum and LV and induces compressive stresses that reduce CBF substantially. This may help explain why some patients with pulmonary hypertension and no critical coronary disease have chest discomfort indistinguishable from angina pectoris.     

Sprint training normalizes Ca(2+) transients and SR function in postinfarction rat myocytes.

Previous studies have shown that myocytes isolated from sedentary (Sed) rat hearts 3 wk after myocardial infarction (MI) undergo hypertrophy, exhibit altered intracellular Ca(2+) concentration ([Ca(2+)](i)) dynamics and abnormal contraction, and impaired sarcoplasmic reticulum (SR) function manifested as prolonged half-time of [Ca(2+)](i) decline. Because exercise training elicits positive adaptations in cardiac contractile function and myocardial Ca(2+) regulation, the present study examined whether 6-8 wk of high-intensity sprint training (HIST) would restore [Ca(2+)](i) dynamics and SR function in MI myocytes toward normal. In MI rats, HIST ameliorated myocyte hypertrophy as indicated by significant (P 相似文献   

Lower inflection point and recruitment with PEEP in ventilated patients with acute respiratory failure.

The lower inflection point (LIP) on the total respiratory system pressure-volume (P-V) curve is widely used to set positive end-expiratory pressure (PEEP) in patients with acute respiratory failure (ARF) on the assumption that LIP represents alveolar recruitment. The aims of this work were to study the relationship between LIP and recruited volume (RV) and to propose a simple method to quantify the RV. In 23 patients with ARF, respiratory system P-V curves were obtained by means of both constant-flow and rapid occlusion technique at four different levels of PEEP and were superimposed on the same P-V plot. The RV was measured as the volume difference at a pressure of 20 cm H(2)O. A third measurement of the RV was done by comparing the exhaled volumes after the same distending pressure of 20 cm H(2)O was applied (equal pressure method). RV increased with PEEP (P < 0.0001); the equal pressure method compares favorably with the other methods (P = 0.0001 by correlation), although individual data cannot be superimposed. No significant difference was found when RV was compared with PEEP in the group of patients with a LIP < or =5 cm H(2)O and the group with a LIP >5 cm H(2)O (76.9 +/- 94.3 vs. 61.2 +/- 51.3, 267.7 +/- 109.9 vs. 209.6 +/- 73.9, and 428.2 +/- 216.3 vs. 375.8 +/- 145.3 ml with PEEP of 5, 10, and 15 cm H(2)O, respectively). A RV was found even when a LIP was not present. We conclude that the recruitment phenomenon is not closely related to the presence of a LIP and that a simple method can be used to measure RV.     

Effect of increased afterload on right ventricular function in newborn pigs

The effect of a progressive increase in right ventricular (RV) afterload was studied in pigs less than 24 h (group I) and 3-5 days old (group III). RV load was applied to increase mean pulmonary arterial pressure (Ppa) until right to left shunt was observed. Initially, pigs in group I had a significantly lower systemic arterial pressure (Psa = 63 +/- 2 vs. 82 +/- 5 mmHg) and higher Ppa (30 +/- 1 vs. 23 +/- 2 mmHg) even though the RV stroke work (RVSW) was similar (54.3 +/- 10.8 vs. 32.4 +/- 2.1 mmHg/ml) to group II. After a progressive rise in afterload, pigs in group I could maintain a higher RV stroke volume than those in group II (1.3 +/- 0.3 vs. 0.4 +/- 0.1 ml; P less than 0.05). At shunt condition, the RVSW was increased by 21 +/- 14% of the initial value in group I vs. a 32 +/- 8% decrease in group II (P less than 0.05). The ductus arteriosus was constricted and right-to-left shunt was observed in all animals at the foramen ovale level even though Ppa exceeded Psa before the rise in the right atrial pressure in group I. Thus, as RV afterload is increased in the pig, the older animals' right ventricle is progressively less capable of maintaining pulmonary blood flow than animals within 24 h of birth.     

Remodeling of resistance arteries in organoid culture is modulated by pressure and pressure pulsation and depends on vasomotion

The hypothesis was tested that pressure and pressure pulsation modulate vascular remodeling. Arterioles ( approximately 200 microm lumen diameter) were dissected from rat cremaster muscle and studied in organoid culture. In the first series, arterioles were kept at a stable pressure level of either 50 or 100 mmHg for 3 days. Both groups showed a progressive increase in myogenic tone during the experiment. Arterioles kept at 50 mmHg showed larger endothelium-dependent dilation, compared with vessels kept at 100 mmHg on day 3. Remodeling, as indicated by the reduction in maximally dilated diameter at 100 mmHg, was larger in arterioles kept at 50 mmHg compared with 100 mmHg: 34 +/- 4.5 versus 10 +/- 4.8 microm (P < 0.05). In the second series, arterioles were subjected to a stable pressure of 60 mmHg or oscillating pressure of 60 +/- 10 mmHg (1.5 Hz) for 4 days. Pressure pulsation induced partial dilation and was associated with less remodeling: 34 +/- 4.0 versus 19 +/- 4.5 microm (P < 0.01) for stable pressure versus oscillating pressure. Vasomotion was frequently observed in all groups, and inward remodeling was larger in vessels with vasomotion: 30 +/- 2.5 microm compared with vessels that did not exhibit vasomotion: 8.0 +/- 5.0 microm (P < 0.01). In conclusion, these results indicate that remodeling is not enhanced by high pressure. Pressure pulsation causes partial dilation and reduces inward remodeling. The appearance of vasomotion is associated with enhanced inward remodeling.     

Human immunodeficiency virus transgenic rats exhibit pulmonary hypertension

Human immunodeficiency virus (HIV)-associated pulmonary arterial hypertension (PAH) is a serious noninfectious disease involving an aberrant increase in pressure in the blood vessels of the lung, which leads to right ventricular (RV) heart failure and can eventually result in death. A lack of viable animal models of HIV-PAH has limited the identification of signaling pathways involved in HIV-mediated onset and progression of PAH. To determine whether the HIV-1 transgenic (HIV Tg) rat displays pathophysiological end points associated with PAH, we evaluated peak RV systolic pressure (RVSP), RV hypertrophy, pulmonary vessel remodeling, and alterations in gene expression by real-time PCR and microarray. RVSP was measured by RV catheterization via the right jugular vein in 3- and 9-mo-old HIV Tg and age-matched Fischer 344 (control) male rats while under 2% isoflurane anesthesia. RVSP was elevated in the HIV Tg rats (34.2 ± 2.5 mmHg) compared with the F344 controls (21.2 ± 2.5 mmHg), with more significant elevations in the 9-mo-old HIV Tg rats (42.5 ± 3.7 mmHg). We observed significant increases in RV wall thickness in HIV Tg rats compared with controls, both histologically and by echocardiograph measurement. HIV Tg rats also show increased thickening of the pulmonary artery and remodeling of small pulmonary arteries, as well as altered expression of gene pathways associated with PAH. These data represent the first analysis of PAH in HIV Tg rats and suggest that this model will be useful for investigating pathways and identifying potential therapies for HIV-PAH.